Increased
risk of developmental neurologic impairment after high exposure to
thimerosal-containing vaccine in first month of life.
Division of Epidemiology and Surveillance, Vaccine Safety
and Development Branch, National Immunization Program, Centers for
Disease Control and Prevention. 1999.
Thomas M. Verstraeten,
Robert Davis, David Gu, Frank DeStefano
Background: Concern
has risen on the presence of the ethylmercury containing
preservative thimerosal in vaccines. We assessed the risk for
neurologic and renal impairment associated with past exposure to
thimerosal-containing vaccine using automated data from the Vaccine
Safety Data link (VSD). VSD is a large linked database from four
health maintenance organizations in Washington, Oregon and
California, containing immunization, medical visit and demographic
data on over 400,000 infants born between '91 and '97.
Methods:
We categorized the cumulative ethylmercury exposure from Thimerosal
containing vaccines after one month of life and assessed the
subsequent risk of degenerative and developmental neurologic
disorders and renal disorders before the age of six. We applied
proportional hazard models adjusting for HMO, year of birth, and
gender, excluding premature babies.
Results: We identified
286 children with degenerative and 3702 with developmental
neurologic disorders, and 310 with renal disorders. The relative
risk (RR) of developing a neurologic development disorder was 1.8 (
95% confidence intervals [CI] =1.1-2.8) when comparing the highest
exposure group at 1 month of age (cumulative dose> 25 ug) to the
unexposed group. Within
this group we also found an elevated risk for the following
disorders: autism (RR 7.6, 95% Cl = 1.8-31.5),
non organic sleep disorders (RR 5.0, 95% Cl = 1.6-15.9}, and speech
disorders (RR 2.1, 95% (1=1.1-4.0). For the neurologic degenerative
and renal disorders group we found no significantly increased risk
or a decreased risk.
Conclusion: This
analysis suggests that high exposure to ethyl mercury from
thimerosal-containing vaccines in the first month of life increases
the risk of subsequent development of neurologic development
impairment,
but not of neurologic degenerative or renal impairment. Further
confirmatory studies are needed.
Pilot
comparative study on the health of vaccinated and unvaccinated 6- to
12- year old U.S. children
J
Transl Sci 3: DOI: 10.15761/JTS.1000186, April 24, 2017
Anthony
R Mawson, Azad R Bhuiyan, Brian D Ray, Binu Jacob
Department
of Epidemiology and Biostatistics, School of Public Health, Jackson
State University, Jackson, MS 39213, USA
National
Home Education Research Institute, PO Box 13939, Salem, OR 97309,
USA
Abstract
Vaccinations
have prevented millions of infectious illnesses, hospitalizations
and deaths among U.S. children, yet the long-term health outcomes of
the vaccination schedule remain uncertain. Studies have been
recommended by the U.S. Institute of Medicine to address this
question. This study aimed 1) to compare vaccinated and unvaccinated
children on a broad range of health outcomes, and 2) to determine
whether an association found between vaccination and
neurodevelopmental disorders (NDD), if any, remained significant
after adjustment for other measured factors. A cross-sectional study
of mothers of children educated at home was carried out in
collaboration with homeschool organizations in four U.S. states:
Florida, Louisiana, Mississippi and Oregon. Mothers were asked to
complete an anonymous online questionnaire on their 6- to
12-year-old biological children with respect to pregnancy-related
factors, birth history, vaccinations, physician-diagnosed illnesses,
medications used, and health services. NDD, a derived diagnostic
measure, was defined as having one or more of the following three
closely-related diagnoses: a learning disability, Attention
Deficient Hyperactivity Disorder, and Autism Spectrum Disorder. A
convenience sample of 666 children was obtained, of which 261 (39%)
were unvaccinated. The vaccinated were less likely than the
unvaccinated to have been diagnosed with chickenpox and pertussis,
but more likely to have been diagnosed with pneumonia, otitis media,
allergies and NDD. After adjustment, vaccination, male gender, and
preterm birth remained significantly associated with NDD. However,
in a final adjusted model with interaction, vaccination but not
preterm birth remained associated with NDD, while the interaction of
preterm birth and vaccination was associated with a 6.6-fold
increased odds of NDD (95% CI: 2.8, 15.5). In
conclusion, vaccinated homeschool children were found to have a
higher rate of allergies and NDD than unvaccinated homeschool
children.
While vaccination remained significantly associated with NDD after
controlling for other factors, preterm birth coupled with
vaccination was associated with an apparent synergistic increase in
the odds of NDD. Further research involving larger, independent
samples and stronger research designs is needed to verify and
understand these unexpected findings in order to optimize the impact
of vaccines on children’s health.
Exerpts
"NDD,
a derived diagnostic measure, was defined as having one or more of
the following three closely-related diagnoses: a learning
disability, Attention Deficient Hyperactivity Disorder, and Autism
Spectrum Disorder."
"Chronic
illness
Vaccinated
children were significantly more likely than the unvaccinated to
have been diagnosed with the following:
allergic rhinitis (10.4% vs. 0.4%, p <0.001; OR 30.1, 95% CI:
4.1, 219.3), other allergies (22.2% vs. 6.9%, p <0.001; OR 3.9,
95% CI: 2.3, 6.6), eczema/atopic dermatitis (9.5% vs. 3.6%, p =
0.035; OR 2.9, 95% CI: 1.4, 6.1), a learning disability (5.7% vs.
1.2%, p = 0.003; OR 5.2, 95% CI: 1.6, 17.4), ADHD (4.7% vs. 1.0%, p
= 0.013; OR 4.2, 95% CI: 1.2, 14.5), ASD
(4.7% vs. 1.0%, p = 0.013; OR 4.2, 95% CI: 1.2, 14.5),
any neurodevelopmental disorder (i.e., learning disability, ADHD or
ASD) (10.5% vs. 3.1%, p <0.001; OR 3.7, 95% CI: 1.7, 7.9) and any
chronic illness (44.0% vs. 25.0%, p <0.001; OR 2.4, 95% CI: 1.7,
3.3)."
Hepatitis
B vaccination of male neonates and autism diagnosis, NHIS
1997-2002.
Gallagher
CM, Goodman MS.
J Toxicol Environ Health A.
2010;73(24):1665-77. doi:
10.1080/15287394.2010.519317.
Abstract
Universal hepatitis
B vaccination was recommended for U.S. newborns in 1991; however,
safety findings are mixed. The association between hepatitis B
vaccination of male neonates and parental report of autism diagnosis
was determined. This cross-sectional study used weighted probability
samples obtained from National Health Interview Survey 1997-2002
data sets. Vaccination status was determined from the vaccination
record. Logistic regression was used to estimate the odds for autism
diagnosis associated with neonatal hepatitis B vaccination among
boys age 3-17 years, born before 1999, adjusted for race, maternal
education, and two-parent household. Boys
vaccinated as neonates had threefold greater odds for autism
diagnosis compared to boys never vaccinated or vaccinated after the
first month of life.
Non-Hispanic white boys were 64% less likely to have autism
diagnosis relative to nonwhite boys. Findings suggest that U.S. male
neonates vaccinated with the hepatitis B vaccine prior to 1999 (from
vaccination record) had a threefold higher risk for parental report
of autism diagnosis compared to boys not vaccinated as neonates
during that same time period. Nonwhite boys bore a greater risk.
Associations
of prenatal and early childhood mercury exposure with autistic
behaviors at 5 years of age: The Mothers and Children's
Environmental Health (MOCEH) study
Science
of The Total Environment
Volumes
605–606, 15 December 2017, Pages 251-257
JiaRyua. ,
Eun-HeeHaa, Boong-NyunKimb, MinaHac, YanghoKimd, HyesookParke,
Yun-ChulHongf, Kyoung-NamKim
Department
of Occupational and Environmental Medicine, School of Medicine, Ewha
Womans University, Seoul, Republic of Korea
Division
of Child & Adolescent Psychiatry, Department of Psychiatry and
Institute of Human Behavioral Medicine, College of Medicine, Seoul
National University, Seoul, Republic of Korea
Department
of Preventive Medicine, College of Medicine, Dankook University,
Cheonan, Republic of Korea
Department
of Occupational and Environmental Medicine, Ulsan University
Hospital, University of Ulsan College of Medicine, Ulsan, Republic
of Korea
Department
of Preventive Medicine, School of Medicine, Ewha Womans University,
Seoul, Republic of Korea
Department
of Preventive Medicine, Seoul National University College of
Medicine, Seoul, Republic of Korea
Institute
of Public Health and Medical Service, Seoul National University
Hospital, Seoul, Republic of Korea
Received
26 April 2017, Revised 24 June 2017, Accepted 26 June 2017,
Available online 28 June 2017.
Abstract
Background
Although
mercury is an established neurotoxin, only few longitudinal studies
have investigated the association between prenatal and early
childhood mercury exposure and autistic behaviors.
Methods
We
conducted a longitudinal cohort study using an ongoing prospective
birth cohort initiated in 2006, wherein blood mercury levels were
measured at early and late pregnancy; in cord blood; and at 2 and 3
years of age. We analyzed 458 mother-child pairs. Autistic behaviors
were assessed using the Social Responsiveness Scale (SRS) at 5 years
of age. Both continuous SRS T-scores and T-scores dichotomized by a
score of ≥ 60 or < 60 were used as outcomes.
Results
The
geometric mean of mercury concentrations in cord blood was 5.52
μg/L. In adjusted models, a doubling of blood mercury levels at
late pregnancy (β = 1.84, 95% confidence interval [CI]: 0.39,
3.29), in cord blood (β = 2.24, 95% CI: 0.22, 4.27), and at 2 years
(β = 2.12, 95% CI: 0.54, 3.70) and 3 years (β = 2.80, 95% CI:
0.89, 4.72) of age was positively associated with the SRS T-scores.
When the SRS T-scores were dichotomized, we observed positive
associations with mercury levels at late pregnancy (relative risk
[RR] = 1.31, 95% CI: 1.08, 1.60) and in cord blood (RR = 1.28, 95%
CI: 1.01, 1.63).
Conclusion
We
found that blood mercury levels at late pregnancy and early
childhood were associated with more autistic behaviors in children
at 5 years of age. Further
study on the long-term effects of mercury exposure is
recommended.
The
association between mercury levels and autism spectrum disorders: A
systematic review and meta-analysis
Journal
of Trace Elements in Medicine and Biology
Volume
44, December 2017, Pages 289-297
Tina
Jafari, Noushin Rostampour, Aziz A.Fallah, Afshin Hesamia
Clinical
Biochemistry Research Center, Shahrekord University of Medical
Sciences, Sharhekord, Iran
Department
of Biochemistry and Nutrition, Faculty of Medicine, Shahrekord
University of Medical Sciences, Shahrekord, Iran
Department
of Internal Medicine, Shahrekord University of Medical Sciences,
Shahrekord, Iran
Department
of Food Hygiene and Quality Control, Faculty of Veterinary Medicine,
Shahrekord University, Shahrekord 34141, Iran
Abstract
Background
& aims
The
relationship between mercury and autism spectrum disorders (ASD) has
always been a topic of controversy among researchers. This study
aimed to assess the relationship between ASD and mercury levels in
hair, urine, blood, red blood cells (RBC), and brain through a
meta-analysis.
Methods
A
systematic search was performed in several databases including
PubMed, ISI Web of Science, Cochrane register of controlled trials,
Google Scholar, Scopus, and MagIran until June 2017. Case-control
studies evaluating concentration of total mercury in different
tissues of ASD patients and comparing them to the healthy subjects
(control group) were identified. Necessary data were extracted and
random effects model was used to calculate overall effect and its
95% corresponding confidence interval (CI) from the effect sizes.
Results
A
total of 44 studies were identified that met the necessary criteria
for meta-analysis. The mercury level in whole blood (Hedges = 0.43,
95% CI: 0.12, 0.74, P = 0.007), RBC (Hedges = 1.61, 95% CI: 0.83,
2.38, P < 0.001), and brain (0.61 ng/g, 95% CI, 0.02, 1.19, P =
0.043) was significantly higher in ASD patients than healthy
subjects, whereas mercury level in hair (−0.14 mg/g, 95% CI:
−0.28, −0.01, P = 0.039) was significantly lower in ASD patients
than healthy subjects. The mercury level in urine was not
significantly different between ASD patients and healthy subjects
(0.51 mg/g creatinine, 95% CI: −0.14, 1.16, P = 0.121).
Conclusions
Results
of the current meta-analysis revealed that mercury is an important
causal factor in the etiology of ASD. It seems that the
detoxification and excretory mechanisms are impaired in ASD patients
which lead to accumulation of mercury in the body. Future
additional studies on mercury levels in different tissues of ASD
patients should be undertaken.
The
Relationship Between the Level of Copper, Lead, Mercury and Autism
Disorders: A Meta-Analysis
Authors
Jafari Mohammadabadi H, Rahmatian A, Sayehmiri F, Rafiei M
Published
21 September 2020 Volume 2020:11 Pages 369—378
1School
of Medicine, Shiraz University of Medical Sciences, Shiraz, Fars,
Iran;
2Faculty
of Medicine, Ilam University of Medical Sciences, Ilam, Iran;
3Student
Research Committee, School of Medicine, Shahid Beheshti University
of Medical Sciences, Tehran, Iran;
4Department
of Biostatistics and Epidemiology, Arak University of Medical
Sciences, Arak, Iran
Background
and Objectives: There is a likelihood of a possible relationship
between the concentrations of copper, lead, and mercury and autism.
The present review was carried out to determine the relationship
between the concentrations of these elements and autism by
meta-analysis.
Methods:
In this study, searching Scopus, PubMed, and Science Direct
databases, 18 articles conducted in different countries from 1982 to
2019 were collected. Studies’ heterogeneity was investigated using
the I2 index. The data were analyzed using R and STATA software.
Results:
In these 18 studies, 1797 patients (981 cases and 816 controls) aged
2 to 16 years were examined. Concentration of the samples (blood,
hair, and nails) for both case and control groups was evaluated.
There was no significant relationship between copper concentration
and autism (SMD (95% CI): 0.02 (− 1.16,1.20); I2=97.7%; P=0.972);
there was a significant relationship between mercury concentration
and autism (SMD (95% CI): 1.96 (0.56,3.35); I2=98.6%; P=0.006);
there was also a significant relationship between lead concentration
and autism (SMD (95% CI): 2.81 (1.64,3.98); I2=97.8%; P=0.000).
Conclusion:
There is, nevertheless, a significant relationship between
mercury concentration and autism. Thus, the concentration of mercury
can be listed as a pathogenic cause (disease-causing) for autism.
The
Putative Role of Environmental Mercury in the Pathogenesis and
Pathophysiology of Autism Spectrum Disorders and Subtypes
Molecular
Neurobiology, First Online: 22 July 2017
G.
Morris, K. Puri, R. E. Frye, M. Maes
1.Tir
Na NogLlanelliUK
2.Department
of Medicine, Hammersmith Hospital Imperial College London, LondonUK
3.Division
of Child and Adolescent Neurology and Children’s Learning
Institute, Department of PediatricsUniversity of Texas, Austin USA
4.Department
of PsychiatryChulalongkorn University Bangkok, Thailand
Abstract
Exposure
to organic forms of mercury has the theoretical capacity to generate
a range of immune abnormalities coupled with chronic nitro-oxidative
stress seen in children with autism spectrum disorder (ASD). The
paper discusses possible mechanisms explaining the neurotoxic
effects of mercury and possible associations between mercury
exposure and ASD subtypes. Environmental
mercury is neurotoxic at doses well below the current reference
levels considered to be safe, with evidence of neurotoxicity in
children exposed to environmental sources including fish consumption
and ethylmercury-containing vaccines. Possible neurotoxic mechanisms
of mercury include direct effects on sulfhydryl groups, pericytes
and cerebral endothelial cells, accumulation within astrocytes,
microglial activation, induction of chronic oxidative stress,
activation of immune-inflammatory pathways and impairment of
mitochondrial functioning. (Epi-)genetic factors which may increase
susceptibility to the toxic effects of mercury in ASD include the
following: a greater propensity of males to the long-term neurotoxic
effects of postnatal exposure and genetic polymorphisms in
glutathione transferases and other glutathione-related genes and in
selenoproteins. Furthermore, immune and inflammatory responses to
immunisations with mercury-containing adjuvants are strongly
influenced by polymorphisms in the human leukocyte antigen (HLA)
region and by genes encoding effector proteins such as cytokines and
pattern recognition receptors. Some epidemiological studies
investigating a possible relationship between high environmental
exposure to methylmercury and impaired neurodevelopment have
reported a positive dose-dependent effect.
Retrospective studies, on the other hand, reported no relationship
between a range of ethylmercury-containing vaccines and chronic
neuropathology or ASD. On the basis of these results, we would argue
that more clinically relevant research is required to examine
whether environmental mercury is associated with ASD or subtypes.
Specific recommendations for future research are discussed.
Blood
Mercury, Arsenic, Cadmium, and Lead in Children with Autism Spectrum
Disorder.
Biol
Trace Elem Res. 2017 May 8. doi: 10.1007/s12011-017-1002-6.
Li
H, Li H, Li Y, Liu Y, Zhao Z
Children's
Hospital of Zhejiang University School of Medicine, Hangzhou,
People's Republic of China.
Laboratory
of Neuroinflammation, StVincent's Centre for Applied Medical
Research and University of New South Wales, Sydney, NSW, Australia.
Children's
Hospital of Zhejiang University School of Medicine, Hangzhou,
People's Republic of China. zhaozy@zju.edu.cn.
Department
of Pediatric Health Care, Children's Hospital of Zhejiang University
School of Medicine, 57 Zhuganxiang Road, Hangzhou, People's Republic
of China
Abstract
Environmental
factors have been implicated in the etiology of autism spectrum
disorder (ASD); however, the role of heavy metals has not been fully
defined. This study investigated whether blood levels of mercury,
arsenic, cadmium, and lead of children with ASD significantly differ
from those of age- and sex-matched controls. One hundred eighty
unrelated children with ASD and 184 healthy controls were recruited.
Data
showed that the children with ASD had significantly (p < 0.001)
higher levels of mercury and arsenic
and a lower level of cadmium. The levels of lead did not differ
significantly between the groups. The
results of this study are consistent with numerous previous studies,
supporting an important role for heavy metal exposure, particularly
mercury, in the etiology of ASD. It
is desirable to continue future research into the relationship
between ASD and heavy metal exposure.
Protective
role of alpha-lipoic acid in impairments of social and stereotyped
behaviors induced by early postnatal administration of thimerosal in
male rat.
Neurotoxicol Teratol. 2018 Feb 23. pii:
S0892-0362(17)30086-7. doi: 10.1016/j.ntt.2018.02.002.
Namvarpour
Z, Nasehi M, Amini A, Zarrindast MR.
Institute
for Cognitive Science Studies (ICSS), Tehran, Iran.
Institute
for Cognitive Science Studies (ICSS), Tehran, Iran; Cognitive and
Neuroscience Research Center (CNRC), Tehran Medical Sciences Branch,
Islamic Azad University, Tehran, Iran.
Department
of Biology and Anatomy, School of Medicine, Shahid Beheshti
University of Medical Sciences, Tehran, Iran.
Institute
for Cognitive Science Studies (ICSS), Tehran, Iran; Department of
Pharmacology, School of Medicine, Tehran University of Medical
Sciences, Tehran, Iran.
Abstract
Aim
Thimerosal, a mercury-containing preservative has been widely used
in a number of biological and drug products, including many
vaccines, and has been studied as a possible etiological factor for
some neurodevelopmental disabilities. Here, the protective effects
of Alpha Lipoic Acid (ALA), an organosulfur compound derived from
Octanoic Acid, on Thimerosal-induced behavioral abnormalities in rat
were examined.
METHODS:
108
male Wistar rats were divided into three cohorts and treated as
follows: 1) Thimerosal at different doses (30, 300, or
3000 μg Hg/kg) in four i.m. injections on 7, 9, 11, 15postnatal
days. 2) ALA (at doses of 5, 10 and 20 mg/kg), following the same
order; 3) single dose of Thimerosal (3000 μg Hg/kg) plus ALA at
different doses (5, 10 or 20 mg/kg), by the previously described
method. A saline treated control group and a ALA vehicle control
(0.1% NaOH) were also included. At 5 and 8 weeks after birth, rats
were evaluated with behavioral tests, to assess locomotor activity,
social interactions and stereotyped behaviors, respectively.
RESULTS:
The
data showed that Thimerosal at all doses (30, 300 and 3000 μg Hg/kg)
significantly impacted locomotor activity. Thimerosal at doses of
300 and 3000 but not 30 μg Hg/kg impaired social and
stereotyped behaviors. In contrast, ALA (at doses of 5, 10 and
20 mg/kg) did not alter behaviors by itself, at doses of 20 mg/kg,
it reduced social interaction deficits induced by the highest dose
of Thimerosal (3000 μg Hg/kg). Moreover, ALA, at all doses
prevented the adverse effects of Thimerosal on stereotyped
behaviors.
CONCLUSIONS:
the
results of this preclinical study, consistent with previous studies
on mice and rats, reveals that neonatal
dose-dependent exposure to Thimerosal mimicking the childhood
vaccine schedule can induce abnormal social interactions and
stereotyped behaviors similar to those observed in
neurodevelopmental disorders such as autism,
and, for the first time, revealed that these abnormalities may be
ameliorated by ALA. This indicates that ALA may protect against
mercurial-induced abnormal behaviors.
Gender-selective
toxicity of thimerosal.
Exp
Toxicol Pathol. 2009 Mar;61(2):133-6. doi:
10.1016/j.etp.2008.07.002. Epub 2008 Sep 3.
Departments
of Medicine and Laboratory Medicine and Pathobiology, University of
Toronto, Ontario, Canada. don.branch@utoronto.ca
Abstract
A
recent report shows a correlation of the historical use of
thimerosal in therapeutic immunizations with the subsequent
development of autism; however, this association remains
controversial. Autism occurs approximately four times more
frequently in males compared to females; thus, studies of thimerosal
toxicity should take into consideration gender-selective effects.
The present study was originally undertaken to determine the maximum
tolerated dose (MTD) of thimersosal in male and female CD1 mice.
However, during the limited MTD studies, it became apparent that
thimerosal has a differential MTD that depends on whether the mouse
is male or female. At
doses of 38.4-76.8mg/kg using 10% DMSO as diluent, seven of seven
male mice compared to zero of seven female mice tested succumbed to
thimerosal.
Although the thimerosal levels used were very high, as we were
originally only trying to determine MTD, it was completely
unexpected to observe a difference of the MTD between male and
female mice. Thus, our studies, although not directly addressing the
controversy surrounding thimerosal and autism, and still preliminary
due to small numbers of mice examined, provide, nevertheless, the
first report of gender-selective toxicity of thimerosal and indicate
that any future studies of thimerosal toxicity should take into
consideration gender-specific differences.
Mercury
toxicokinetics--dependency on strain and gender.
Toxicol
Appl Pharmacol. 2010 Mar 15;243(3):283-91. doi:
10.1016/j.taap.2009.08.026. Epub 2009 Sep 2.
Ekstrand
J1, Nielsen JB, Havarinasab S, Zalups RK, Söderkvist P, Hultman P.
Molecular
and Immunological Pathology, Department of Clinical and Experimental
Medicine, Linköping University, Sweden.
Abstract
Mercury
(Hg) exposure from dental amalgam fillings and thimerosal in
vaccines is not a major health hazard, but adverse health effects
cannot be ruled out in a small and more susceptible part of the
exposed population. Individual differences in toxicokinetics may
explain susceptibility to mercury. Inbred, H-2-congenic A.SW and
B10.S mice and their F1- and F2-hybrids were given HgCl2 with 2.0 mg
Hg/L drinking water and traces of (203)Hg. Whole-body retention
(WBR) was monitored until steady state after 5 weeks, when the organ
Hg content was assessed. Despite similar Hg intake, A.SW
males attained a 20-30% significantly higher WBR and 2- to 5-fold
higher total renal Hg retention/concentration than A.SW females and
B10.S mice. A selective renal Hg accumulation but of lower magnitude
was seen also in B10.S males compared with females.
Differences in WBR and organ Hg accumulation are therefore regulated
by non-H-2 genes and gender. Lymph nodes lacked the strain- and
gender-dependent Hg accumulation profile of kidney, liver and
spleen. After 15 days without Hg A.SW mice showed a 4-fold higher
WBR and liver Hg concentration, but 11-fold higher renal Hg
concentration, showing the key role for the kidneys in explaining
the slower Hg elimination in A.SW mice. The trait causing higher
mercury accumulation was not dominantly inherited in the F1 hybrids.
F2 mice showed a large inter-individual variation in Hg
accumulation, showing that multiple genetic factors influence the Hg
toxicokinetics in the mouse. The genetically heterogeneous human
population may therefore show a large variation in mercury
toxicokinetics.
A
Review of the Differences in Developmental, Psychiatric, and Medical
Endophenotypes Between Males and Females with Autism Spectrum
Disorder
J
Dev Phys Disabil. 2015 Feb; 27(1): 119–139.
Eric
Rubenstein, Department of Epidemiology, Johns Hopkins Bloomberg
School of Public Health, Lisa D. Wiggins, and Li-Ching Lee
Abstract
Autism
spectrum disorder (ASD) is over four times more prevalent in males
compared to females.
Increased understanding of sex differences in ASD endophenotypes
could add insight into possible etiologies and the assessment and
management of the disorder. Consequently, the purpose of this review
is to describe current literature regarding sex differences in the
developmental, psychiatric, and medical endophenotypes of ASD in
order to illustrate current knowledge and areas in need of further
research. Our review found that repetitive behaviors and restricted
interests are more common in males than females with ASD.
Intellectual disability is more common in females than males with
ASD. Attention to detail may be more common in males than females
with ASD and epilepsy may be more common in females than males with
ASD, although limited research in these areas prevent definitive
conclusions from being drawn. There does not appear to be a sex
difference in other developmental, psychiatric, and medical symptoms
associated with ASD, or the research was contradictory or too sparse
to establish a sex difference. Our review is unique in that it
offers detailed discussion of sex differences in three major
endophenotypes of ASD. Further research is needed to better
understand why sex differences exist in certain ASD traits and to
evaluate whether phenotypic sex differences are related to different
pathways of development, assessment, and treatment of the
disorder.
Mercury
toxicity: Genetic susceptibility and synergistic effects
Medical Veritas 2 (2005) 535–542
Boyd
E. Haley, PhD. Professor and Chair, Department of Chemistry,
University of Kentucky
Abstract
Mercury
toxicity and intoxication (poisoning) are realities that every
American needs to face. Both the Environmental Protection Agency and
National Academy of Science state that between 8 to 10% of American
women have mercury levels that would render any child they gave
birth to neurological disorders. One of six children in the USA have
a neurodevelopmental disorder according to the Centers for Disease
Control and Prevention. Yet our dentistry and medicine continue to
expose all patients to mercury. This article discusses the obvious
sources of mercury exposures that can be easily prevented. It also
points out that genetic susceptibility and exposures to other
materials that synergistically enhance mercury and ethylmercury
toxicity need to be evaluated, and that by their existence prevent
the actual determination of a “safe level” of mercury exposure
for all. The mercury sources we consider are from dentistry and from
drugs, mainly vaccines, that, in today’s world are not only
unnecessary sources, but also sources that are being increasingly
recognized as being significantly deleterious to the health of many.
Excerpt
"4.
Hormonal effects: Testosterone and Estrogen
Testosterone
and estrogen-like compounds give vastly different results. Using
female hormones we found them not toxic to the neurons alone and to
be consistently protective against thimerosal toxicity. In fact, at
high levels they could afford total protection for 24 hours against
neuronal death in this test system (data not plotted). However,
testosterone which appeared protective at very low levels (0.01 to
0.1 micromolar), dramatically increased neuron death at higher
levels (0.5 to 1.0 micromolar). In fact, 1.0 micromolar levels of
testosterone that by itself did not significantly increase neuron
death (red flattened oval), within 3 hours when added with 50
nanomolar thimerosal (solid circles) caused 100% neuron death. Fifty
nanomolar thimerosal at this time point did not significantly cause
any cell death.
These
testosterone results, while not conclusive because of the in vitro
neuron culture type of testing, clearly demonstrated that male
versus female hormones may play a major role in autism risk and may
explain the high ratio of boys to girls in autism (4 to 1) and
autism related disorders."
Autism:
a form of lead and mercury toxicity
Environ Toxicol
Pharmacol. 2014 Nov;38(3):1016-24. doi: 10.1016/j.etap.2014.10.005.
Epub 2014 Nov 6.
Yassa HA
Abstract
AIM: Autism
is a developmental disability characterized by severe deficits in
social interaction and communication. The definite cause of autism
is still unknown. The aim of this study is to find out the relation
between exposure to Lead and/or mercury as heavy metals and autistic
symptoms, dealing with the heavy metals with chelating agents can
improve the autistic symptoms.
METHOD: Blood and hair samples
were obtained from 45 children from Upper Egypt with autism between
the ages of 2 and 10 years and 45 children served as controls in the
same age range, after taken an informed consent and fill a
questionnaire to assess the risk factors. The samples were analyzed
blindly for lead and mercury by using atomic absorption and ICP-MS.
Data from the two groups were compared, then follow up of the
autistic children after treatment with chelating agents were
done.
RESULTS: The results obtained showed significant
difference among the two groups, there was high level of mercury and
lead among those kids with autism. Significant decline in the blood
level of lead and mercury with the use of DMSA as a chelating agent.
In addition, there was decline in the autistic symptoms with the
decrease in the lead and mercury level in blood.
CONCLUSION:
Lead
and mercury considered as one of the main causes of autism.
Environmental exposure as well as defect in heavy metal metabolism
is responsible for the high level of heavy metals. Detoxification by
chelating agents had great role in improvement of those kids.
Do
aluminum vaccine adjuvants contribute to the rising prevalence of
autism?
J
Inorg Biochem. 2011 Nov;105(11):1489-99. Epub 2011 Aug
23.
Tomljenovic
L, Shaw CA.
Neural
Dynamics Research Group, Department of Ophthalmology and Visual
Sciences, University of British Columbia, 828 W. 10th Ave,
Vancouver, BC, Canada V5Z 1L8.
Abstract
Autism
spectrum disorders (ASD) are serious multisystem developmental
disorders and an urgent global public health concern. Dysfunctional
immunity and impaired brain function are core deficits in ASD.
Aluminum (Al), the most commonly used vaccine adjuvant, is a
demonstrated neurotoxin and a strong immune stimulator. Hence,
adjuvant Al has the potential to induce neuroimmune disorders. When
assessing adjuvant toxicity in children, two key points ought to be
considered: (i) children should not be viewed as "small adults"
as their unique physiology makes them much more vulnerable to toxic
insults; and (ii) if exposure to Al from only few vaccines can lead
to cognitive impairment and autoimmunity in adults, is it
unreasonable to question whether the current pediatric schedules,
often containing 18 Al adjuvanted vaccines, are safe for children?
By applying Hill's criteria for establishing causality between
exposure and outcome we investigated whether exposure to Al from
vaccines could be contributing to the rise in ASD prevalence in the
Western world. Our results show that: (i) children from countries
with the highest ASD prevalence appear to have the highest exposure
to Al from vaccines; (ii) the increase in exposure to Al adjuvants
significantly correlates with the increase in ASD prevalence in the
United States observed over the last two decades (Pearson r=0.92,
p<0.0001); and (iii) a significant correlation exists between the
amounts of Al administered to preschool children and the current
prevalence of ASD in seven Western countries, particularly at
3-4months of age (Pearson r=0.89-0.94, p=0.0018-0.0248).
The
application of the Hill's criteria to these data indicates that the
correlation between Al in vaccines and ASD may be causal.
Because
children represent a fraction of the population most at risk for
complications following exposure to Al, a more rigorous evaluation
of Al adjuvant safety seems warranted.
The
putative role of environmental aluminium in the development of
chronic neuropathology in adults and children. How strong is the
evidence and what could be the mechanisms involved?
Metabolic
Brain Disease, October 2017, Volume 32, Issue 5, pp 1335–1355
Gerwyn
Morris, Basant K. Puri, Richard E. Frye
Tir
Na Nog, Llanelli, UK, Department of MedicineImperial College London,
Hammersmith Hospital, London UK, College of Medicine, Department of
PediatricsUniversity of Arkansas for Medical Sciences, Arkansas
Children’s Hospital Research Institute, Little Rock
Abstract
The
conceptualisation of autistic spectrum disorder
and Alzheimer’s disease has undergone something of a paradigm
shift in recent years and rather than being viewed as single
illnesses with a unitary pathogenesis and pathophysiology they are
increasingly considered to be heterogeneous syndromes with a complex
multifactorial aetiopathogenesis, involving a highly complex and
diverse combination of genetic, epigenetic and environmental
factors. One
such environmental factor implicated as a potential cause in both
syndromes is aluminium,
as an element or as part of a salt, received, for example, in oral
form or as an adjuvant. Such administration has the potential to
induce pathology via several routes such as provoking dysfunction
and/or activation of glial cells which play an indispensable role in
the regulation of central nervous system homeostasis and
neurodevelopment. Other routes include the generation of oxidative
stress, depletion of reduced glutathione, direct and indirect
reductions in mitochondrial performance and integrity, and
increasing the production of proinflammatory cytokines in both the
brain and peripherally. The mechanisms whereby environmental
aluminium could contribute to the development of the highly specific
pattern of neuropathology seentransulfuration in Alzheimer’s
disease are described. Also detailed are several mechanisms whereby
significant quantities of aluminium introduced via immunisation
could produce chronic neuropathology in genetically susceptible
children. Accordingly,
it is recommended that the use of aluminium salts in immunisations
should be discontinued and that adults should take steps to minimise
their exposure to environmental aluminium.
Administration
of aluminium to neonatal mice in vaccine-relevant amounts is
associated with adverse long term neurological outcomes.
J
Inorg Biochem. 2013 Nov;128:237-44. doi:
10.1016/j.jinorgbio.2013.07.022. Epub 2013 Jul 19.
Shaw
CA, Li Y, Tomljenovic L.
Dept.
of Ophthalmology and Visual Sciences, University of British
Columbia, Vancouver, British Columbia, Canada; Program in
Experimental Medicine, University of British Columbia, Vancouver,
British Columbia, Canada; Program in Neuroscience, University of
British Columbia, Vancouver, British Columbia, Canada. Electronic
address: cashawlab@gmail.com.
Abstract
Our
previous ecological studies of autism spectrum disorder (ASD) has
demonstrated a correlation between increasing ASD rates and
aluminium (Al) adjuvants in common use in paediatric vaccines in
several Western countries. The correlation between ASD rate and Al
adjuvant amounts appears to be dose-dependent and satisfies 8 of 9
Hill criteria for causality. We have now sought to provide an animal
model to explore potential behavioural phenotypes and central
nervous system (CNS) alterations using s.c. injections of Al
hydroxide in early postnatal CD-1 mice of both sexes. Injections of
a "high" and "low" Al adjuvant levels were
designed to correlate to either the U.S. or Scandinavian paediatric
vaccine schedules vs. control saline-injected mice. Both male and
female mice in the "high Al" group showed significant
weight gains following treatment up to sacrifice at 6 months of age.
Male mice in the "high Al" group showed significant
changes in light-dark box tests and in various measures of behaviour
in an open field. Female mice showed significant changes in the
light-dark box at both doses, but no significant changes in open
field behaviours. These current data implicate Al injected in early
postnatal life in some CNS alterations that may be relevant for a
better understanding of the aetiology of ASD.
Repetitive
administration of aluminium to neonatal mice in amounts comparable
to those to children receive via routine vaccinations significantly
increases anxiety and reduces exploratory behaviour and locomotor
activities. The neurodisruptive effects of aluminium are
long-lasting and persist for 6 months following injection.
Aluminum-Induced
Entropy in Biological Systems: Implications for Neurological Disease
Journal
of Toxicology, Volume 2014 (2014), Article ID 491316, 27 pages
Christopher
A. Shaw,1,2,3 Stephanie Seneff,4 Stephen D. Kette,5 Lucija
Tomljenovic,1 John W. Oller Jr.,6 and Robert M. Davidson7
1Neural
Dynamics Research Group, Department of Ophthalmology and Visual
Sciences, 828 W. 10th Avenue, Vancouver, British Columbia, Canada
V5Z 1L8
2Program Experimental Medicine, University of British
Columbia, Vancouver, Canada V5Z 1L8
3Program
in Neurosciences, University of British Columbia, Vancouver, Canada
V5Z 1L8
4MIT
Computer Science and Artificial Intelligence Laboratory, 32 Vassar
Street, Cambridge, MA 02139, USA
5Hudson,
FL 34667, USA
6Department
of Communicative Disorders, University of Louisiana, Lafayette, LA
70504-3170, USA
7Internal
Medicine Group Practice, PhyNet Inc., 4002 Technology Center,
Longview, TX 75605, USA
Over
the last 200 years, mining, smelting, and refining of aluminum (Al)
in various forms have increasingly exposed living species to this
naturally abundant metal. Because of its prevalence in the earth’s
crust, prior to its recent uses it was regarded as inert and
therefore harmless. However, Al is invariably toxic to living
systems and has no known beneficial role in any biological systems.
Humans are increasingly exposed to Al from food, water, medicinals,
vaccines, and cosmetics, as well as from industrial occupational
exposure. Al disrupts biological self-ordering, energy transduction,
and signaling systems, thus increasing biosemiotic entropy.
Beginning with the biophysics of water, disruption progresses
through the macromolecules that are crucial to living processes
(DNAs, RNAs, proteoglycans, and proteins). It injures cells,
circuits, and subsystems and can cause catastrophic failures ending
in death. Al forms toxic complexes with other elements, such as
fluorine, and interacts negatively with mercury, lead, and
glyphosate. Al negatively impacts the central nervous system in all
species that have been studied, including humans. Because of the
global impacts of Al on water dynamics and biosemiotic systems, CNS
disorders in humans are sensitive indicators of the Al toxicants to
which we are being exposed.
Exerpts:
"Animal models of
neurological disease plainly suggest that the ubiquitous presence of
Al in human beings implicates Al toxicants as causally involved in
Lou Gehrig’s disease (ALS), Alzheimer’s disease and autism
spectrum disorders."
"All
these findings plausibly implicate Al adjuvants in pediatric
vaccines as causal factors contributing to increased rates of autism
spectrum disorders in countries where multiple doses are almost
universally administered."
Clinical
clues for autoimmunity and neuroinflammation in patients with
autistic regression.
Dev
Med Child Neurol. 2017 Apr 6. doi: 10.1111/dmcn.13432.
Scott
O, Shi D, Andriashek D, Clark B, Goez HR.
Department
of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
Faculty
of Medicine and Dentistry, University of Alberta, Edmonton, AB,
Canada.
Department
of Pediatrics, Glenrose Rehabilitation Hospital, Edmonton, AB,
Canada.
Division
of Pediatric Neurology, University of Alberta, Edmonton, AB, Canada
Abstract
AIM:
Autistic
regression is a unique variant within the autism spectrum disorders
(ASDs), with recent reports raising the possibility of immune
aetiology. This
study
explores clinical clues for an association between autistic
regression and autoimmunity.
METHOD:
Single-centre
charts of children diagnosed with ASD in 2014 were reviewed. We
compared the rates of: (1) familial autoimmunity in first-degree and
second-
degree
relatives; (2) febrile illness preceding initial parental concern,
as a potential precipitant of immune activation; and (3) possible
non-immune
precipitants
such as pregnancy and postnatal complications.
RESULTS:
The
charts of 206 children with ASD and 33 diagnosed with autistic
regression variant were reviewed. The incidence of febrile illness
in the 6 months prior
to
initial parental concern was significantly higher in the children
with autistic regression compared with those with ASD (30% vs 0%;
p<0.001). The overall
prevalence
of familial autoimmunity was also higher in children with autistic
regression compared with those with ASD (33% vs 12%; p<0.001).
Type 1 diabetes and autoimmune thyroiditis were both more common in
families with children with autistic regression. Other non-immune
risk factors did not differ between the two groups.
INTERPRETATION:
Our
findings suggest that predisposition to autoimmunity, and
immune/inflammatory activation, may be associated with autistic
regression.
Biological
plausibility of the gut-brain axis in autism.
Ann
N Y Acad Sci. 2017 Nov;1408(1):5-6. doi: 10.1111/nyas.13516. Epub
2017 Nov 1.
Vasquez
A
Abstract
Organic
abnormalities with neuroinflammatory and psychiatric consequences
involving abnormal kynurenine and purine metabolism,
neurotransmitter and cytokine imbalances, and altered levels of
nutrients and metabolites are noted in autism, and many of these
abnormalities-specifically including increased intestinal
permeability, microbial metabolites, and heightened serum levels of
endotoxin-originate from the gut.
A
comparison of temporal trends in United States autism prevalence to
trends in suspected environmental factors
Environ
Health. 2014; 13: 73.
Cynthia
D Nevison
Institute
for Arctic and Alpine Research, University of Colorado, Boulder,
Boulder, CO 80309-0450 USA
The
prevalence of diagnosed autism has increased rapidly over the last
several decades among U.S. children. Environmental factors are
thought to be driving this increase and a list of the top ten
suspected environmental toxins was published recently.
Methods
Temporal
trends in autism for birth years 1970–2005 were derived from a
combination of data from the California Department of Developmental
Services (CDDS) and the United States Individuals with Disabilities
Education Act (IDEA). Temporal trends in suspected toxins were
derived from data compiled during an extensive literature survey.
Toxin and autism trends were compared by visual inspection and
computed correlation coefficients. Using IDEA data, autism
prevalence vs. birth year trends were calculated independently from
snapshots of data from the most recent annual report, and by
tracking prevalence at a constant age over many years of reports.
The ratio of the snapshot:tracking trend slopes was used to estimate
the "real" fraction of the increase in autism.
Results
The
CDDS and IDEA data sets are qualitatively consistent in suggesting a
strong increase in autism prevalence over recent decades. The
quantitative comparison of IDEA snapshot and constant-age tracking
trend slopes suggests that ~75-80% of the tracked increase in autism
since 1988 is due to an actual increase in the disorder rather than
to changing diagnostic criteria. Most of the suspected environmental
toxins examined have flat or decreasing temporal trends that
correlate poorly to the rise in autism. Some, including lead,
organochlorine pesticides and vehicular emissions, have strongly
decreasing trends. Among the suspected toxins surveyed,
polybrominated diphenyl ethers, aluminum adjuvants, and the
herbicide glyphosate have increasing trends that correlate
positively to the rise in autism.
Conclusions
Diagnosed
autism prevalence has risen dramatically in the U.S over the last
several decades and continued to trend upward as of birth year 2005.
The increase is mainly real and has occurred mostly since the late
1980s. In contrast, children’s exposure to most of the top ten
toxic compounds has remained flat or decreased over this same time
frame. Environmental factors with increasing temporal trends can
help suggest hypotheses for drivers of autism that merit further
investigation.
Toxic
Metals and Essential Elements in Hair and Severity of Symptoms among
Children with Autism
Maedica
(Buchar). 2012 Jan; 7(1): 38–48.
Eleonor
BLAUROCK-BUSCH,a Omnia R. AMIN,b Hani H. DESSOKI,c and Thanaa RABAH
d
aLecturer
and Advisor, International Board of Clinical Metal Toxicology &
German Medical Association of Clinical Metal Toxicology, Hersbruck,
Germany
bAssociate
Professor of Psychiatry, Cairo University, Egypt
cAssociate
Professor of Psychiatry, Beni-Suef University, Egypt - Beni-Suef
University
dResearcher
of Public Health and Biostatistics, National Research Center, Egypt
Address
for correspondence: Eleonor Blaurock-Busch, Laboratory for Clinical
and Environmental Analyses. Robenstr 20, D-912217, Hersbruck,
Germania. Phone: +0049 91514332 ; Email: ed.ecartorcim@bbew
ABSTRACT
Objective:
The objective of this study was to assess the levels of ten toxic
metals and essential elements in hair samples of children with
autism, and to correlate the level of these elements with the
severity of autism.
Method:
The participants were 44 children, age 3 to 9 years, with Autistic
Spectrum Disorder (ASD) according to Diagnostic and Statistical
Manual of Mental Disorders 4th Edition, (DSM-IV). The severity of
autistic symptomatology was measured by the Childhood Autism Rating
Scale (CARS). Hair analysis was performed to evaluate the long term
metal exposure and mineral level.
Results:
By comparing hair concentration of autistic vs nonautistic children,
elevated hair concentrations were noted for aluminum, arsenic,
cadmium, mercury, antimony, nickel, lead, and vanadium. Hair levels
of calcium, iron, iodine, magnesium, manganese, molybdenum, zinc,
and selenium were considered deficient. There was a significant
positive correlation between lead & verbal communication (p =
0.020) and general impression (p = 0.008). In addition, there was a
significant negative correlation between zinc & fear and
nervousness (p = 0.022).
Conclusion:
Our data supports the historic evidence that heavy metals play a
role in the development of ASD. In combination with an inadequate
nutritional status the toxic effect of metals increase along with
the severity of symptoms.
Autism
is an Acquired Cellular Detoxification Deficiency Syndrome with
Heterogeneous
Genetic Predisposition
Volume 8 • Issue 1 • 1000224
Autism
Open Access, an open access journal, ISSN: 2165-7890
DOI:
10.4172/2165-7890.1000224
James
Lyons-Weiler*
Institute
for Pure and Applied Knowledge, USA
Abstract
Neurodevelopmental
disorders, including autism spectrum disorders, have a complex
biological and medical basis involving diverse genetic risk and
myriad environmental exposures. Teasing apart the role of specific
stressors is made challenging due to the large number of apparently
contributing associations, gene x environment interactions and
phenomimicry. Historically, these conditions have been rare, making
causality assessment at the population level infeasible. Only a few
vaccines have been tested for association with autism, and it has
been shown that improved diagnosis only explains a percentage of the
increase in diagnosis. Now the rates are so high in some countries
that public school programs cannot handle to large numbers of
special needs students, and professionals are quitting their jobs
due to security concerns. Here, I present a mechanistic biomedical
process model (theory) of the pathophysiology of autism that
reconciles the apparent paradox between the high degree of causal
heterogeneity in environmental toxins, the absence of common "autism
genes" and the high degree of genetic concordance
(heritability) of ASD and ASD-like traits. In brief, the
environmental toxin sampling liability for ASD varies among families
involving different local exposures following injury to normal
cellular endoplasmic detoxification and mitochondrial processes from
toxic metals. The literature strongly supports that autism is most
accurately seen as an acquired cellular detoxification deficiency
syndrome with heterogeneous genetic predisposition that manifests
pathophysiologic consequences of accumulated, run-away cellular
toxicity. At a more general level, it is a form of a
toxicant-induced loss of tolerance of toxins, and of chronic and
sustained ER overload (“ER hyperstress”), contributing to
neuronal and glial apoptosis via the unfolded protein response
(UPR). Inherited risk of impaired cellular detoxification and
circulating metal re-toxification in neurons and glial cells
accompanied by chronic UPR is key. This model explains the aberrant
protein disorder observed in ASD; the great diversity of genes that
are found to have low, but real contributions to ASD risk and the
sensitivity of individuals with ASD to environmental toxins. The
hindrance of detoxification and loss of cellular energetics leads to
apoptosis, release of cytokines and chronic neuroinflammation and
microglial activation, all observed hallmarks of ASD. Interference
with the development of normal complex (redundant) synapses leads to
a pathological variation in neuronal differentiation, axon and
dendrite outgrowth, and synaptic protein expression. The most
general outcomes are overall simplification of gross synaptic
anatomy and, neurofunctionally, a loss of inhibitory feedback and
aberrations in long-term connections between distant regions of the
brain. Failed resolution of the ER stress response leads to
re-distribution of neurotoxic metals, and the impaired neurocellular
processes lead to subsequent accumulation of a variety of additional
types of toxins with secondary, sometime life-threatening
comorbidities such as seizures, with overlapping (not mutually
exclusive) causality. Reduction of exposure to toxins known to cause
mitopathy (mercury) and endoplasmic reticulum dysfunction (mercury
and aluminum) during pregnancy and during the early years of
development will reduce the risk of ER overload and ER hyperstress,
and of ASD diagnosis. This knowledge has immediate clinical
translational relevance: Post-vaccination symptoms should be heeded
as a sign of susceptibility to toxin; Vitamin D can be increased to
drive the healthy early phases of the unfolded protein response
(UPR), and mutations in ASD genes encoding proteins with high
intrinsic disorder may contraindicate the use of aluminum and
mercury for carriers of risk alleles. Clinicians should be alert to
a patient’s Vitamin D receptor (BSM) mutational status prior to
recommending increased doses. Approaches to improving overall brain
health in autistics must be de-stigmatized and given high priority.
Reduction of lifetime exposures of industrial and agricultural
toxins will improve brain health for the entire human population.
Purely genetic studies of ASD, and studies that do not include
vaccination as an environmental exposure with potential liability
and interactions with genes, are unethical. To qualify as science,
studies must test plausible hypotheses, and the absence of
association from poorly designed, unethically executed, and
underpowered and unsound whole-population association studies have
been harmful distractions in the quest for understanding. Skilled
pediatricians and ob/gyns will seek evidence of genetic
predisposition to environmental susceptibility in the form of
non-synonymous substitutions in brain proteins that require
ER-folding, and they will provide informed cautions on exposures
(from all sources) to environmental toxins to patients and parents
of patients with signs of metal and chemical sensitivity. To aid in
this, a list of ASD environmental susceptibility protein-encoded
genes is presented. A clinical exome sequence test, followed by
loss-of-function prediction analysis, would point to individuals
most susceptible to vaccine metal-induced ER hyper stress.
Assessment
of infantile mineral imbalances in autism spectrum disorders (ASDs).
Int
J Environ Res Public Health. 2013 Nov 11;10(11):6027-43. doi:
10.3390/ijerph10116027.
Yasuda
H1, Tsutsui T.
La
Belle Vie Research Laboratory, 8-4 Nihonbashi-Tomizawacho, Chuo-ku,
Tokyo 103-0006, Japan. yasuda@lbv.co.jp
Abstract
The
interactions between genes and the environment are now regarded as
the most probable explanation for autism. In this review, we
summarize the results of a metallomics study in which scalp hair
concentrations of 26 trace elements were examined for 1,967 autistic
children (1,553 males and 414 females aged 0-15 years-old), and
discuss recent advances in our understanding of epigenetic roles of
infantile mineral imbalances in the pathogenesis of autism. In the
1,967 subjects, 584 (29.7%) and 347 (17.6%) were found deficient in
zinc and magnesium, respectively, and the incidence rate of zinc
deficiency was estimated at 43.5% in male and 52.5% in female
infantile subjects aged 0-3 years-old. In contrast, 339 (17.2%), 168
(8.5%) and 94 (4.8%) individuals were found to suffer from high
burdens of aluminum, cadmium and lead, respectively, and 2.8% or
less from mercury and arsenic. High toxic metal burdens were more
frequently observed in the infants aged 0-3 years-old, whose
incidence rates were 20.6%, 12.1%, 7.5%, 3.2% and 2.3% for aluminum,
cadmium, lead, arsenic and mercury, respectively. These findings
suggest that infantile zinc- and magnesium-deficiency and/or toxic
metal burdens may be critical and induce epigenetic alterations in
the genes and genetic regulation mechanisms of neurodevelopment in
the autistic children, and demonstrate that a time factor "infantile
window" is also critical for neurodevelopment and probably for
therapy. Thus, early metallomics analysis may lead to early
screening/estimation and treatment/prevention for the autistic
neurodevelopment disorders.
Abnormal
measles-mumps-rubella antibodies and CNS autoimmunity in children
with autism.
J
Biomed Sci.
2002
Jul-Aug;9(4):359-64.
Singh
VK,
Lin
SX,
Newell
E,
Nelson
C.,
Department of Biology and Biotechnology Center, Utah State
University, Logan, Utah 84322, USA.
singhvk@cc.usu.edu
Abstract
Autoimmunity
to the central nervous system (CNS), especially to myelin basic
protein (MBP), may play a causal role in autism, a
neurodevelopmental disorder. Because many autistic children harbor
elevated levels of measles antibodies, we conducted a serological
study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using
serum samples of 125 autistic children and 92 control children,
antibodies were assayed by ELISA or immunoblotting methods. ELISA
analysis showed a significant increase in the level of MMR
antibodies in autistic children. Immunoblotting analysis revealed
the presence of an unusual MMR antibody in 75 of 125 (60%) autistic
sera but not in control sera. This antibody specifically detected a
protein of 73-75 kD of MMR. This protein band, as analyzed with
monoclonal antibodies, was immunopositive for measles hemagglutinin
(HA) protein but not for measles nucleoprotein and rubella or mumps
viral proteins. Thus the MMR antibody in autistic sera detected
measles HA protein, which is unique to the measles subunit of the
vaccine. Furthermore, over 90% of MMR antibody-positive autistic
sera were also positive for MBP autoantibodies, suggesting a strong
association between MMR and CNS autoimmunity in autism. Stemming
from this evidence, we suggest that an
inappropriate antibody response to MMR, specifically the measles
component thereof, might be related to pathogenesis of autism.
Infection,
vaccines and other environmental triggers of
autoimmunity.
Autoimmunity.
2005 May;38(3):235-45.
Molina V, Shoenfeld Y., Department of
Medicine B and The Center for Autoimmune Diseases, Sheba Medical
Center, Tel-Hashomer, Israel.
Abstract
The etiology of
autoimmune diseases is still not clear but genetic, immunological,
hormonal and environmental factors are considered to be important
triggers. Most often autoimmunity is not followed by clinical
symptoms unless an additional event such as an environmental factor
favors an overt expression. Many environmental factors are known to
affect the immune system and may play a role as triggers of the
autoimmune mosaic. Infections: bacterial, viral and parasitic
infections are known to induce and exacerbate autoimmune diseases,
mainly by the mechanism of molecular mimicry. This was studied for
some syndromes as for the association between SLE and EBV infection,
pediatric autoimmune neuropsychiatric disorders associated with
streptococcal infection and more. Vaccines,
in several reports were found to be temporally followed by a new
onset of autoimmune diseases. The same mechanisms that act in
infectious invasion of the host, apply equally to the host response
to vaccination.
It has been accepted for diphtheria and tetanus toxoid, polio and
measles vaccines and GBS. Also this theory has been accepted for MMR
vaccination and development of autoimmune thrombocytopenia, MS has
been associated with HBV vaccination. Occupational and other
chemical exposures are considered as triggers for autoimmunity. A
debate still exists about the role of silicone implants in induction
of scleroderma like disease. Not only foreign chemicals and agents
have been associated with induction of autoimmunity, but also an
intrinsic hormonal exposure, such as estrogens. This might explain
the sexual dimorphism in autoimmunity. Better understanding of
these environmental risk factors will likely lead to explanation of
the mechanisms of onset and progression of autoimmune diseases and
may lead to effective preventive involvement in specific high-risk
groups. So by diagnosing a new patient with autoimmune disease a
wide anamnes is work should be done.
Impact
of environmental factors on the prevalence of autistic disorder
after 1979
Journal
of Public Health and Epidemiology, Vol.6(9), pp. 271-284, September
2014
Theresa A. Deisher, Ngoc V. Doan, Angelica Omaiye,
Kumiko Koyama, Sarah Bwabye
Abstract
The aim of this
study was to investigate a previously overlooked, universally
introduced environmental factor, fetal and retroviral contaminants
in childhood vaccines, absent prior to change points (CPs) in
autistic disorder (AD) prevalence with subsequent dose-effect
evidence and known pathologic mechanisms of action. Worldwide
population based cohort study was used for the design of this study.
The United States, Western Australia, United Kingdom and Denmark
settings were used. All live born infants who later developed
autistic disorder delivered after 1 January 1970, whose redacted
vaccination and autistic disorder diagnosis information is publicly
available in databases maintained by the US Federal Government,
Western Australia, UK, and Denmark. The live births, grouped by
father’s age, were from the US and Australia. The children
vaccinated with MMRII, Varicella and Hepatitis A vaccines varied
from 19 to 35 months of age at the time of vaccination. Autistic
disorder birth year change points were identified as 1980.9, 1988.4
and 1996 for the US, 1987 for UK, 1990.4 for Western Australia, and
1987.5 for Denmark. Change points in these countries corresponded to
introduction of or increased doses of human fetal cell
line-manufactured vaccines, while no relationship was found between
paternal age or Diagnostic and Statistical Manual (DSM) revisions
and autistic disorder diagnosis. Further, linear regression revealed
that Varicella and Hepatitis A immunization coverage was
significantly correlated to autistic disorder cases. R software was
used to calculate change points. Autistic
disorder change points years are coincident with introduction of
vaccines manufactured using human fetal cell lines, containing fetal
and retroviral contaminants, into childhood vaccine regimens. This
pattern was repeated in the US, UK, Western Australia and Denmark.
Thus, rising autistic disorder prevalence is directly related to
vaccines manufactured utilizing human fetal cells. Increased
paternal age and DSM revisions were not related to rising autistic
disorder prevalence.
A
Positive Association found between Autism Prevalence and Childhood
Vaccination uptake across the U.S. Population
Journal
of Toxicology and Environmental Health, Part A: Current
Issues
Volume
74, Issue 14, 2011, Pages 903 - 916
Author:
Gayle DeLonga
Abstract
The
reason for the rapid rise of autism in the United States that began
in the 1990s is a mystery. Although individuals probably have a
genetic predisposition to develop autism, researchers suspect that
one or more environmental triggers are also needed. One of those
triggers might be the battery of vaccinations that young children
receive. Using regression analysis and controlling for family income
and ethnicity, the relationship between the proportion of children
who received the recommended vaccines by age 2 years and the
prevalence of autism (AUT) or speech or language impairment (SLI) in
each U.S. state from 2001 and 2007 was determined. A positive and
statistically significant relationship was found: The higher the
proportion of children receiving recommended vaccinations, the
higher was the prevalence of AUT or SLI. A 1% increase in
vaccination was associated with an additional 680 children having
AUT or SLI. Neither parental behavior nor access to care affected
the results, since vaccination proportions were not significantly
related (statistically) to any other disability or to the number of
pediatricians in a U.S. state.
The
results suggest that although mercury has been removed from many
vaccines, other culprits may link vaccines to autism.
Further
study into the relationship between vaccines and autism is
warranted.
Neonatal
administration of a vaccine preservative, thimerosal, produces
lasting impairment of nociception and apparent activation of opioid
system in rats.
Brain
Res. 2009 Dec 8;1301:143-51. Epub 2009 Sep 9.
Olczak
M, Duszczyk M, Mierzejewski P, Majewska MD. Department of
Pharmacology and Physiology of the Nervous System, Institute of
Psychiatry and Neurology, Warsaw, Poland.
Abstract
Thimerosal
(THIM), an organomercury preservative added to many child vaccines
is a suspected factor in pathogenesis of neurodevelopmental
disorders. We examined the pharmacokinetics of Hg in the brain,
liver and kidneys after i.m. THIM injection in suckling rats and we
tested THIM effect on nociception. THIM solutions were injected to
Wistar and Lewis rats in a vaccination-like mode on PN days 7, 9, 11
and 15 in four equal doses. For Wistar rats these were: 12, 48, 240,
720, 1440, 2160, 3000 microg Hg/kg and for Lewis: 54, 216, 540 and
1080 microg Hg/kg. Pharmacokinetic analysis revealed that Hg from
THIM injections accumulates in the rat brain in significant amounts
and remains there longer than 30 days after the injection. At the
6th week of age animals were examined for pain sensitivity using the
hot plate test. THIM treated rats of both strains and sexes
manifested statistically significantly elevated pain threshold
(latency for paw licking, jumping) on a hot plate (56 degrees C).
Wistar rats were more sensitive to this effect than Lewis rats.
Protracted THIM-induced hypoalgesia was reversed by naloxone (5
mg/kg, i.p.) injected before the hot plate test, indicative of
involvement of endogenous opioids. This was confirmed by augmented
catalepsy after morphine (2.5 mg/kg, s.c.) injection. Acute THIM
injection to 6-week-old rats also produced hypoalgesia, but this
effect was transient and was gone within 14 days.
Present
findings show that THIM administration to suckling or adult rats
impairs sensitivity to pain, apparently due to activation the
endogenous opioid system.
Effect
of thimerosal on the neurodevelopment of premature rats.
World
J Pediatr. 2013 Nov;9(4):356-60. doi: 10.1007/s12519-013-0443-z.
Epub 2013 Nov 14.
Chen
YN1, Wang J, Zhang J, Li SJ, He L, Shao DD, Du HY.
The
Key Laboratory of Biomedical Information Engineering of Ministry of
Education, and Institute of Biomedical Engineering, School of Life
Science and Technology, Xi'an Jiaotong University, Xi'an, 710049,
China.
Abstract
BACKGROUND:
This
study was undertaken to determine the effect of thimerosal on the
neurodevelopment of premature rats.
METHODS:
Thimerosal
was injected into premature SD rats at a dose of 32.8, 65.6, 98.4 or
131.2 μg/kg on postnatal day 1. Expression of dopamine D4 receptor
(DRD4) and serotonin 2A receptor (5-HT2AR), apoptosis in the
prefrontal cortex on post-injection day 49, and learning and memory
function were studied and compared with those in a control group
injected with saline.
RESULTS:
Expression
of DRD4 and 5-HT2AR and learning function decreased, and apoptosis
increased significantly in the 131.2 μg/kg group (P<0.001).
Memory function was significantly impaired by 65.6 (P<0.05), 98.4
and 131.2 μg/kg (P<0.001).
CONCLUSIONS:
The
negative adverse consequences on neurodevelopment observed in the
present study are consistent with previous studies; this study
raised serious concerns about adverse neurodevelopmental disorder
such as autism in humans following the ongoing worldwide routine
administration of thimerosal containing vaccines to infants.
Transcriptomic
analyses of neurotoxic effects in mouse brain after intermittent
neonatal administration of thimerosal.
Toxicol
Sci. 2014 Jun;139(2):452-65. doi: 10.1093/toxsci/kfu049. Epub 2014
Mar 27.
State
Key Laboratory of Biomembrane and Membrane Biotechnology, Institute
of Zoology, Chinese Academy of Sciences, Beijing 100101, China.Li
X1, Qu F, Xie W, Wang F, Liu H, Song S, Chen T, Zhang Y, Zhu S, Wang
Y, Guo C, Tang TS.
Abstract
Thimerosal
is a vaccine antimicrobial preservative which has long been
suspected an iatrogenic factor possibly contributing to
neurodevelopmental disorders including autism. The association
between infant vaccine thimerosal exposure and autism remains an
open question. Although thimerosal has been removed from mandatory
childhood vaccines in the United States, thimerosal-preserved
vaccines are still widely used outside of the United States
especially in developing countries. Notably, thimerosal-containing
vaccines are being given to the newborns within the first 12-24 h
after birth in some countries. To examine the possible neurotoxic
effects of early neonatal exposure to a higher level of thimerosal,
FVB mice were subcutaneously injected with thimerosal-mercury at a
dose which is 20× higher than that used for regular Chinese infant
immunization during the first 4 months of life. Thimerosal-treated
mice exhibited neural development delay, social interaction
deficiency, and inclination of depression. Apparent
neuropathological changes were also observed in adult mice
neonatally treated with thimerosal. High-throughput RNA sequencing
of autistic-behaved mice brains revealed the alternation of a number
of canonical pathways involving neuronal development, neuronal
synaptic function, and the dysregulation of endocrine system.
Intriguingly, the elevation of anterior pituitary secreting hormones
occurred exclusively in male but not in female thimerosal-treated
mice, demonstrating for the first time the gender bias of
thimerosal-mercury toxicity with regard to endocrine system. Our
results indicate that higher dose of neonatal thimerosal-mercury
(20× higher than that used in human) is capable of inducing
long-lasting substantial dysregulation of neurodevelopment, synaptic
function, and endocrine system, which could be the causal
involvements of autistic-like behavior in mice.
Lasting
neuropathological changes in rat brain after intermittent neonatal
administration of thimerosal.
Folia
Neuropathol. 2010;48(4):258-69. Olczak M, Duszczyk M, Mierzejewski
P, Wierzba-Bobrowicz T, Majewska MD.
Department
of Pharmacology and Physiology of the Nervous System, Institute of
Psychiatry and Neurology, ul. Sobieskiego 9, Warsaw,
Poland.
Abstract
Thimerosal,
an organomercurial added as a preservative to some vaccines, is a
suspected iatrogenic factor, possibly contributing to paediatric
neurodevelopmental disorders including autism. We examined the
effects of early postnatal administration of thimerosal (four i.m.
injections, 12 or 240 μg THIM-Hg/kg, on postnatal days 7, 9, 11 and
15) on brain pathology in Wistar rats. Numerous neuropathological
changes were observed in young adult rats which were treated
postnatally with thimerosal. They included: ischaemic degeneration
of neurons and "dark" neurons in the prefrontal and
temporal cortex, the hippocampus and the cerebellum, pathological
changes of the blood vessels in the temporal cortex, diminished
synaptophysin reaction in the hippocampus, atrophy of astroglia in
the hippocampus and cerebellum, and positive caspase-3 reaction in
Bergmann astroglia. These
findings document neurotoxic effects of thimerosal, at doses
equivalent to those used in infant vaccines or higher, in developing
rat brain, suggesting likely involvement of this mercurial in
neurodevelopmental disorders.
Persistent
behavioral impairments and alterations of brain dopamine system
after early postnatal administration of thimerosal in rats.
Behav
Brain Res.
2011
Sep 30;223(1):107-18. doi: 10.1016/j.bbr.2011.04.026. Epub 2011 Apr
28.
Olczak
M,
Duszczyk
M,
Mierzejewski
P,
Meyza
K,
Majewska
MD.
Department of Pharmacology and Physiology of the Nervous System,
Institute of Psychiatry and Neurology, 02-957 Warsaw,
Poland.
Abstract
The
neurotoxic organomercurial thimerosal (THIM), used for decades as
vaccine preservative, is a suspected factor in the pathogenesis of
some neurodevelopmental disorders. Previously we showed that
neonatal administration of THIM at doses equivalent to those used in
infant vaccines or higher, causes lasting alterations in the brain
opioid system in rats. Here we investigated neonatal treatment with
THIM (at doses 12, 240, 1440 and 3000 μg Hg/kg) on behaviors, which
are characteristically altered in autism, such as locomotor
activity, anxiety, social interactions, spatial learning, and on the
brain dopaminergic system in Wistar rats of both sexes. Adult male
and female rats, which were exposed to the entire range of THIM
doses during the early postnatal life, manifested impairments of
locomotor activity and increased anxiety/neophobia in the open field
test. In animals of both sexes treated with the highest THIM dose,
the frequency of prosocial interactions was reduced, while the
frequency of asocial/antisocial interactions was increased in males,
but decreased in females. Neonatal THIM treatment did not
significantly affect spatial learning and memory. THIM-exposed rats
also manifested reduced haloperidol-induced catalepsy, accompanied
by a marked decline in the density of striatal D₂
receptors, measured by immunohistochemical staining, suggesting
alterations to the brain dopaminergic system. Males were more
sensitive than females to some neurodisruptive/neurotoxic actions of
THIM. These
data document that early postnatal THIM administration causes
lasting neurobehavioral impairments and neurochemical alterations in
the brain, dependent on dose and sex. If similar changes occur in
THIM/mercurial-exposed children, they could contribute do
neurodevelopmental disorders.
B-Lymphocytes
from a Population of Children with Autism Spectrum Disorder and
Their Unaffected Siblings Exhibit Hypersensitivity to Thimerosal
J
Toxicol. 2013;2013:801517. Epub 2013 Jun 9.
Sharpe
MA, Gist TL, Baskin DS.
Department
of Neurosurgery, The Methodist Neurological Institute, Houston,
TX.
Abstract
The
role of thimerosal containing vaccines in the development of autism
spectrum disorder (ASD) has been an area of intense debate, as has
the presence of mercury dental amalgams and fish ingestion by
pregnant mothers. We studied the effects of thimerosal on cell
proliferation and mitochondrial function from B-lymphocytes taken
from individuals with autism, their nonautistic twins, and their
nontwin siblings. Eleven families were examined and compared to
matched controls. B-cells were grown with increasing levels of
thimerosal, and various assays (LDH, XTT, DCFH, etc.) were performed
to examine the effects on cellular proliferation and mitochondrial
function. A subpopulation of eight individuals (4 ASD, 2 twins, and
2 siblings) from four of the families showed thimerosal
hypersensitivity, whereas none of the control individuals displayed
this response. The thimerosal concentration required to inhibit cell
proliferation in these individuals was only 40% of controls. Cells
hypersensitive to thimerosal also had higher levels of oxidative
stress markers, protein carbonyls, and oxidant generation. This
suggests certain individuals with a mild mitochondrial defect may be
highly susceptible to mitochondrial specific toxins like the vaccine
preservative thimerosal.
Thimerosal-Derived
Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible
Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA
J
Toxicol. 2012; 2012: 373678. Published online Jun 28, 2012. doi:
10.1155/2012/373678
Martyn
A. Sharpe, * Andrew D. Livingston, and David S.
Baskin
Abstract
Thimerosal generates ethylmercury in
aqueous solution and is widely used as preservative. We have
investigated the toxicology of Thimerosal in normal human
astrocytes, paying particular attention to mitochondrial function
and the generation of specific oxidants. We
find that ethylmercury not only inhibits mitochondrial respiration
leading to a drop in the steady state membrane potential, but also
concurrent with these phenomena increases the formation of
superoxide, hydrogen peroxide, and Fenton/Haber-Weiss generated
hydroxyl radical. These oxidants increase the levels of cellular
aldehyde/ketones. Additionally, we find a five-fold increase in the
levels of oxidant damaged mitochondrial DNA bases and increases in
the levels of mtDNA nicks and blunt-ended breaks. Highly damaged
mitochondria are characterized by having very low membrane
potentials, increased superoxide/hydrogen peroxide production, and
extensively damaged mtDNA and proteins. These mitochondria appear to
have undergone a permeability transition, an observation supported
by the five-fold increase in Caspase-3 activity observed after
Thimerosal treatment.
Thioredoxin:
A novel, independent diagnosis marker in children with autism.
Int
J Dev Neurosci. 2014 Nov 26. pii: S0736-5748(14)00191-9. doi:
10.1016/j.ijdevneu.2014.11.007.
Zhang
QB1, Gao SJ1, Zhao HX2.
Abstract
BACKGROUND:
Oxidative
stress increases serum thioredoxin (TRX), a redox-regulating protein
with antioxidant activity recognized as an oxidative-stress marker.
The aim of this study was to assess the clinical significance of
serum TRX levels in Autism spectrum disorders (ASD).
METHODS:
Eighty
patients diagnosed with ASD and 100 sex and age matched typically
developing children were assessed for serum TRX content at
admission. TRX were assayed with solid-phase sandwich ELISA, and
severity of ASD was evaluated with the Childhood Autism Rating Scale
(CARS) Score.
RESULTS:
The
results indicated that the median serum TRX levels were
significantly (P<0.0001) higher in children with ASD as compared
to typically developing children [17.9(IQR: 10.7-25.8)ng/ml and
5.5(3.6-9.2)ng/ml, respectively]. Levels of TRX increased with
increasing severity of ASD as defined by the CARS score. After
adjusting for all other possible covariates, TRX still was an
independent diagnosis marker of ASD with an adjusted OR of 1.454
(95% CI, 1.232-1.892; P<0.0001). Based on the receiver operating
characteristic (ROC) curve, the optimal cut-off value of serum TRX
levels as an indicator for auxiliary diagnosis of autism was
projected to be 10.6ng/ml. Further, we found that an increased
diagnosis of ASD was associated with TRX levels ≥10.6ng/ml
(adjusted OR 15.31, 95% CI: 7.36-31.85) after adjusting for possible
confounders.
CONCLUSIONS:
Our
study demonstrated that serum TRX levels were associated with ASD,
and elevated levels could be considered as a novel, independent
diagnosis indicator of ASD.
Inhibition
of the human thioredoxin system. A molecular mechanism of mercury
toxicity.
J
Biol Chem. 2008 May 2;283(18):11913-23. doi: 10.1074/jbc.M710133200.
Epub 2008 Mar 4.
Carvalho
CM1, Chew EH, Hashemy SI, Lu J, Holmgren A.
Abstract
Mercury
toxicity mediated by different forms of mercury is a major health
problem; however, the molecular mechanisms underlying toxicity
remain elusive. We analyzed the effects of mercuric chloride
(HgCl(2)) and monomethylmercury (MeHg) on the proteins of the
mammalian thioredoxin system, thioredoxin reductase (TrxR) and
thioredoxin (Trx), and of the glutaredoxin system, glutathione
reductase (GR) and glutaredoxin (Grx). HgCl(2) and MeHg inhibited
recombinant rat TrxR with IC(50) values of 7.2 and 19.7 nm,
respectively. Fully reduced human Trx1 bound mercury and lost all
five free thiols and activity after incubation with HgCl(2) or MeHg,
but only HgCl(2) generated dimers. Mass spectra analysis
demonstrated binding of 2.5 mol of Hg(2+) and 5 mol of MeHg(+)/mol
of Trx1 with the very strong Hg(2+) complexes involving active site
and structural disulfides. Inhibition of both TrxR and Trx activity
was observed in HeLa and HEK 293 cells treated with HgCl(2) or MeHg.
GR was inhibited by HgCl(2) and MeHg in vitro, but no decrease in GR
activity was detected in cell extracts treated with mercurials.
Human Grx1 showed similar reactivity as Trx1 with both mercurial
compounds, with the loss of all free thiols and Grx dimerization in
the presence of HgCl(2), but no inhibition of Grx activity was
observed in lysates of HeLa cells exposed to mercury. Overall,
mercury inhibition was selective toward the thioredoxin system. In
particular, the remarkable potency of the mercury compounds to bind
to the selenol-thiol in the active site of TrxR should be a major
molecular mechanism of mercury toxicity.
Effects
of selenite and chelating agents on mammalian thioredoxin reductase
inhibited by mercury: implications for treatment of mercury
poisoning.
FASEB
J. 2011 Jan;25(1):370-81. doi: 10.1096/fj.10-157594. Epub 2010 Sep
1.
Carvalho
CM1, Lu J, Zhang X, Arnér ES, Holmgren A.
Abstract
Mercury
toxicity is a highly interesting topic in biomedicine due to the
severe endpoints and treatment limitations. Selenite serves as an
antagonist of mercury toxicity, but the molecular mechanism of
detoxification is not clear. Inhibition of the selenoenzyme
thioredoxin reductase (TrxR) is a suggested mechanism of toxicity.
Here, we demonstrated enhanced inhibition of activity by inorganic
and organic mercury compounds in NADPH-reduced TrxR, consistent with
binding of mercury also to the active site selenolthiol. On
treatment with 5 μM selenite and NADPH, TrxR inactivated by HgCl(2)
displayed almost full recovery of activity. Structural analysis
indicated that mercury was complexed with TrxR, but enzyme-generated
selenide removed mercury as mercury selenide, regenerating the
active site selenocysteine and cysteine residues required for
activity. The antagonistic effects on TrxR inhibition were extended
to endogenous antioxidants, such as GSH, and clinically used
exogenous chelating agents BAL, DMPS, DMSA, and α-lipoic acid.
Consistent with the in vitro results, recovery of TrxR activity and
cell viability by selenite was observed in HgCl(2)-treated HEK 293
cells. These results stress the role of TrxR as a target of
mercurials and provide the mechanism of selenite as a detoxification
agent for mercury poisoning.
Serological
association of measles virus and human herpesvirus-6 with brain
autoantibodies in autism.
Clin
Immunol Immunopathol.
1998
Oct;89(1):105-8.
Singh
VK,
Lin
SX,
Yang
VC.
College of Pharmacy, University of Michigan, Ann Arbor, Michigan,
48109-1065, USA.
Abstract
Considering
an autoimmunity and autism connection, brain autoantibodies to
myelin basic protein (anti-MBP) and neuron-axon filament protein
(anti-NAFP) have been found in autistic children. In this current
study, we examined associations between virus serology and
autoantibody by simultaneous analysis of measles virus antibody
(measles-IgG), human herpesvirus-6 antibody (HHV-6-IgG), anti-MBP,
and anti-NAFP. We found that measles-IgG and HHV-6-IgG titers were
moderately higher in autistic children but they did not
significantly differ from normal controls. Moreover, we found that a
vast majority of virus serology-positive autistic sera was also
positive for brain autoantibody: (i) 90% of measles-IgG-positive
autistic sera was also positive for anti-MBP; (ii) 73% of
measles-IgG-positive autistic sera was also positive for anti-NAFP;
(iii) 84% of HHV-6-IgG-positive autistic sera was also positive for
anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was also
positive for anti-NAFP. This
study is the first to report an association between virus serology
and brain autoantibody in autism; it supports the hypothesis that a
virus-induced autoimmune response may play a causal role in
autism.
Metabolic
biomarkers of increased oxidative stress and impaired methylation
capacity in children with autism
American
Journal of Clinical Nutrition, Vol. 80, No. 6, 1611-1617, December
2004
Department
of Pediatrics, University of Arkansas for Medical Sciences, and the
Arkansas Children's Hospital Research
Institute
Abstract
Background:
Autism is a complex neurodevelopmental disorder that usually
presents in early childhood and that is thought to be influenced by
genetic and environmental factors. Although abnormal metabolism of
methionine and homocysteine has been associated with other
neurologic diseases, these pathways have not been evaluated in
persons with autism.
Objective:
The purpose of this study was to evaluate plasma concentrations of
metabolites in the methionine transmethylation and transsulfuration
pathways in children diagnosed with autism.
Design:
Plasma concentrations of methionine, S-adenosylmethionine (SAM),
S-adenosylhomocysteine (SAH), adenosine, homocysteine,
cystathionine, cysteine, and oxidized and reduced glutathione were
measured in 20 children with autism and in 33 control children. On
the basis of the abnormal metabolic profile, a targeted nutritional
intervention trial with folinic acid, betaine, and methylcobalamin
was initiated in a subset of the autistic children.
Results:
Relative to the control children, the children with autism had
significantly lower baseline plasma concentrations of methionine,
SAM, homocysteine, cystathionine, cysteine, and total glutathione
and significantly higher concentrations of SAH, adenosine, and
oxidized glutathione. This metabolic profile is consistent with
impaired capacity for methylation (significantly lower ratio of SAM
to SAH) and increased oxidative stress (significantly lower redox
ratio of reduced glutathione to oxidized glutathione) in children
with autism. The intervention trial was effective in normalizing the
metabolic imbalance in the autistic children.
Conclusions:
An
increased vulnerability to oxidative stress and a decreased capacity
for methylation may contribute to the development and clinical
manifestation of autism.
Classification
and adaptive behavior prediction of children with autism spectrum
disorder based upon multivariate data analysis of markers of
oxidative stress and DNA methylation
Daniel
P. Howsmon, Uwe Kruger, Stepan Melnyk, S. Jill James, Juergen Hahn
Published:
March 16, 2017, https://doi.org/10.1371/journal.pcbi.1005385
Daniel
P. Howsmon
Affiliations
Department of Chemical and Biological Engineering, Rensselaer
Polytechnic Institute, Troy, New York, United States of America,
Center for Biotechnology and Interdisciplinary Studies, Rensselaer
Polytechnic Institute, Troy, New York, United States of America
ORCID
logo http://orcid.org/0000-0002-7177-1342
Uwe
Kruger
Affiliation
Department of Biomedical Engineering, Rensselaer Polytechnic
Institute, Troy, New York, United States of America
ORCID
logo http://orcid.org/0000-0001-5664-9499
Stepan
Melnyk
Affiliation
Department of Pediatrics, University of Arkansas for Medical
Sciences, Little Rock, Arkansas, United States of America
S.
Jill James
Affiliation
Department of Pediatrics, University of Arkansas for Medical
Sciences, Little Rock, Arkansas, United States of America
Juergen
Hahn
E-mail:
hahnj@rpi.edu
Affiliations
Department of Chemical and Biological Engineering, Rensselaer
Polytechnic Institute, Troy, New York, United States of America,
Center for Biotechnology and Interdisciplinary Studies, Rensselaer
Polytechnic Institute, Troy, New York, United States of America,
Department of Biomedical Engineering, Rensselaer Polytechnic
Institute, Troy, New York, United States of America
Abstract
The
number of diagnosed cases of Autism Spectrum Disorders (ASD) has
increased dramatically over the last four decades; however, there is
still considerable debate regarding the underlying pathophysiology
of ASD. This lack of biological knowledge restricts diagnoses to be
made based on behavioral observations and psychometric tools.
However, physiological measurements should support these behavioral
diagnoses in the future in order to enable earlier and more accurate
diagnoses. Stepping
towards this goal of incorporating biochemical data into ASD
diagnosis, this paper analyzes measurements of metabolite
concentrations of the folate-dependent one-carbon metabolism and
transulfuration pathways taken from blood samples of 83 participants
with ASD and 76 age-matched neurotypical peers.
Fisher Discriminant Analysis enables multivariate classification of
the participants as on the spectrum or neurotypical which results
in 96.1% of all neurotypical participants being correctly identified
as such while still correctly identifying 97.6% of the ASD cohort.
Furthermore, kernel partial least squares is used to predict
adaptive behavior, as measured by the Vineland Adaptive Behavior
Composite score, where measurement of five metabolites of the
pathways was sufficient to predict the Vineland score with an R2 of
0.45 after cross-validation. This level of accuracy for
classification as well as severity prediction far exceeds any other
approach in this field and is a strong indicator that the
metabolites under consideration are strongly correlated with an ASD
diagnosis but also that the statistical analysis used here offers
tremendous potential for extracting important information from
complex biochemical data sets.
Newborn
screening for autism: in search of candidate biomarkers.
Biomark
Med. 2013 Apr;7(2):247-60. doi: 10.2217/bmm.12.108.
Mizejewski
GJ1, Lindau-Shepard B, Pass KA.
Division
of Translational Medicine, Wadsworth Center, NYS Department of
Health, PO Box 509, Albany, NY 12201 0509, USA.
Abstract
BACKGROUND:
Autism
spectrum disorder (ASD) represents a wide range of
neurodevelopmental disorders characterized by impairments in social
interaction, language, communication and range of interests. Autism
is usually diagnosed in children 3-5 years of age using behavioral
characteristics; thus, diagnosis shortly after birth would be
beneficial for early initiation of treatment.
AIM:
This
retrospective study sought to identify newborns at risk for ASD
utilizing bloodspot specimens in an immunoassay.
MATERIALS
& METHODS:
The
present study utilized stored frozen specimens from ASD children
already diagnosed at 15-36 months of age. The newborn specimens and
controls were analyzed by immunoassay in a multiplex system that
included 90 serum biomarkers and subjected to statisical analysis.
RESULTS:
Three
sets of five biomarkers associated with ASD were found that differed
from control groups. The 15 candidate biomarkers were then discussed
regarding their association with ASD.
CONCLUSION:
This
study determined that a statistically selected panel of 15
biomarkers successfully discriminated presumptive newborns at risk
for ASD from those of nonaffected controls.
Exerpt:
"GST
[Glutathione S-transferase] is a metabolic biomarker directly
associated with ASD. The human gene product for GST constitutes a
candidate susceptibility protein due to its tissue distribution and
role in oxidative stress and methionine metabolism, which results in
neuronal injury and death."
“Results
of a recent study further demonstrated that glutathione, total
glutathione and activity levels of GST were significantly lower in
autistic patients as compared with control subjects; however,
homocysteine, thioredoxin reductase and perioxidoxin levels were
remarkably higher.”
“Autistic
children with metabolic disturbances are known to display reduced
metabolic activities of GST, cysteine, glutathione and methionine,
which are associated with methionine transmethylation and
trans-sulfation.”
Altered
urinary porphyrins and mercury exposure as biomarkers for autism
severity in Egyptian children with autism spectrum disorder
Metabolic
Brain Disease
Eman
M. KhaledNagwa A. MeguidGeir BjørklundEmail authorAmr GoudaMohamed
H. BaharyAdel HashishNermin M. SallamSalvatore ChirumboloMona A.
El-Bana
Abstract
Autism
spectrum disorder (ASD) is a complex neurodevelopmental disorder
that affects social, communication, and behavioral development.
Recent evidence supported but also questioned the hypothetical role
of compounds containing mercury (Hg) as contributors to the
development of ASD. Specific alterations in the urinary excretion of
porphyrin-containing ring catabolites have been associated with
exposure to Hg in ASD patients. In the present study, the level of
urinary porphyrins, as biomarkers of Hg toxicity in children with
ASD, was evaluated, and its correlation with severity of the
autistic behavior further explored. A total of 100 children was
enrolled in the present study. They were classified into three
groups: children with ASD (40), healthy controls (40), and healthy
siblings of the ASD children (20). Children with ASD were diagnosed
using DSM-IV-TR, ADI-R, and CARS tests. Urinary porphyrins were
evaluated within the three groups using high-performance liquid
chromatography (HPLC), after plasma evaluation of mercury (Hg) and
lead (Pb) in the same groups. Results
showed that children with ASD had significantly higher levels of Hg,
Pb, and the porphyrins pentacarboxyporphyrin, coproporphyrin,
precoproporphyrin, uroporphyrins, and hexacarboxyporphyrin compared
to healthy controls and healthy siblings of the ASD children.
However, there was no significant statistical difference in the
level of heptacarboxyporphyrin among the three groups, while a
significant positive correlation between the levels of
coproporphyrin and precoproporphyrin and autism severity was
observed. Mothers
of ASD children showed a higher percentage of dental amalgam
restorations compared to the mothers of healthy controls suggesting
that high Hg levels in children with ASD may relate to the increased
exposure to Hg from maternal dental amalgam during pregnancy and
lactation.
The results showed that the ASD children in the present study had
increased blood Hg and Pb levels compared with healthy control
children indicating that disordered porphyrin metabolism might
interfere with the pathology associated with the autistic neurologic
phenotype. The
present study indicates that coproporphyrin and precoproporhyrin may
be utilized as possible biomarkers for heavy metal exposure and
autism severity in children with ASD.
Porphyrinuria
in childhood autistic disorder: Implications for environmental
toxicity
Toxicology
and Applied Pharmacology, 2006
Robert
Natafa, Corinne Skorupkab, Lorene Ametb, Alain Lama, Anthea
Springbettc and Richard Lathed, aLaboratoire Philippe Auguste,
Paris, France, Association ARIANE, Clichy, France, Department of
Statistics, Roslin Institute, Roslin, UK, Pieta Research,
This
new study from France utilizes a new and sophisticated measurement
for environmental toxicity by assessing porphyrin levels in autistic
children. It provides clear and unequivocal evidence that children
with autism spectrum disorders are more toxic than their
neurotypical peers.
Excerpt:
"Coproporphyrin levels were elevated in children with autistic
disorder relative to control groups...the elevation was significant.
These data implicate environmental toxicity in childhood autistic
disorder."
Abstract
To
address a possible environmental contribution to autism, we carried
out a retrospective study on urinary porphyrin levels, a biomarker
of environmental toxicity, in 269 children with neurodevelopmental
and related disorders referred to a Paris clinic (2002–2004),
including 106 with autistic disorder. Urinary porphyrin levels
determined by high-performance liquid chromatography were compared
between diagnostic groups including internal and external control
groups. Coproporphyrin levels were elevated in children with
autistic disorder relative to control groups. Elevation was
maintained on normalization for age or to a control heme pathway
metabolite (uroporphyrin) in the same samples. The elevation was
significant (P < 0.001). Porphyrin levels were unchanged in
Asperger's disorder, distinguishing it from autistic disorder. The
atypical molecule precoproporphyrin, a specific indicator of heavy
metal toxicity, was also elevated in autistic disorder (P <
0.001) but not significantly in Asperger's. A subgroup with autistic
disorder was treated with oral dimercaptosuccinic acid (DMSA) with a
view to heavy metal removal. Following DMSA there was a significant
(P = 0.002) drop in urinary porphyrin excretion. These
data implicate environmental toxicity in childhood autistic
disorder.
An
investigation of porphyrinuria in Australian children with autism.
J
Toxicol Environ Health A. 2008;71(20):1349-51. doi:
10.1080/15287390802271723.
Austin
DW, Shandley K.
Swinburne
Autism Bio-Research Initiative (SABRI), Faculty of Life and Social
Sciences, Swinburne University of Technology, Melbourne, Australia.
daustin@swin.edu.au
Abstract
Two
recent studies, from France (Nataf et al., 2006) and the United
States (Geier & Geier, 2007), identified atypical urinary
porphyrin profiles in children with an autism spectrum disorder
(ASD). These profiles serve as an indirect measure of environmental
toxicity generally, and mercury (Hg) toxicity specifically, with the
latter being a variable proposed as a causal mechanism of ASD
(Bernard et al., 2001; Mutter et al., 2005). To examine whether this
phenomenon occurred in a sample of Australian children with ASD, an
analysis of urinary porphyrin profiles was conducted. A consistent
trend in abnormal porphyrin levels was evidenced when data was
compared with those previously reported in the literature. The
results are suggestive of environmental toxic exposure impairing
heme synthesis. Three
independent studies from three continents have now demonstrated that
porphyrinuria is concomitant with ASD, and that Hg may be a likely
xenobiotic to produce porphyrin profiles of this nature.
Porphyrinuria
in Korean children with autism: correlation with oxidative stress.
J
Toxicol Environ Health A. 2010;73(10):701-10. doi:
10.1080/15287391003614000.
Youn
SI1, Jin SH, Kim SH, Lim S.
Department
of Basic Eastern Medical Science, Graduate School, KyungHee
University, Seoul, Republic of Korea.
Abstract
Autism
spectrum disorder (ASD) is a neurodevelopmental disorder believed to
be associated with heavy metal exposure, especially mercury (Hg),
and is characterized by disturbances in metal elimination. Various
studies correlated elevated heavy metal body burden with ASD
diagnoses as evidenced by increased urinary porphyrin levels in
patients. Urinary porphyrins were also determined in Korean patients
diagnosed with ASD (n = 65) who visited AK Eastern Medicinal Clinic
in Kangnam-gu, Seoul, from June 2007 to September 2008, compared to
controls (n = 9) residing in the same area, by means of Metametrix
(CLIA-approved) laboratory testing. Further, urinary organic acids
as indicators of hepatic detoxification/oxidative stress were also
analyzed among patients diagnosed with ASD. Significant increases
were found in patients diagnosed with ASD for proporphyrins,
pentacarboxyporphyrin, precoproporphyrin, coproporphyrins, and total
porphyrins. Significant correlations were observed between hepatic
detoxification/oxidative stress markers and urinary porphyrins. In
agreement with published data, the present results demonstrated that
measurement of porphyrins serves as a reliable tool for diagnosis of
heavy metal involvement in ASD.
Uncoupling
of ATP-mediated Calcium Signaling and Dysregulated IL-6 Secretion in
Dendritic Cells by Nanomolar Thimerosal
Environmental
Health Perspectives, July 2006.
Samuel
R. Goth, Ruth A. Chu Jeffrey P. Gregg
1
National Institute of Environmental Health Sciences Center for
Children’s Environmental Health
2
Department of Veterinary Molecular Biosciences and
3
Department of Medical Pathology, University of California–Davis,
Davis, California, USA
4
MIND (Medical Investigation of Neurodevelopmental Disorders)
Institute, University of California–Davis, Sacramento, California,
USA
Address
correspondence to I.N. Pessah, Department of Veterinary Medicine,
Molecular Biosciences, 1311 Haring Hall, One Shields Ave.,
University of California, Davis, CA
Abstract
Dendritic
cells (DCs), a rare cell type widely distributed in the soma, are
potent antigen-presenting cells that initiate primary immune
responses. DCs rely on intracellular redox state and calcium (Ca2+)
signals for proper development and function, but the relationship
between these two signaling systems is unclear. Thimerosal (THI) is
a mercurial used to preserve vaccines and consumer products, and is
used experimentally to induce Ca2+ release from microsomal stores.
We tested adenosine triphosphate (ATP)-mediated Ca2+ responses of
DCs transiently exposed to nanomolar THI. Transcriptional and
immunocytochemical analyses show that murine myeloid immature DCs
(IDCs) and mature DCs (MDCs) express inositol 1,4,5-trisphosphate
receptor (IP3R) and ryanodine receptor (RyR) Ca2+ channels, known
targets of THI. IDCs express the RyR1 isoform in a punctate
distribution that is densest near plasma membranes and within
dendritic processes, whereas IP3Rs are more generally distributed.
RyR1 positively and negatively regulates purinergic signaling
because ryanodine (Ry) blockade a) recruited 80% more ATP
responders, b) shortened ATP-mediated Ca2+ transients > 2-fold,
and c) produced a delayed and persistent rise (≥ 2-fold) in
baseline Ca2+. THI (100 nM, 5 min) recruited more ATP responders,
shortened the ATP-mediated Ca2+ transient (≥ 1.4-fold), and
produced a delayed rise (≥ 3-fold) in the Ca2+ baseline, mimicking
Ry. THI and Ry, in combination, produced additive effects leading to
uncoupling of IP3R and RyR1 signals. THI altered ATP-mediated
interleukin-6 secretion, initially enhancing the rate of cytokine
secretion but suppressing cytokine secretion overall in Dcs.
Dendritic
cells are exquisitely sensitive to Thimerosal, with one mechanism
involving the uncoupling of positive and negative regulation of Ca2+
signals contributed by RyR1.
Excerpt:
"Our findings that DCs primarily express the RyR1 channel
complex and that this complex is uncoupled by very low levels of THI
with dysregulated IL-6 secretion raise intriguing questions about a
molecular basis for immune dyregulation and the possible role of the
RyR1 complex in genetic susceptibility of the immune system to
mercury."
Myeloid
dendritic cells frequencies are increased in children with autism
spectrum disorder and associated with amygdala volume and repetitive
behaviors
Brain,
Behavior, and Immunity, Volume 31, July 2013, Pages 69–75,
Inflammation and Mental Health
Elizabeth
Breecea, b, Brian Paciottib, Christine Wu Nordahlb, c, Sally
Ozonoffb, c, Judy A. Van de Waterb, d, Sally J. Rogersb, c, David
Amaralb, c, Paul Ashwood
a
Department of Medical Microbiology and Immunology, University of
California, Davis, USA
b
The M.I.N.D. Institute, University of California, Davis, USA
c
Department of Psychiatry and Behavioral Sciences, University of
California, Davis, USA
d
Division of Rheumatology, Allergy and Clinical Immunology,
University of California, Davis, USA
Abstract
The
pathophysiology of autism spectrum disorder (ASD) is not yet known;
however, studies suggest that dysfunction of the immune system
affects many children with ASD. Increasing evidence points to
dysfunction of the innate immune system including activation of
microglia and perivascular macrophages, increases in inflammatory
cytokines/chemokines in brain tissue and CSF, and abnormal
peripheral monocyte cell function. Dendritic cells are major players
in innate immunity and have important functions in the phagocytosis
of pathogens or debris, antigen presentation, activation of naïve T
cells, induction of tolerance and cytokine/chemokine production. In
this study, we assessed circulating frequencies of myeloid dendritic
cells (defined as Lin-1−BDCA1+CD11c+ and Lin-1−BDCA3+CD123−)
and plasmacytoid dendritic cells (Lin-1−BDCA2+CD123+ or
Lin-1−BDCA4+ CD11c−) in 57 children with ASD, and 29 typically
developing controls of the same age, all of who were enrolled as
part of the Autism Phenome Project (APP). The frequencies of
dendritic cells and associations with behavioral assessment and MRI
measurements of amygdala volume were compared in the same
participants. The frequencies of myeloid dendritic cells were
significantly increased in children with ASD compared to typically
developing controls (p < 0.03). Elevated frequencies of myeloid
dendritic cells were positively associated with abnormal right and
left amygdala enlargement, severity of gastrointestinal symptoms and
increased repetitive behaviors. The frequencies of plasmacytoid
dendritic cells were also associated with amygdala volumes as well
as developmental regression in children with ASD. Dendritic
cells play key roles in modulating immune responses and differences
in frequencies or functions of these cells may result in immune
dysfunction in children with ASD. These data further implicate
innate immune cells in the complex pathophysiology of ASD.
Comparison
of Blood and Brain Mercury Levels in Infant Monkeys Exposed to
Methylmercury or Vaccines Containing Thimerosal
Environmental
Health Perspectives, Aug 2005.
Thomas
Burbacher, PhD [University of Washington].
This
study demonstrates clearly and unequivocally that ethyl mercury, the
kind of mercury found in vaccines, not only ends up in the brain,
but leaves double the amount of inorganic mercury as methyl mercury,
the kind of mercury found in fish. Methyl mercury (organic mercury)
has a half-life in the brain measured in days (Rice), while
thimerosal (organic mercury) once in the brain converts to inorganic
mercury at much higher rates, and inorganic mercury has a half-life
in the brain measured in years and decades (Rooney). This work is
groundbreaking because little is known about ethyl mercury, and many
health authorities have asserted that the mercury found in vaccines
is the "safe kind." This study also delivers a strong
rebuke of the Institute of Medicine's recommendation in 2004 to no
longer pursue the mercury-autism connection.
Excerpt:
"A recently published IOM review (IOM 2004) appears to have
abandoned the earlier recommendation [of studying mercury and
autism] as well as back away from the American Academy of Pediatrics
goal [of removing mercury from vaccines]. This approach is difficult
to understand, given our current limited knowledge of the
toxicokinetics and developmental neurotoxicity of thimerosal, a
compound that has been (and will continue to be) injected in
millions of newborns and infants."
Excerpt: “ The
average brain-to-blood partitioning ratio of total Hg in the
thimerosal group was slightly higher than that in the MeHg group
(3.5 ± 0.5 vs. 2.5 ± 0.3, t-test, p = 0.11). Thus,
the brain to-blood Hg concentration ratio established for MeHg will
underestimate the amount of Hg in the brain after exposure to
thimerosal.
“
Abstract
Thimerosal is a preservative that has been
used in manufacturing vaccines since the 1930s. Reports have
indicated that infants can receive ethylmercury (in the form of
thimerosal) at or above the U.S. Environmental Protection Agency
guidelines for methylmercury exposure, depending on the exact
vaccinations, schedule, and size of the infant. In this study we
compared the systemic disposition and brain distribution of total
and inorganic mercury in infant monkeys after thimerosal exposure
with those exposed to MeHg. Monkeys were exposed to MeHg (via oral
gavage) or vaccines containing thimerosal (via intramuscular
injection) at birth and 1, 2, and 3 weeks of age. Total blood Hg
levels were determined 2, 4, and 7 days after each exposure. Total
and inorganic brain Hg levels were assessed 2, 4, 7, or 28 days
after the last exposure. The initial and terminal half-life of Hg in
blood after thimerosal exposure was 2.1 and 8.6 days, respectively,
which are significantly shorter than the elimination half-life of Hg
after MeHg exposure at 21.5 days. Brain concentrations of total Hg
were significantly lower by approximately 3-fold for the
thimerosal-exposed monkeys when compared with the MeHg infants,
whereas the average brain-to-blood concentration ratio was slightly
higher for the thimerosal-exposed monkeys (3.5 ± 0.5 vs. 2.5 ±
0.3). A
higher percentage of the total Hg in the brain was in the form of
inorganic Hg for the thimerosal-exposed monkeys (34% vs. 7%).
The results indicate that MeHg is not a suitable reference for risk
assessment from exposure to thimerosal-derived Hg. Knowledge of the
toxicokinetics and developmental toxicity of thimerosal is needed to
afford a meaningful assessment of the developmental effects of
thimerosal-containing vaccines. Key words: brain and blood
distribution, elimination half-life, ethylmercury, infant nonhuman
primates, methylmercury, thimerosal.
The
retention time of inorganic mercury in the brain--a systematic
review of the evidence.
Toxicol
Appl Pharmacol. 2014 Feb 1;274(3):425-35. doi:
10.1016/j.taap.2013.12.011. Epub 2013 Dec 22.
Rooney
JP.
Academic
Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity
College, 152-160 Pearse Street, Dublin 2, Ireland. Electronic
address: jrooney@rcsi.ie.
Abstract
Reports
from human case studies indicate a half-life for inorganic mercury
in the brain in the order of years-contradicting older radioisotope
studies that estimated half-lives in the order of weeks to months in
duration. This study systematically reviews available evidence on
the retention time of inorganic mercury in humans and primates to
better understand this conflicting evidence. A broad search strategy
was used to capture 16,539 abstracts on the Pubmed database.
Abstracts were screened to include only study types containing
relevant information. 131 studies of interest were identified. Only
1 primate study made a numeric estimate for the half-life of
inorganic mercury (227-540 days). Eighteen human mercury poisoning
cases were followed up long term including autopsy. Brain inorganic
mercury concentrations at death were consistent with a half-life of
several years or longer. 5 radionucleotide studies were found, one
of which estimated head half-life (21 days). This estimate has
sometimes been misinterpreted to be equivalent to brain
half-life-which ignores several confounding factors including
limited radioactive half-life and radioactive decay from surrounding
tissues including circulating blood. No autopsy cohort study
estimated a half-life for inorganic mercury, although some noted
bioaccumulation of brain mercury with age. Modelling studies
provided some extreme estimates (69 days vs 22 years). Estimates
from modelling studies appear sensitive to model assumptions,
however predications based on a long half-life (27.4 years) are
consistent with autopsy findings. In summary, shorter estimates of
half-life are not supported by evidence from animal studies, human
case studies, or modelling studies based on appropriate assumptions.
Evidence
from such studies point to a half-life of inorganic mercury in human
brains of several years to several decades.
This finding carries important implications for pharmcokinetic
modelling of mercury and potentially for the regulatory toxicology
of mercury.
Alkyl
Mercury-Induced Toxicity: Multiple Mechanisms of Action.
Rev
Environ Contam Toxicol. 2017;240:105-149.
Risher
JF, Tucker P.
Division
of Toxicology and Human Health Sciences, Agency for Toxic Substances
and Disease Registry, 1600 Clifton Road (MS F-58), Atlanta, GA,
30333, USA.
Abstract
There
are a number of mechanisms by which alkylmercury compounds cause
toxic action in the body. Collectively, published studies reveal
that there are some similarities between the mechanisms of the toxic
action of the mono-alkyl mercury compounds methylmercury (MeHg) and
ethylmercury (EtHg). This paper represents a summary of some of the
studies regarding these mechanisms of action in order to facilitate
the understanding of the many varied effects of alkylmercurials in
the human body. The similarities in mechanisms of toxicity for MeHg
and EtHg are presented and compared. The
difference in manifested toxicity of MeHg and EtHg are likely the
result of the differences in exposure, metabolism, and elimination
from the body, rather than differences in mechanisms of action
between the two.
Exerpts:
Summary
and Conclusions
There are many commonalities/similarities in
the mechanisms of toxic action of methylmercury and ethylmercury
(from thimerosal)... Evidence for the similarity of the various
mechanisms of toxicity include the following:
• Both MeHg
and EtHg bind to the amino acid cysteine (Clarkson 1995; Wu et al.
2008)...
• Both decrease glutathione activity, thus
providing less protection from the oxidative stress caused by MeHg
and EtHg (Carocci et al. 2014; Ndountse and Chan (2008); Choi et al.
1996; Franco et al. 2006; Mori et al. 2007; Muller et al. 2001;
Ndountse and Chan 2008; Wu et al. 2008)...
• Both disrupt
glutamate homeostasis (Farina et al. 2003a, b; Manfroi et al. 2004;
Mutkus et al. 2005; Yin et al. 2007).
• Both cause
oxidative stress/creation of ROS (Dreiem and Seegal 2007; Garg and
Chang 2006; Myhre et al. 2003; Sharpe et al. 2012; Yin et al.
2007)...
• Both cause effects on receptor
binding/neurotransmitter release involving one or more transmitters
(Basu et al. 2008; Coccini et al. 2000; Cooper et al. 2003; Fonfria
et al. 2001; Ida-Eto et al. 2011; Ndountse and Chan 2008; Yuan and
Atchison 2003).
• Both cause DNA damage or impair DNA
synthesis (Burke et al. 2006; Sharpe et al. 2012; Wu et al. 2008).
Metabolic
endophenotype and related genotypes are associated with oxidative
stress in children with autism.
Am
J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):947-56.
James
SJ1, Melnyk S, Jernigan S, Cleves MA, Halsted CH, Wong DH, Cutler P,
Bock K, Boris M, Bradstreet JJ, Baker SM, Gaylor DW.
Department
of Pediatrics, University of Arkansas for Medical Sciences, Arkansas
Children's Hospital Research Institute, Little Rock, Arkansas
Abstract
Autism
is a behaviorally defined neurodevelopmental disorder usually
diagnosed in early childhood that is characterized by impairment in
reciprocal communication and speech, repetitive behaviors, and
social withdrawal. Although both genetic and environmental factors
are thought to be involved, none have been reproducibly identified.
The metabolic phenotype of an individual reflects the influence of
endogenous and exogenous factors on genotype. As such, it provides a
window through which the interactive impact of genes and environment
may be viewed and relevant susceptibility factors identified.
Although abnormal methionine metabolism has been associated with
other neurologic disorders, these pathways and related polymorphisms
have not been evaluated in autistic children. Plasma levels of
metabolites in methionine transmethylation and transsulfuration
pathways were measured in 80 autistic and 73 control children. In
addition, common polymorphic variants known to modulate these
metabolic pathways were evaluated in 360 autistic children and 205
controls.
The metabolic results indicated that plasma methionine and the ratio
of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), an
indicator of methylation capacity, were significantly decreased in
the autistic children relative to age-matched controls. In addition,
plasma levels of cysteine, glutathione, and the ratio of reduced to
oxidized glutathione, an indication of antioxidant capacity and
redox homeostasis, were significantly decreased. Differences in
allele frequency and/or significant gene-gene interactions were
found for relevant genes encoding the reduced folate carrier (RFC
80G > A), transcobalamin II (TCN2 776G > C),
catechol-O-methyltransferase (COMT 472G > A),
methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A >
C), and glutathione-S-transferase (GST M1). We propose that an
increased vulnerability to oxidative stress (endogenous or
environmental) may contribute to the development and clinical
manifestations of autism.
Brain
and tissue levels of mercury after chronic methylmercury exposure in
the monkey.
J
Toxicol Environ Health. 1989;27(2):189-98.
Rice
DC
Toxicology
Research Division, Health Protection Branch, Health and Welfare,
Ottawa, Ontario, Canada.
Abstract
Estimated
half-lives of mercury following methylmercury exposure in humans are
52-93 d for whole body and 49-164 d for blood. In its most recent
1980 review, the World Health Organization concluded that there was
no evidence to suggest that brain half-life differed from whole-body
half-life. In the present study, female monkeys (Macaca
fascicularis) were dosed for at least 1.7 yr with 10, 25, or 50
micrograms/kg.d of mercury as methylmercuric chloride. Dosing was
discontinued, and blood half-life was determined to be about 14 d.
Approximately 230 d after cessation of dosing, monkeys were
sacrificed and organ and regional brain total mercury levels
determined. One monkey that died while still being dosed had brain
mercury levels three times higher than levels in blood. Theoretical
calculations were performed assuming steady-state brain:blood ratios
of 3, 5, or 10. Brain mercury levels were at least three orders of
magnitude higher than those predicted by assuming the half-life in
brain to be the same as that in blood. Estimated half-lives in brain
were between 56 (brain:blood ratio of 3) and 38 (brain:blood ratio
of 10) days. In addition, there was a dose-dependent difference in
half-lives for some brain regions. These data clearly indicate
that brain half-life is considerably longer than blood half-life in
the monkey under conditions of chronic dosing.
Interplay
of glia activation and oxidative stress formation in fluoride and
aluminium exposure.
Pathophysiology.
2015 Mar;22(1):39-48. doi: 10.1016/j.pathophys.2014.12.001. Epub
2014 Dec 13.
Akinrinade
ID1, Memudu AE2, Ogundele OM3, Ajetunmobi OI4.
BACKGROUND:
Oxidative
stress formation is pivotal in the action of environmental agents
which trigger the activation of glial cells and neuroinflammation to
stimulate compensatory mechanisms aimed at restoring homeostasis.
AIM:
This
study sets to demonstrate the interplay of fluoride (F) and
aluminium (Al) in brain metabolism. Specifically, it reveals how
oxidative stress impacts the activation of astrocytes (GFAP),
mediates proinflammatory responses (microglia and B-cells: CD68 and
CD 20 respectively) and shows the pattern of lipid peroxidation in
the brain following fluoride and (or) aluminium treatment in vivo.
METHOD:
Male
adult Wistar rats were treated with low and high doses of fluoride,
aluminium or combination of fluoride-aluminium for 30 days. The
control group received distilled water for the duration of the
treatment. Blood and brain tissue homogenates were prepared for
colorimetric assay of stress biomarkers [malonialdehyde (MDA) and
superoxide dismutase (SOD)]. Subsequent analysis involved
immunodetection of astrocytes (anti-GFAP), microglial (anti-CD68)
and B-cells (anti-CD20) in coronal sections of the prefrontal cortex
using antigen retrieval immunohistochemistry.
RESULT
AND CONCLUSION:
Aluminium,
fluoride and a combination of aluminium-fluoride treatments caused
an increase in brain lipid peroxidation products and reactive oxygen
species (ROS) formation. Similarly, an increase in glial activation
and inflammatory response were seen in these groups versus the
control. Oxidative stress induced glial activation (GFAP) and
increased the expression of B cells (CD20). This also corresponded
to the extent of tissue damage and lipid peroxidation observed.
Taken together, the results suggest a close link between oxidative
stress neuroinflamation and degeneration in aluminium-fluoride
toxicity.
Increases
in the Number of Reactive Glia in the Visual Cortex of Macaca
fascicularis Following Subclinical Long-Term Methyl Mercury
Exposure
Toxicology
and Applied Pharmacology, 1994
Charleston
JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM.,
Department of Pathology, School of Medicine, University of
Washington
Abstract
The
number of neurons, astrocytes, reactive glia, oligodendrocytes,
endothelia, and pericytes in the cortex of the calcarine sulcus of
adult female Macaca fascicularis following long-term subclinical
exposure to methyl mercury (MeHg) and mercuric chloride (inorganic
mercury; IHg) has been estimated by use of the optical volume
fractionator stereology technique. Four groups of monkeys were
exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6,
12, 18, and 12 months followed by 6 months without exposure
(clearance group). A fifth group of monkeys was administered IHg (as
HgCl2; 200 micrograms Hg/kg body wt/day) by constant rate
intravenous infusion via an indwelling catheter for 3 months.
Reactive glia showed a significant increase in number for every
treatment group, increasing 72% in the 6-month, 152% in the
12-month, and 120% in the 18-month MeHg exposed groups, and the
number of reactive glia in the clearance group remained elevated
(89%). The IHg exposed group showed a 165% increase in the number of
reactive glia. The IHg exposed group and the clearance group had low
levels of MeHg present within the tissue; however, the level of IHg
was elevated in both groups. These
results suggest that the IHg may be responsible for the increase in
reactive glia.
All other cell types, including the neurons, showed no significant
change in number at the prescribed exposure level and durations. The
identities of the reactive glial cells and the implications for the
long-term function and survivability of the neurons due to changes
in the glial population following subclinical long-term exposure to
mercury are discussed.
Modeling
the interplay between neurons and astrocytes in autism using human
induced pluripotent stem cells
Biological
Psychiatry, Available online 3 October 2017
Fabiele
Baldino Russo, Beatriz Camille Freitas, Graciela Conceição
Pignatari, Isabella Rodrigues Fernandes, Jonathan Sebat, Alysson
Renato Muotri, Patricia Cristina Baleeiro Beltrão-Braga
Department
of Microbiology, Institute of Biomedical Sciences, University of São
Paulo, São Paulo, SP, Brazil
Department
of Surgery, School of Veterinary Medicine, University of São Paulo,
São Paulo, SP, Brazil
Department
of Pediatrics/Rady Children's Hospital San Diego, Department of
Cellular & Molecular Medicine, Stem Cell Program, University of
California San Diego School of Medicine, Sanford Consortium for
Regenerative Medicine, La Jolla, CA, USA
Department
of Psychiatry, Cellular and Molecular Medicine, University of
California, San Diego, La Jolla, CA 92093, USA
Department
of Obstetrics, School of Arts, Sciences and Humanities, University
of São Paulo, São Paulo, SP, Brazil
Received
12 September 2016, Revised 14 August 2017, Accepted 17 September
2017,
Abstract
Background
Autism
Spectrum Disorders (ASD) are neurodevelopmental disorders with
unclear etiology and imprecise genetic causes. The main goal of this
work was to investigate neuronal connectivity and the interplay
between neurons and astrocytes from non-syndromic ASD individuals
using induced Pluripotent Stem Cells (iPSCs).
Methods
Our
iPSCs were derived from a clinically well-characterized cohort of
three non-syndromic ASD individuals, sharing common behaviors, and
three controls, two clones each. We generated mixed neural cultures
analyzing synaptogenesis and neuronal activity using a
multi-electrode array (MEA) platform. Furthermore, using an enriched
astrocytes population we investigated their role in neuronal
maintenance.
Results
Our
results revealed that ASD-derived neurons had a significant decrease
in synaptic gene expression and protein levels, glutamate
neurotransmitter release and, consequently, reduced spontaneous
firing rate. Based on co-culture experiments, we observed that
ASD-derived astrocytes interfered with proper neuronal development.
In contrast, control-derived astrocytes rescued the morphological
neuronal phenotype and synaptogenesis defects from ASD neuronal
co-cultures. Furthermore, after identifying IL-6 secretion from
astrocytes in our ASD individuals as a possible culprit for neural
defects, we were able to increase synaptogenesis by blocking IL-6
levels.
Conclusions
Our
findings reveal astrocytes contribution to neuronal phenotype and
confirm previous studies linking IL-6 and autism, suggesting
potential novel therapeutic pathways for a subtype of ASD
individuals. This
is the first report demonstrating that glial dysfunctions could
contribute to non-syndromic autism pathophysiology using iPSCs
modeling disease technology.
Neuroglial
Activation and Neuroinflammation in the Brain of Patients with
Autism
Annals
of Neurology, Feb 2005.
Diana
L. Vargas, MD, Johns Hopkins University.
Abstract
Autism
is a neurodevelopmental disorder characterized by impaired
communication and social interaction and may be accompanied by
mental retardation and epilepsy. Its cause remains unknown, despite
evidence that genetic, environmental, and immunological factors may
play a role in its pathogenesis. To investigate whether
immune-mediated mechanisms are involved in the pathogenesis of
autism, we used immunocytochemistry, cytokine protein arrays, and
enzyme-linked immunosorbent assays to study brain tissues and
cerebrospinal fluid (CSF) from autistic patients and determined the
magnitude of neuroglial and inflammatory reactions and their
cytokine expression profiles. Brain tissues from cerebellum,
midfrontal, and cingulate gyrus obtained at autopsy from 11 patients
with autism were used for morphological studies. Fresh-frozen
tissues available from seven patients and CSF from six living
autistic patients were used for cytokine protein profiling. We
demonstrate an active neuroinflammatory process in the cerebral
cortex, white matter, and notably in cerebellum of autistic
patients. Immunocytochemical studies showed marked activation of
microglia and astroglia, and cytokine profiling indicated that
macrophage chemoattractant protein (MCP)-1 and tumor growth
factor-beta1, derived from neuroglia, were the most prevalent
cytokines in brain tissues. CSF showed a unique proinflammatory
profile of cytokines, including a marked increase in MCP-1. Our
findings indicate that innate neuroimmune reactions play a
pathogenic role in an undefined proportion of autistic patients,
suggesting that future therapies might involve modifying neuroglial
responses in the brain.
Excerpt:
"Because
this neuroinflammatory process appears to be associated with an
ongoing and chronic mechanism of CNS dysfunction, potential
therapeutic interventions should focus on the control of its
detrimental effects and thereby eventually modify the clinical
course of autism."
Aluminium
in brain tissue in autism
Journal
of Trace Elements in Medicine and Biology
Matthew Mold,
Dorcas Umar, Andrew King, Christopher Exley,
The
Birchall Centre, Lennard-Jones Laboratories, Keele University,
Staffordshire, ST5 5BG, United Kingdom
Life
Sciences, Keele University, Staffordshire, ST5 5BG, United Kingdom
Department
of Clinical Neuropathology, Kings College Hospital, London, SE5 9RS,
United Kingdom
26
November 2017
Abstract
Autism
spectrum disorder is a neurodevelopmental disorder of unknown
aetiology. It is suggested to involve both genetic susceptibility
and environmental factors including in the latter environmental
toxins. Human exposure to the environmental toxin aluminium has been
linked, if tentatively, to autism spectrum disorder. Herein we have
used transversely heated graphite furnace atomic absorption
spectrometry to measure, for the first time, the aluminium content
of brain tissue from donors with a diagnosis of autism. We have also
used an aluminium-selective fluor to identify aluminium in brain
tissue using fluorescence microscopy. The aluminium content of brain
tissue in autism was consistently high. The mean (standard
deviation) aluminium content across all 5 individuals for each lobe
were 3.82(5.42), 2.30(2.00), 2.79(4.05) and 3.82(5.17) μg/g dry wt.
for the occipital, frontal, temporal and parietal lobes
respectively. These
are some of the highest values for aluminium in human brain tissue
yet recorded and one has to question why, for example, the aluminium
content of the occipital lobe of a 15 year old boy would be 8.74
(11.59) μg/g dry wt.?
Aluminium-selective fluorescence microscopy was used to identify
aluminium in brain tissue in 10 donors. While
aluminium was imaged associated with neurones it appeared to be
present intracellularly in microglia-like cells and other
inflammatory non-neuronal cells in the meninges, vasculature, grey
and white matter. The pre-eminence of intracellular aluminium
associated with non-neuronal cells was a standout observation in
autism brain tissue and may offer clues as to both the origin of the
brain aluminium as well as a putative role in autism spectrum
disorder.
Microglial
activation and increased microglial density observed in the
dorsolateral prefrontal cortex in autism.
Biol
Psychiatry. 2010 Aug 15;68(4):368-76. doi:
10.1016/j.biopsych.2010.05.024.
Morgan
JT1, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J,
Courchesne E, Everall IP.
Department
of Neuroscience, School of Medicine, University of California, San
Diego
BACKGROUND:
In
the neurodevelopmental disorder autism, several neuroimmune
abnormalities have been reported. However, it is unknown whether
microglial somal volume or density are altered in the cortex and
whether any alteration is associated with age or other potential
covariates.
METHODS:
Microglia
in sections from the dorsolateral prefrontal cortex of
nonmacrencephalic male cases with autism (n = 13) and control cases
(n = 9) were visualized via ionized calcium binding adapter molecule
1 immunohistochemistry. In addition to a neuropathological
assessment, microglial cell density was stereologically estimated
via optical fractionator and average somal volume was quantified via
isotropic nucleator.
RESULTS:
Microglia
appeared markedly activated in 5 of 13 cases with autism, including
2 of 3 under age 6, and marginally activated in an additional 4 of
13 cases. Morphological alterations included somal enlargement,
process retraction and thickening, and extension of filopodia from
processes. Average microglial somal volume was significantly
increased in white matter (p = .013), with a trend in gray matter (p
= .098). Microglial cell density was increased in gray matter (p =
.002). Seizure history did not influence any activation measure.
CONCLUSIONS:
The
activation profile described represents a neuropathological
alteration in a sizeable fraction of cases with autism. Given its
early presence, microglial activation may play a central role in the
pathogenesis of autism in a substantial proportion of patients.
Alternatively, activation may represent a response of the innate
neuroimmune system to synaptic, neuronal, or neuronal network
disturbances, or reflect genetic and/or environmental abnormalities
impacting multiple cellular populations.
Transcriptome
analysis reveals dysregulation of innate immune response genes and
neuronal activity-dependent genes in autism
Nature
Communications 5, Article number: 5748 doi:10.1038/ncomms6748
Received
28 September 2014 Accepted 03 November 2014 Published 10 December
2014
Department
of Medicine, McKusick-Nathans Institute of Genetic Medicine, Johns
Hopkins University School of Medicine, Baltimore, Maryland 21205,
USA
Simone
Gupta, Shannon E. Ellis, Foram N. Ashar, Anna Moes, Joel S. Bader
Dan E. Arking
Department
of Biomedical Engineering, Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205, USA
Joel
S. Bader & Jianan Zhan
Department
of Neurology, University of Alabama at Birmingham, Birmingham,
Alabama 35294, USA
Andrew
B. West
Abstract
Recent
studies of genomic variation associated with autism have suggested
the existence of extreme heterogeneity. Large-scale transcriptomics
should complement these results to identify core molecular pathways
underlying autism. Here we report results from a large-scale RNA
sequencing effort, utilizing region-matched autism and control
brains to identify neuronal and microglial genes robustly
dysregulated in autism cortical brain. Remarkably,
we note that a gene expression module corresponding to M2-activation
states in microglia is negatively correlated with a differentially
expressed neuronal module, implicating dysregulated microglial
responses in concert with altered neuronal activity-dependent genes
in autism brains. These
observations provide pathways and candidate genes that highlight the
interplay between innate immunity and neuronal activity in the
aetiology of autism.
Nanomolar
aluminum induces pro-inflammatory and pro-apoptotic gene expression
in human brain cells in primary culture.
J
Inorg Biochem. 2005 Sep;99(9):1895-8.
Lukiw
WJ1, Percy ME, Kruck TP.
Neuroscience
Center of Excellence and Department of Ophthalmology, Louisiana
State University Health Sciences Center, 2020 Gravier Street, Suite
8B8, New Orleans, LA 70112-2272, USA. wlukiw@lsuhsc.edu
Abstract
Aluminum,
the most abundant neurotoxic metal in our biosphere, has been
implicated in the etiology of several neurodegenerative disorders
including Alzheimer's disease (AD). To further understand aluminum's
influence on gene expression, we examined total messenger RNA levels
in untransformed human neural cells exposed to 100 nanomolar
aluminum sulfate using high density DNA microarrays that interrogate
the expression of every human gene. Preliminary data indicate that
of the most altered gene expression levels, 17/24 (70.8%) of
aluminum-affected genes, and 7/8 (87.5%) of aluminum-induced genes
exhibit expression patterns similar to those observed in AD. The
seven genes found to be significantly up-regulated by aluminum
encode pro-inflammatory or pro-apoptotic signaling elements,
including NF-kappaB subunits, interleukin-1beta precursor, cytosolic
phospholipase A2, cyclooxygenase-2, beta-amyloid precursor protein
and DAXX, a regulatory protein known to induce apoptosis and repress
transcription. The
promoters of genes up-regulated by aluminum are enriched in binding
sites for the stress-inducible transcription factors HIF-1 and
NF-kappaB, suggesting a role for aluminum, HIF-1 and NF-kappaB in
driving atypical, pro-inflammatory and pro-apoptotic gene
expression. The effect
of aluminum on specific stress-related gene expression patterns in
human brain cells clearly warrant further investigation.
Aberrant
NF-kappaB expression in autism spectrum condition: a mechanism for
neuroinflammation.
Front
Psychiatry. 2011 May 13;2:27. doi: 10.3389/fpsyt.2011.00027.
eCollection 2011.
Young
AM1, Campbell E, Lynch S, Suckling J, Powis SJ.
Bute
Medical School, University of St. Andrews Fife, Scotland, UK.
Abstract
Autism
spectrum condition (ASC) is recognized as having an inflammatory
component. Post-mortem brain samples from patients with ASC display
neuroglial activation and inflammatory markers in cerebrospinal
fluid, although little is known about the underlying molecular
mechanisms. Nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-κB) is a protein found in almost all cell types and
mediates regulation of immune response by inducing the expression of
inflammatory cytokines and chemokines, establishing a feedback
mechanism that can produce chronic or excessive inflammation. This
article describes immunodetection and immunofluorescence
measurements of NF-κB in human post-mortem samples of orbitofrontal
cortex tissue donated to two independent centers: London Brain Bank,
Kings College London, UK (ASC: n = 3, controls: n = 4) and
Autism Tissue Program, Harvard Brain Bank, USA (ASC: n = 6,
controls: n = 5). The hypothesis was that concentrations of
NF-κB would be elevated, especially in activated microglia in ASC,
and pH would be concomitantly reduced (i.e., acidification).
Neurons, astrocytes, and microglia all demonstrated increased
extranuclear and nuclear translocated NF-κB p65 expression in brain
tissue from ASC donors relative to samples from matched controls.
These between-groups differences were increased in astrocytes and
microglia relative to neurons, but particularly pronounced for
highly mature microglia. Measurement of pH in homogenized samples
demonstrated a 0.98-unit difference in means and a strong (F = 98.3;
p = 0.00018) linear relationship to the expression of nuclear
translocated NF-κB in mature microglia. Acridine orange staining
localized pH reductions to lysosomal compartments. In
summary, NF-κB is aberrantly expressed in orbitofrontal cortex in
patients with ASC, as part of a putative molecular cascade leading
to inflammation, especially of resident immune cells in brain
regions associated with the behavioral and clinical symptoms of
ASC.
A
Study of Nuclear Transcription Factor-Kappa B in Childhood Autism
PLoS
One. 2011; 6(5): e19488.
Usha
S. Naik,1 Charitha Gangadharan,2 Kanakalatha Abbagani,1 Balakrishna
Nagalla,3 Niranjan Dasari,1 and Sunil K. Manna2,*
Monica
Uddin, Editor
Department
of Psychiatry, Osmania Medical College, Hyderabad, India
Laboratory
of Immunology, Centre for DNA Fingerprinting and Diagnostics,
Nampally, Hyderabad, India
National
Institute of Nutrition, Hyderabad, India
University
of Michigan, United States of America
Abstract
Background
Several
children with autism show regression in language and social
development while maintaining normal motor milestones. A clear
period of normal development followed by regression and subsequent
improvement with treatment, suggests a multifactorial etiology. The
role of inflammation in autism is now a major area of study. Viral
and bacterial infections, hypoxia, or medication could affect both
foetus and infant. These stressors could upregulate transcription
factors like nuclear factor kappa B (NF-κB), a master switch for
many genes including some implicated in autism like tumor necrosis
factor (TNF). On this hypothesis, it was proposed to determine NF-κB
in children with autism.
Methods
Peripheral
blood samples of 67 children with autism and 29 control children
were evaluated for NF-κB using electrophoretic mobility shift assay
(EMSA). A phosphor imaging technique was used to quantify values.
The fold increase over the control sample was calculated and
statistical analysis was carried out using SPSS 15.
Results
We
have noted significant increase in NF-κB DNA binding activity in
peripheral blood samples of children with autism. When the fold
increase of NF-κB in cases (n = 67) was compared with that of
controls (n = 29), there was a significant difference (3.14 vs.
1.40, respectively; p<0.02).
Conclusion
This
finding has immense value in understanding many of the known
biochemical changes reported in autism. As NF-κB is a response to
stressors of several kinds and a master switch for many genes,
autism may then arise at least in part from an NF-κB pathway gone
awry.
Autism:
A Brain Disorder, or A Disorder That Affects the Brain?
Clinical
Neuropsychiatry, 2005
Martha
R. Herbert M.D., Ph.D., Harvard University
Autism
is defined behaviorally, as a syndrome of abnormalities involving
language, social reciprocity and hyperfocus or reduced behavioral
flexibility. It is clearly heterogeneous, and it can be accompanied
by unusual talents as well as by impairments, but its underlying
biological and genetic basis in unknown. Autism has been modeled as
a brain-based, strongly genetic disorder, but emerging findings and
hypotheses support a broader model of the condition as a genetically
influenced and systemic. These include imaging, neuropathology and
psychological evidence of pervasive (and not just specific) brain
and phenotypic features; postnatal evolution and chronic persistence
of brain, behavior and tissue changes (e.g. inflammation) and
physical illness symptomatology (e.g. gastrointestinal, immune,
recurrent infection); overlap with other disorders; and reports of
rate increases and improvement or recovery that support a role for
modulation of the condition by environmental factors (e.g.
exacerbation or triggering by toxins, infectious agents, or others
stressors, or improvement by treatment). Modeling autism more
broadly encompasses previous work, but also encourages the expansion
of research and treatment to include intermediary domains of
molecular and cellular mechanisms, as well as chronic tissue,
metabolic and somatic changes previously addressed only to a limited
degree. The heterogeneous biologies underlying autism may
conceivably converge onto the autism profile via multiple mechanisms
on the one hand and processing and connectivity abnormalities on the
other may illuminate relevant final common pathways and contribute
to focusing on the search for treatment targets in this biologically
and etiologically heterogeneous behavioral syndrome.
Multivariate
techniques enable a biochemical classification of children with
autism spectrum disorder versus typically‐developing peers: A
comparison and validation study
Daniel
P. Howsmon Troy Vargason Robert A. Rubin Leanna Delhey Marie
Tippett Shannon Rose Sirish C. Bennuri John C. Slattery Stepan
Melnyk S. Jill James Richard E. Frye Juergen Hahn
Bioengineering
& Translational Medicine, 14 May 2018
https://doi.org/10.1002/btm2.10095
Funding
information National Institutes of Health, Grant/Award Number:
1R01AI110642
Abstract
Autism
spectrum disorder (ASD) is a developmental disorder which is
currently only diagnosed through behavioral testing. Impaired
folate‐dependent one carbon metabolism (FOCM) and transsulfuration
(TS) pathways have been implicated in ASD, and recently a study
involving multivariate analysis based upon Fisher Discriminant
Analysis returned very promising results for predicting an ASD
diagnosis. This article takes another step toward the goal of
developing a biochemical diagnostic for ASD by comparing five
classification algorithms on existing data of FOCM/TS metabolites,
and also validating the classification results with new data from an
ASD cohort. The comparison results indicate a high sensitivity and
specificity for the original data set and up to a 88% correct
classification of the ASD cohort at an expected 5% misclassification
rate for typically‐developing controls. These results form the
foundation for the development of a biochemical test for ASD which
promises to aid diagnosis of ASD and provide biochemical
understanding of the disease, applicable to at least a subset of the
ASD population.
Activation
of Methionine Synthase by Insulin-like Growth Factor-1 and Dopamine:
a Target for Neurodevelopmental Toxins and Thimerosal
Mol
Psychiatry. 2004 Apr;9(4):358-70.
Waly
M, Olteanu H, Banerjee R, Choi SW, Mason JB, Parker BS, Sukumar S,
Shim S, Sharma A, Benzecry JM, Power-Charnitsky VA, Deth RC.
Department of Pharmaceutical Sciences, Northeastern University,
Boston, MA
Abstract
Methylation
events play a critical role in the ability of growth factors to
promote normal development. Neurodevelopmental toxins, such as
ethanol and heavy metals, interrupt growth factor signaling, raising
the possibility that they might exert adverse effects on
methylation. We found that insulin-like growth factor-1 (IGF-1)- and
dopamine-stimulated methionine synthase (MS) activity and
folate-dependent methylation of phospholipids in SH-SY5Y human
neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent
mechanism. The stimulation of this pathway increased DNA
methylation, while its inhibition increased methylation-sensitive
gene expression. Ethanol potently interfered with IGF-1 activation
of MS and blocked its effect on DNA methylation, whereas it did not
inhibit the effects of dopamine. Metal ions potently affected IGF-1
and dopamine-stimulated MS activity, as well as folate-dependent
phospholipid methylation: Cu(2+) promoted enzyme activity and
methylation, while Cu(+), Pb(2+), Hg(2+) and Al(3+) were inhibitory.
The ethylmercury-containing preservative thimerosal inhibited both
IGF-1- and dopamine-stimulated methylation with an IC(50) of 1 nM
and eliminated MS activity. Our findings outline a novel growth
factor signaling pathway that regulates MS activity and thereby
modulates methylation reactions, including DNA methylation. The
potent inhibition of this pathway by ethanol, lead, mercury,
aluminum and thimerosal suggests that it may be an important target
of neurodevelopmental toxins.
Validation
of the Phenomenon of Autistic Regression Using Home
Videotapes
Archives
of General Psychiatry, 2005
Emily
Werner, PhD; Geraldine Dawson, PhD, University of
Washington
Abstract
Objective
To validate parental report of autistic regression using behavioral
data coded from home videotapes of children with autism spectrum
disorder (ASD) vs typical development taken at 12 and 24 months of
age.
Design
Home videotapes of 56 children’s first and second birthday parties
were collected from parents of young children with ASD with and
without a reported history of regression and typically developing
children. Child behaviors were coded by raters blind to child
diagnosis and regression history. A parent interview that elicited
information about parents’ recall of early symptoms from birth was
also administered.
Setting
Participants were recruited from a multidisciplinary study of autism
conducted at a major university.
Participants
Fifteen children with ASD with a history of regression, 21 children
with ASD with early-onset autism, and 20 typically developing
children and their parents participated.
Main
Outcome Measures Observations of children’s communicative, social,
affective, repetitive behaviors, and toy play coded from videotapes
of the toddlers’ first and second birthday parties.
Results
Analyses revealed that infants with ASD with regression show similar
use of joint attention and more frequent use of words and babble
compared with typical infants at 12 months of age. In contrast,
infants with ASD with early onset of symptoms and no regression
displayed fewer joint attention and communicative behaviors at 12
months of age. By 24 months of age, both groups of toddlers with ASD
displayed fewer instances of word use, vocalizations, declarative
pointing, social gaze, and orienting to name as compared with
typically developing 24-month-olds.
Parent
interview data suggested that some children with regression
displayed difficulties in regulatory behavior before the regression
occurred.
Conclusion
This
study validates the existence of early autistic regression.
Blood
Levels of Mercury Are Related to Diagnosis of Autism: A Reanalysis
of an Important Data Set
Journal
of Child Neurology, Vol. 22, No. 11, 1308-1311 (2007)
M.
Catherine DeSoto, PhD, Robert T. Hitlan, PhD -Department of
Psychology, University of Northern Iowa, Cedar Falls, Iowa
Abstract
The
question of what is leading to the apparent increase in autism is of
great importance. Like the link between aspirin and heart attack,
even a small effect can have major health implications. If there is
any link between autism and mercury, it is absolutely crucial that
the first reports of the question are not falsely stating that no
link occurs. We
have reanalyzed the data set originally reported by Ip et al. in
2004 and have found that the original p value was in error and that
a significant relation does exist between the blood levels of
mercury and diagnosis of an autism spectrum disorder. Moreover, the
hair sample analysis results offer some support for the idea that
persons with autism may be less efficient and more variable at
eliminating mercury from the blood.
Empirical
Data Confirm Autism Symptoms Related to Aluminum and Acetaminophen
Exposure
Entropy,
November 7, 2012
Stephanie
Seneff, Robert M. Davidson and Jingjing Liu
Computer
Science and Artificial Intelligence Laboratory, Massachusetts
Institute of Technology, Cambridge, MA 02139, USA, Internal
Medicine Group Practice, PhyNet, Inc., Longview, TX 75604,
USA
Abstract
Autism
is a condition characterized by impaired cognitive and social
skills, associated with compromised immune function. The incidence
is alarmingly on the rise, and environmental factors are
increasingly suspected to play a role. This paper investigates word
frequency patterns in the U.S. CDC Vaccine Adverse Events Reporting
System (VAERS) database. Our results provide strong evidence
supporting a link between autism and the aluminum in vaccines. A
literature review showing toxicity of aluminum in human physiology
offers further support. Mentions of autism in VAERS increased
steadily at the end of the last century, during a period when
mercury was being phased out, while aluminum adjuvant burden was
being increased. Using standard log-likelihood ratio techniques, we
identify several signs and symptoms that are significantly more
prevalent in vaccine reports after 2000, including cellulitis,
seizure, depression, fatigue, pain and death, which are also
significantly associated with aluminum-containing vaccines.
We
propose that children with the autism diagnosis are especially
vulnerable to toxic metals such as aluminum and mercury due to
insufficient serum sulfate and glutathione.
A
strong correlation between autism and the MMR (Measles, Mumps,
Rubella) vaccine is also observed, which may be partially explained
via an increased sensitivity to acetaminophen administered to
control fever.
Glutathione-related
factors and oxidative stress in autism, a review.
Curr
Med Chem. 2012;19(23):4000-5.
Ghanizadeh
A1, Akhondzadeh S, Hormozi M, Makarem A, Abotorabi-Zarchi M,
Firoozabadi A.
Research
Center for Psychiatry and Behavioral Sciences, Shiraz University of
Medical Sciences, School of Medicine, Shiraz, Iran.
ghanizad@sina.tums.ac.ir
Abstract
Autism
spectrum disorders are complex neuro-developmental disorders whose
neurobiology is proposed to be associated with oxidative stress
which is induced by reactive oxygen species. The process of
oxidative stress can be a target for therapeutic interventions. In
this study, we aimed to review the role of oxidative stress, plasma
glutathione (GSH), and related factors as the potential sources of
damage to the brain as well as the possible related factors which
reduce the oxidative stress. Methylation capacity, sulfates level,
and the total glutathione level are decreased in autism. On the
other hand, both oxidized glutathione and the ratio of oxidized to
reduced glutathione are increased in autism. In addition, the
activity of glutathione peroxidase, superoxide dismutase, and
catalase, as a part of the antioxidative stress system are
decreased. The
current literature suggests an imbalance of oxidative and
anti-oxidative stress systems in autism. Glutathione is involved in
neuro-protection against oxidative stress and neuro-inflammation in
autism by improving the anti-oxidative stress system. Decreasing the
oxidative stress might be a potential treatment for autism.
Developmental
Regression and Mitochondrial Dysfunction in a Child With Autism
J
Child Neurol. 2006 Feb;21(2):170-2.
Jon
S. Poling, MD, PhD, Department of Neurology and Neurosurgery
Johns
Hopkins Hospital
Jon S. Poling, Richard E. Frye, John
Shoffner and Andrew W. Zimmerman
Abstract
Autistic
spectrum disorders can be associated with mitochondrial dysfunction.
We present a singleton case of developmental regression and
oxidative phosphorylation disorder in a 19-month-old girl. Subtle
abnormalities in the serum creatine kinase level, aspartate
aminotransferase, and serum bicarbonate led us to perform a muscle
biopsy, which showed type I myofiber atrophy, increased lipid
content, and reduced cytochrome c oxidase activity. There were
marked reductions in enzymatic activities for complex I and III.
Complex IV (cytochrome c oxidase) activity was near the 5%
confidence level. To determine the frequency of routine laboratory
abnormalities in similar patients, we performed a retrospective
study including 159 patients with autism (Diagnostic and Statistical
Manual of Mental Disorders-IV and Childhood Autism Rating Scale) not
previously diagnosed with metabolic disorders and 94 age-matched
controls with other neurologic disorders. Aspartate aminotransferase
was elevated in 38% of patients with autism compared with 15% of
controls (P <.0001). The serum creatine kinase level also was
abnormally elevated in 22 (47%) of 47 patients with autism. These
data suggest that further metabolic evaluation is indicated in
autistic patients and that defects of oxidative phosphorylation
might be prevalent.
Excerpt:
"Children
who have (mitochondrial-related) dysfunctional cellular energy
metabolism might be more prone to undergo autistic regression
between 18 and 30 months of age if they also have infections or
immunizations at the same time.”
Oxidative
Stress in Autism: Elevated Cerebellar 3-nitrotyrosine
Levels
American
Journal of Biochemistry and Biotechnology 4 (2): 73-84,
2008
Elizabeth
M. Sajdel-Sulkowska, - Dept of Psychiatry, Harvard Medical
School
Shows
a potential link between mercury and the autopsied brains of young
people with autism. A marker for oxidative stress was 68.9% higher
in autistic brain issue than controls (a statistically significant
result), while mercury levels were 68.2% higher.
Abstract
It
has been suggested that oxidative stress and/or mercury compounds
play an important role in the pathophysiology of autism. This study
compared for the first time the cerebellar levels of the oxidative
stress marker 3-nitrotyrosine (3-NT), mercury (Hg) and the
antioxidant selenium (Se) levels between control and autistic
subjects. Tissue homogenates were prepared in the presence of
protease inhibitors from the frozen cerebellar tissue of control
(n=10; mean age, 15.5 years; mean PMI, 15.5 hours) and autistic
(n=9; mean age 12.1 years; mean PMI, 19.3 hours) subjects. The
concentration of cerebellar 3-NT, determined by ELISA, in controls
ranged from 13.69 to 49.04 pmol g-1
of
tissue; the concentration of 3-NT in autistic cases ranged from 3.91
to 333.03 pmol g-1
of
tissue. Mean cerebellar 3-NT was elevated in autism by 68.9% and the
increase was statistically significant (p=0.045). Cerebellar Hg,
measured by atomic absorption spectrometry ranged from 0.9 to 35
pmol g-1
tissue
in controls (n=10) and from 3.2 to 80.7 pmol g-1
tissue
in autistic cases (n=9); the 68.2% increase in cerebellar Hg was not
statistically significant. However, there was a positive correlation
between cerebellar 3-NT and Hg levels (r=0.7961, p=0.0001). A small
decrease in cerebellar Se levels in autism, measured by atomic
absorption spectroscopy, was not statistically significant but was
accompanied by a 42.9% reduction in the molar ratio of Se to Hg in
the autistic cerebellum. While preliminary, the results of the
present study add elevated oxidative stress markers in brain to the
growing body of data reflecting greater oxidative stress in
autism.
Excerpt: The
preliminary data suggest a need for more extensive studies of
oxidative stress, its relationship to the environmental factors and
its possible attenuation by antioxidants in autism.”
Large
Brains in Autism: The Challenge of Pervasive
Abnormality
Neuroscientist.
2005 Oct;11(5):417-40.
Herbert
MR., Harvard University
Pediatric
Neurology, Center for Morphometric Analysis, Massachusetts General
Hospital, Charleston, MA
Abstract
The
most replicated finding in autism neuroanatomy-a tendency to
unusually large brains-has seemed paradoxical in relation to the
specificity of the abnormalities in three behavioral domains that
define autism. We now know a range of things about this phenomenon,
including that brains in autism have a growth spurt shortly after
birth and then slow in growth a few short years afterward, that only
younger but not older brains are larger in autism than in controls,
that white matter contributes disproportionately to this volume
increase and in a nonuniform pattern suggesting postnatal pathology,
that functional connectivity among regions of autistic brains is
diminished, and that neuroinflammation (including microgliosis and
astrogliosis) appears to be present in autistic brain tissue from
childhood through adulthood. Alongside these pervasive brain tissue
and functional abnormalities, there have arisen theories of
pervasive or widespread neural information processing or signal
coordination abnormalities (such as weak central coherence, impaired
complex processing, and underconnectivity), which are argued to
underlie the specific observable behavioral features of autism. This
convergence of findings and models suggests that a systems- and
chronic disease-based reformulation of function and pathophysiology
in autism needs to be considered, and it opens the possibility for
new treatment targets..
Excerpt:
"Oxidative
stress, brain inflammation, and microgliosis have been much
documented in association with toxic exposures including various
heavy metals...the awareness that the brain as well as medical
conditions of children with autism may be conditioned by chronic
biomedical abnormalities such as inflammation opens the possibility
that meaningful biomedical interventions may be possible well past
the window of maximal neuroplasticity in early childhood because the
basis for assuming that all deficits can be attributed to fixed
early developmental alterations in neural architecture has now been
undermined."
Evidence
of Toxicity, Oxidative Stress, and Neuronal Insult in Autism
J
Toxicol Environ Health B Crit Rev. 2006 Nov-Dec;9(6):485-99.
Kern
JK, Jones AM.
Department
of Psychiatry, University of Texas Southwestern Medical Center at
Dallas, Dallas, Texas
Abstract
According
to the Autism Society of America, autism is now considered to be an
epidemic. The increase in the rate of autism revealed by
epidemiological studies and government reports implicates the
importance of external or environmental factors that may be
changing. This article discusses the evidence for the case that some
children with autism may become autistic from neuronal cell death or
brain damage sometime after birth as result of insult; and addresses
the hypotheses that toxicity and oxidative stress may be a cause of
neuronal insult in autism. The article first describes the Purkinje
cell loss found in autism, Purkinje cell physiology and
vulnerability, and the evidence for postnatal cell loss. Second, the
article describes the increased brain volume in autism and how it
may be related to the Purkinje cell loss. Third, the evidence for
toxicity and oxidative stress is covered and the possible
involvement of glutathione is discussed. Finally, the article
discusses what may be happening over the course of development and
the multiple factors that may interplay and make these children more
vulnerable to toxicity, oxidative stress, and neuronal insult.
Oxidative
Stress in Autism
Pathophysiology.
2006 Aug;13(3):171-81. Epub 2006 Jun 12.
Chauhan
A, Chauhan V.
NYS
Institute for Basic Research in Developmental Disabilities, 1050
Forest Hill Road, Staten Island, NY
Abstract
Autism
is a severe developmental disorder with poorly understood etiology.
Oxidative stress in autism has been studied at the membrane level
and also by measuring products of lipid peroxidation, detoxifying
agents (such as glutathione), and antioxidants involved in the
defense system against reactive oxygen species (ROS). Lipid
peroxidation markers are elevated in autism, indicating that
oxidative stress is increased in this disease. Levels of major
antioxidant serum proteins, namely transferrin (iron-binding
protein) and ceruloplasmin (copper-binding protein), are decreased
in children with autism. There is a positive correlation between
reduced levels of these proteins and loss of previously acquired
language skills in children with autism. The alterations in
ceruloplasmin and transferrin levels may lead to abnormal iron and
copper metabolism in autism. The membrane phospholipids, the prime
target of ROS, are also altered in autism. The levels of
phosphatidylethanolamine (PE) are decreased, and phosphatidylserine
(PS) levels are increased in the erythrocyte membrane of children
with autism as compared to their unaffected siblings. Several
studies have suggested alterations in the activities of antioxidant
enzymes such as superoxide dismutase, glutathione peroxidase, and
catalase in autism. Additionally, altered glutathione levels and
homocysteine/methionine metabolism, increased inflammation,
excitotoxicity, as well as mitochondrial and immune dysfunction have
been suggested in autism. Furthermore, environmental and genetic
factors may increase vulnerability to oxidative stress in autism.
Taken together, these studies suggest increased oxidative stress in
autism that may contribute to the development of this disease. A
mechanism linking oxidative stress with membrane lipid
abnormalities, inflammation, aberrant immune response, impaired
energy metabolism and excitotoxicity, leading to clinical symptoms
and pathogenesis of autism is proposed.
Excerpt:
"Upon
completion of this article, participants should be able to: 1. Be
aware of laboratory and clinical evidence of greater oxidative
stress in autism. 2. Understand how gut, brain, nutritional, and
toxic status in autism are consistent with greater oxidative stress.
3. Describe how anti-oxidant nutrients are used in the contemporary
treatment of autism."
Thimerosal
Neurotoxicity is Associated with Glutathione Depletion: Protection
with Glutathione Precursors
Neurotoxicology.
2005 Jan;26(1):1-8.
James
SJ, Slikker W 3rd, Melnyk S, New E, Pogribna M, Jernigan
S.
Department
of Pediatrics, University of Arkansas for Medical Sciences and
Arkansas Children's Hospital Research Institute, Little Rock, AR
Abstract
Thimerosol
is an antiseptic containing 49.5% ethyl mercury that has been used
for years as a preservative in many infant vaccines and in flu
vaccines. Environmental methyl mercury has been shown to be highly
neurotoxic, especially to the developing brain. Because mercury has
a high affinity for thiol (sulfhydryl (-SH)) groups, the
thiol-containing antioxidant, glutathione (GSH), provides the major
intracellular defense against mercury-induced neurotoxicity.
Cultured neuroblastoma cells were found to have lower levels of GSH
and increased sensitivity to thimerosol toxicity compared to
glioblastoma cells that have higher basal levels of intracellular
GSH. Thimerosal-induced
cytotoxicity was associated with depletion of intracellular GSH in
both cell lines.
Pretreatment with 100 microM glutathione ethyl ester or
N-acetylcysteine (NAC), but not methionine, resulted in a
significant increase in intracellular GSH in both cell types.
Further, pretreatment of the cells with glutathione ethyl ester or
NAC prevented cytotoxicity with exposure to 15 microM Thimerosal.
Although Thimerosal has been recently removed from most children's
vaccines, it is still present in flu vaccines given to pregnant
women, the elderly, and to children in developing countries. The
potential protective effect of GSH or NAC against mercury toxicity
warrants further research as possible adjunct therapy to individuals
still receiving Thimerosal-containing vaccinations.
Toxic
metals and oxidative stress part I: mechanisms involved in
metal-induced oxidative damage.
Curr
Top Med Chem. 2001 Dec;1(6):529-39.
Ercal
N1, Gurer-Orhan H, Aykin-Burns N.
University
of Missouri-Rolla, Department of Chemistry, 65409-0010, USA.
nercal@umr.edu
Abstract
Toxic
metals (lead, cadmium, mercury and arsenic) are widely found in our
environment. Humans are exposed to these metals from numerous
sources, including contaminated air, water, soil and food. Recent
studies indicate that transition metals act as catalysts in the
oxidative reactions of biological macromolecules therefore the
toxicities associated with these metals might be due to oxidative
tissue damage. Redox-active metals, such as iron, copper and
chromium, undergo redox cycling whereas redox-inactive metals, such
as lead, cadmium, mercury and others deplete cells' major
antioxidants, particularly thiol-containing antioxidants and
enzymes. Either redox-active or redox-inactive metals may cause an
increase in production of reactive oxygen species (ROS) such as
hydroxyl radical (HO.), superoxide radical (O2.-) or hydrogen
peroxide (H2O2). Enhanced generation of ROS can overwhelm cells'
intrinsic antioxidant defenses, and result in a condition known as
"oxidative stress". Cells under oxidative stress display
various dysfunctions due to lesions caused by ROS to lipids,
proteins and DNA. Consequently,
it is suggested that metal-induced oxidative stress in cells can be
partially responsible for the toxic effects of heavy metals. Several
studies are underway to determine the effect of antioxidant
supplementation following heavy metal exposure. Data suggest that
antioxidants may play an important role in abating some hazards of
heavy metals. In
order to prove the importance of using antioxidants in heavy metal
poisoning, pertinent biochemical mechanisms for metal-induced
oxidative stress should be reviewed.
Aluminum
adjuvant linked to gulf war illness induces motor neuron death in
mice
Neuromolecular
Med. 2007;9(1):83-100.
Petrik
MS, Wong MC, Tabata RC, Garry RF, Shaw CA.
Department
of Ophthalmology and Program in Neuroscience, University of British
Columbia, Vancouver, British Columbia, Canada.
Abstract
Gulf
War illness (GWI) affects a significant percentage of veterans of
the 1991 conflict, but its origin remains unknown. Associated with
some cases of GWI are increased incidences of amyotrophic lateral
sclerosis and other neurological disorders. Whereas many
environmental factors have been linked to GWI, the role of the
anthrax vaccine has come under increasing scrutiny. Among the
vaccine's potentially toxic components are the adjuvants aluminum
hydroxide and squalene. To examine whether these compounds might
contribute to neuronal deficits associated with GWI, an animal model
for examining the potential neurological impact of aluminum
hydroxide, squalene, or aluminum hydroxide combined with squalene
was developed. Young, male colony CD-1 mice were injected with the
adjuvants at doses equivalent to those given to US military service
personnel. All mice were subjected to a battery of motor and
cognitive-behavioral tests over a 6-mo period postinjections.
Following sacrifice, central nervous system tissues were examined
using immunohistochemistry for evidence of inflammation and cell
death. Behavioral testing showed motor deficits in the aluminum
treatment group that expressed as a progressive decrease in strength
measured by the wire-mesh hang test (final deficit at 24 wk; about
50%). Significant cognitive deficits in water-maze learning were
observed in the combined aluminum and squalene group (4.3 errors per
trial) compared with the controls (0.2 errors per trial) after 20
wk. Apoptotic neurons were identified in aluminum-injected animals
that showed significantly increased activated caspase-3 labeling in
lumbar spinal cord (255%) and primary motor cortex (192%) compared
with the controls. Aluminum-treated groups also showed significant
motor neuron loss (35%) and increased numbers of astrocytes (350%)
in the lumbar spinal cord. The findings suggest a possible role for
the aluminum adjuvant in some neurological features associated with
GWI and possibly an additional role for the combination of
adjuvants.
Enrichment
of Elevated Plasma F2t-Isoprostane Levels in Individuals with Autism
Who Are Stratified by Presence of Gastrointestinal Dysfunction
PLoS
ONE 8(7): e68444.
Gorrindo P, Lane CJ, Lee EB, McLaughlin B,
Levitt P (July 3, 2013)
Funding: This work was supported in
part by National Institutes of Health awards National Institute of
Child Health and Human Development R21HD065289 (PL), National
Institute of General Medical Sciences T32GM07347 for the Vanderbilt
Medical Scientist Training Program (PG), National Center for
Research Resources TL1RR024978 (PG), and National Center for
Advancing Translational Sciences UL1TR000445 for the Vanderbilt
Institute for Clinical and Translational Research. Additional
support was provided by the Marino Autism Research Institute, the
Pediatric Clinical Research Center at Vanderbilt University, The
Scott Family Foundation, and the Vanderbilt Autism Treatment Network
Site, a program funded by Autism Speaks.
AbstractEtiology is
unknown in the majority of individuals with autism spectrum disorder
(ASD). One strategy to investigate pathogenesis is to stratify this
heterogeneous disorder based on a prominent phenotypic feature that
enriches for homogeneity within population strata. Co-occurring
gastrointestinal dysfunction (GID) characterizes a subset of
children with ASD. Our current objective was to investigate a
potential pathophysiological measure to test the hypothesis that
children with both ASD and GID have a more severe metabolic
dysfunction than children with ASD-only, given that the highly
metabolically active brain and gastrointestinal system may
additively contribute measurable impairment. Plasma levels of
F2t-Isoprostanes (F2-IsoPs), a gold standard biomarker of oxidative
stress, were measured in 87 children in four groups: ASD-GID,
ASD-only, GID-only and Unaffected. F2-IsoP levels were elevated in
all 3 clinical groups compared to the Unaffected group, with the
ASD-GID group significantly elevated above the ASD-only group (mean,
SD in pg/mg: ASD-GID 53.6, 24.4; ASD-only 36.5, 13.3; p = 0.007).
Adjusting for age, sex, and triglyceride levels, F2-IsoP levels
remained significantly different between study groups, with a
moderate effect size of ηp2 = 0.187 (p = 0.001). Elevation
in peripheral oxidative stress is consistent with, and may
contribute to, the more severe functional impairments in the ASD-GID
group. With
unique medical, metabolic, and behavioral features in children with
ASD-GID, the present findings serve as a compelling rationale for
both individualized approaches to clinical care and integrated
studies of biomarker enrichment in ASD subgroups that may better
address the complex etiology of ASD.
Reduced
levels of mercury in first baby haircuts of autistic children.
Int
J Toxicol. 2003 Jul-Aug;22(4):277-85.
Holmes AS, Blaxill MF,
Haley BE.
Abstract
Reported rates of autism have increased
sharply in the United States and the United Kingdom. One possible
factor underlying these increases is increased exposure to mercury
through thimerosal-containing vaccines, but vaccine exposures need
to be evaluated in the context of cumulative exposures during
gestation and early infancy. Differential rates of postnatal mercury
elimination may explain why similar gestational and infant exposures
produce variable neurological effects. First baby haircut samples
were obtained from 94 children diagnosed with autism using
Diagnostic and Statistical Manual of Mental Disorders, 4th edition
(DSM IV) criteria and 45 age- and gender-matched controls.
Information on diet, dental amalgam fillings, vaccine history, Rho D
immunoglobulin administration, and autism symptom severity was
collected through a maternal survey questionnaire and clinical
observation. Hair mercury levels in the autistic group were 0.47 ppm
versus 3.63 ppm in controls, a significant difference. The mothers
in the autistic group had significantly higher levels of mercury
exposure through Rho D immunoglobulin injections and amalgam
fillings than control mothers. Within the autistic group, hair
mercury levels varied significantly across mildly, moderately, and
severely autistic children, with mean group levels of 0.79, 0.46,
and 0.21 ppm, respectively. Hair mercury levels among controls were
significantly correlated with the number of the mothers' amalgam
fillings and their fish consumption as well as exposure to mercury
through childhood vaccines, correlations that were absent in the
autistic group. Hair excretion patterns among autistic infants were
significantly reduced relative to control. These data cast doubt on
the efficacy of traditional hair analysis as a measure of total
mercury exposure in a subset of the population. In light of the
biological plausibility of mercury's role in neurodevelopmental
disorders, the present study provides further insight into one
possible mechanism by which early mercury exposures could increase
the risk of autism.
A
Case Series of Children with Apparent Mercury Toxic Encephalopathies
Manifesting with Clinical Symptoms of Regressive Autistic
Disorder
J
Toxicol Environ Health A. 2007 May 15;70(10):837-51.
Geier
DA, Geier MR.
Institute of Chronic Illnesses, Inc., Silver
Spring, Maryland, USA.
Abstract
Impairments in social
relatedness and communication, repetitive behaviors, and stereotypic
abnormal movement patterns characterize autism spectrum disorders
(ASDs). It is clear that while genetic factors are important to the
pathogenesis of ASDs, mercury exposure can induce immune, sensory,
neurological, motor, and behavioral dysfunctions similar to traits
defining or associated with ASDs. The Institutional Review Board of
the Institute for Chronic Illnesses (Office for Human Research
Protections, U.S. Department of Health and Human Services, IRB
number IRB00005375) approved the present study. A case series of
nine patients who presented to the Genetic Centers of America for a
genetic/developmental evaluation are discussed. Eight of nine
patients (one patient was found to have an ASD due to Rett's
syndrome) (a) had regressive ASDs; (b) had elevated levels of
androgens; (c) excreted significant amounts of mercury post
chelation challenge; (d) had biochemical evidence of decreased
function in their glutathione pathways; (e) had no known significant
mercury exposure except from Thimerosal-containing
vaccines/Rho(D)-immune globulin preparations; and (f) had alternate
causes for their regressive ASDs ruled out. There was a significant
dose-response relationship between the severity of the regressive
ASDs observed and the total mercury dose children received from
Thimerosal-containing vaccines/Rho (D)-immune globulin preparations.
Based upon differential diagnoses, 8 of 9 patients examined were
exposed to significant mercury from Thimerosal-containing
biologic/vaccine preparations during their fetal/infant
developmental periods, and subsequently, between 12 and 24 mo of
age, these
previously normally developing children suffered mercury toxic
encephalopathies that manifested with clinical symptoms consistent
with regressive ASDs. Evidence for mercury intoxication should be
considered in the differential diagnosis as contributing to some
regressive ASDs.
The
Changing Prevalence of Autism In California
Journal
of Autism and Developmental Disorders, April 2003
Mark
Blaxill, MBA
This
study helps to refute the supposition made by some researchers that
autism's epidemic may only be due to "diagnostic substitution".
Excerpt:
"They
have suggested that 'diagnostic substitution' accounts for an
apparent increase in the incidence of autism in California that is
not real. This hypothesized substitution is not supported by proper
and detailed analyses of the California data."
California
Autism Prevalence Trends from 1931 to 2014 and Comparison to
National ASD Data from IDEA and ADDM.
J
Autism Dev Disord. 2018 Jul 5.
Nevison
C, Blaxill M, Zahorodny W.
Abstract
Time
trends in U.S. autism prevalence from three ongoing datasets
[Individuals with Disabilities Education Act, Autism and
Developmental Disabilities Monitoring Network, and California
Department of Developmental Services (CDDS)] are calculated using
two different methods: (1) constant-age tracking of 8 year-olds and
(2) age-resolved snapshots. The data are consistent across methods
in showing a strong upward trend over time. The prevalence of autism
in the CDDS dataset, the longest of the three data records,
increased from 0.001% in the cohort born in 1931 to 1.2% among 5
year-olds born in 2012. This
increase began around ~ 1940 at a rate that has gradually
accelerated over time, including notable change points around birth
years 1980, 1990 and, most recently, 2007.
Diagnostic
Substitution for Intellectual Disability: A Flawed Explanation for
the Rise in Autism
Journal
of Autism and Developmental Disorders First Online: 06 June 2017,
DOI: 10.1007/s10803-017-3187-0
Cynthia
D. Nevison, Mark Blaxill
Abstract
Time
trends in autism spectrum disorder (ASD) and intellectual disability
(ID) prevalence from the United States Individuals with Disabilities
Education Act data were computed from 2000 to 2011 for each state
and each age from 6 to 17. These
trends did not support the hypothesis that diagnostic substitution
for ID can explain the ASD rise over recent decades,
although the hypothesis appeared more plausible when the data were
aggregated across all states and ages. Nationwide ID prevalence
declined steeply over the last two decades, but the decline was
driven mainly by ~15 states accounting for only one-fourth of the
U.S. school population. More
commonly, including in the most populous states, ID prevalence
stayed relatively constant while ASD prevalence rose sharply.
Mitochondrial
Energy-Deficient Endophenotype in Autism
American
Journal of Biochemistry and Biotechnology 4 (2): 198-207, 2008
J.
Jay Gargus and Faiqa Imtiaz
Department
of Physiology and Biophysics and Department of Pediatrics, Section
of Human Genetics, School of Medicine, University of California,
Irvine, Arabian Diagnostics Laboratory, King Faisal Specialist
Hospital and Research Centre
Abstract:
While evidence points to a multigenic etiology of most autism, the
pathophysiology of the disorder has yet to be defined and the
underlying genes and biochemical pathways they subserve remain
unknown. Autism is considered to be influenced by a combination of
various genetic, environmental and immunological factors; more
recently, evidence has suggested that increased
vulnerability
to oxidative stress may be involved in the etiology of this
multifactorial disorder.
Furthermore,
recent studies have pointed to a subset of autism associated with
the biochemical endophenotype of mitochondrial energy deficiency,
identified as a subtle impairment in fat and carbohydrate oxidation.
This phenotype is similar, but more subtle than those seen in
classic mitochondrial defects. In some cases the beginnings of the
genetic underpinnings of these mitochondrial defects are emerging,
such as mild mitochondrial dysfunction and secondary carnitine
deficiency observed in the subset of autistic patients with an
inverted duplication of chromosome 15q11-q13. In addition, rare
cases of familial autism associated with sudden infant death
syndrome (SIDS) or associated with abnormalities in cellular calcium
homeostasis, such as malignant hyperthermia or cardiac arrhythmia,
are beginning to emerge. Such
special cases suggest that the pathophysiology of autism may
comprise pathways that are directly or indirectly involved in
mitochondrial energy production
and to further probe this connection three new avenues seem worthy
of exploration: 1) metabolomic clinical studies provoking controlled
aerobic exercise stress to expand the biochemical phenotype, 2)
high-throughput expression arrays to directly survey activity of the
genes underlying these biochemical pathways and 3) model systems,
either based upon neuronal stem cells or model genetic organisms, to
discover novel genetic and environmental inputs into these
pathways.
Pathways
to Defective Brain Function and Plasticity
American
Journal of Biochemistry and Biotechnology 4 (2): 167-176,
2008
Matthew
P. Anderson, Brian S. Hooker and Martha R. Herbert
Departments
of Neurology and Pathology, Harvard Medical School/Beth Israel
Deaconess Medical Center, Harvard Institutes of Medicine, High
Throughput Biology Team, Fundamental Science Directorate, Pacific
Northwest National Laboratory, Pediatric Neurology/Center for
Morphometric Analysis, Massachusetts General Hospital/Harvard
Medical School, and Center for Child and Adolescent Development,
Cambridge Health Alliance/Harvard Medical School
Abstract:
We review evidence to support a model where the disease process
underlying autism may begin when an in utero or early postnatal
environmental, infectious, seizure, or autoimmune insult triggers an
immune response that increases reactive oxygen species (ROS)
production in the brain that leads to DNA damage (nuclear and
mitochondrial) and metabolic enzyme blockade and that these
inflammatory and oxidative stressors persist beyond early
development (with potential further exacerbations), producing
ongoing functional consequences. In organs with a high metabolic
demand such as the central nervous system, the continued use of
mitochondria with damaged DNA and impaired metabolic enzyme function
may generate additional ROS which will cause persistent activation
of the innate immune system leading to more ROS production. Such a
mechanism would self-sustain and possibly progressively worsen. The
mitochondrial dysfunction and altered redox signal transduction
pathways found in autism would conspire to activate both astroglia
and microglia. These activated cells can then initiate a
broad-spectrum proinflammatory gene response. Beyond the direct
effects of ROS on neuronal function, receptors on neurons that bind
the inflammatory mediators may serve to inhibit neuronal signaling
to protect them from excitotoxic damage during various pathologic
insults (e.g., infection).
In
autism, over-zealous neuroinflammatory responses could not only
influence neural developmental processes, but may more significantly
impair neural signaling involved in cognition in an ongoing fashion.
This
model makes specific predictions in patients and experimental animal
models and suggests a number of targets sites of intervention. Our
model of potentially reversible pathophysiological mechanisms in
autism motivates our hope that effective therapies may soon appear
on the horizon.
Heavy-Metal
Toxicity—With Emphasis on Mercury
John
Neustadt, ND, and Steve Pieczenik, MD, PhD
Research
Review
Conclusion:
Metals are ubiquitous in our environment, and exposure to them is
inevitable. However, not all people accumulate toxic levels of
metals or exhibit symptoms of metal toxicity, suggesting that
genetics play a role in their potential to damage health.
Metal
toxicity creates multisystem dysfunction, which appears to be
mediated primarily through mitochondrial damage from glutathione
depletion.
Accurate
screening can increase the likelihood that patients with potential
metal toxicity are identified. The most accurate screening method
for assessing chronic-metals exposure and metals load in the body is
a provoked urine test.
Evidence
of Mitochondrial Dysfunction in Autism and Implications for
Treatment
American
Journal of Biochemistry and Biotechnology 4 (2): 208-217,
2008
Daniel
A. Rossignol, J. Jeffrey Bradstreet, International Child Development
Resource Center,
Abstract
Classical
mitochondrial diseases occur in a subset of individuals with autism
and are usually caused by genetic anomalies or mitochondrial
respiratory pathway deficits. However, in many cases of autism,
there is evidence of mitochondrial dysfunction (MtD) without the
classic features associated with mitochondrial disease. MtD appears
to be more common in autism and presents with less severe signs and
symptoms. It is not associated with discernable mitochondrial
pathology in muscle biopsy specimens despite objective evidence of
lowered mitochondrial functioning.
Exposure
to environmental toxins is the likely etiology for MtD in autism.
This dysfunction then contributes to a number of diagnostic symptoms
and comorbidities observed in autism including: cognitive
impairment, language deficits, abnormal energy metabolism, chronic
gastrointestinal problems, abnormalities in fatty acid oxidation,
and increased oxidative stress. MtD and oxidative stress may also
explain the high male to female ratio found in autism due to
increased male vulnerability to these dysfunctions.
Biomarkers
for mitochondrial dysfunction have been identified, but seem widely
under-utilized despite available therapeutic interventions.
Nutritional supplementation to decrease oxidative stress along with
factors to improve reduced glutathione, as well as hyperbaric oxygen
therapy (HBOT) represent supported and rationale approaches. The
underlying pathophysiology and autistic symptoms of affected
individuals would be expected to either improve or cease worsening
once effective treatment for MtD is implemented.
Evidence
of Mitochondrial Dysfunction in Autism: Biochemical Links,
Genetic-Based Associations, and Non-Energy-Related Mechanisms
Oxid
Med Cell Longev. 2017 May 29.
Keren
K. Griffiths and Richard J. Levy
Department
of Anesthesiology, Columbia University Medical Center, New York, NY,
USA
Abstract
Autism
spectrum disorder (ASD), the fastest growing developmental
disability in the United States, represents a group of
neurodevelopmental disorders characterized by impaired social
interaction and communication as well as restricted and repetitive
behavior. The underlying cause of autism is unknown and therapy is
currently limited to targeting behavioral abnormalities. Emerging
studies suggest a link between mitochondrial dysfunction and ASD.
Here, we review the evidence demonstrating this potential
connection. We focus specifically on biochemical links,
genetic-based associations, non-energy related mechanisms, and novel
therapeutic strategies.
Conclusion
The
literature reviewed here suggests a link between abnormalities in
mitochondrial homeostasis and ASD and provides biochemical and
genetic evidence to support a role for mitochondrial dysfunction in
the pathogenesis of the autism phenotype.
Mechanistically, the connection may involve defects in bioenergetic
capacity as well as non-energy related pathways. However, it is not
clear if mitochondrial impairments cause ASD or if they are merely
associated with the disease process. Positive patient behavioral
responses to conventional mitochondrial disease therapies are
promising, however, further investigation is necessary. Future work
should focus on determining how mitochondrial dysfunction causes the
autistic phenotype as well as how defects in mitochondrial
homeostasis predispose individuals to ASD via interaction with
environmental toxins, dietary factors, and epigenetic modifications
during critical periods of development. Establishing a causative
relationship between mitochondrial dysfunction and ASD and
elucidating the exact mechanisms will permit the development of more
precisely targeted therapies in the future. Ultimately, with
improved knowledge and innovation, we may one day be able to prevent
or cure autism.
Proximity
to point sources of environmental mercury release as a predictor of
autism prevalence
Health
& Place, 2008
Raymond
F. Palmer, Stephen Blanchard, Robert Wood
University
of Texas Health Science Center, San Antonio Department of Family and
Community Medicine, Our Lady of the Lake University, San Antonio
Texas, Chair, Department of Sociology
This
study should be viewed as hypothesis-generating - a first step in
examining the potential role of environmental mercury and childhood
developmental disorders. Nothing is known about specific exposure
routes, dosage, timing, and individual susceptibility.
We
suspect that persistent low-dose exposures to various environmental
toxicants, including mercury, that occur during critical windows of
neural development among genetically susceptible children (with a
diminished capacity for metabolizing accumulated toxicants) may
increase the risk for developmental disorders such as autism.
Successfully
identifying the specific combination of environmental exposures and
genetic susceptibilities can inform the development of targeted
prevention intervention strategies.
Epidemiology
of autism spectrum disorder in Portugal: prevalence, clinical
characterization, and medical conditions
Developmental
Medicine & Child Neurology, 2007
Guiomar
Oliveira MD PhD, Centro de Desenvolvimento da Criança, Hospital
Pediátrico de Coimbra; Assunção Ataíde BSc, Direcção Regional
de Educação do Centro Coimbra;
Carla
Marques MSc, Centro de Desenvolvimento da Criança, Hospital
Pediátrico de Coimbra; Teresa S Miguel BSc, Direcção Regional de
Educação do Centro, Coimbra;
Ana
Margarida Coutinho BSc, Instituto Gulbenkian de Ciência, Oeiras;
Luísa Mota-Vieira PhD, Unidade de Genética e Patologia
moleculares, Hospital do Divino Espírito Santo, Ponta Delgada,
Açores; Esmeralda Gonçalves PhD; Nazaré Mendes Lopes PhD,
Faculdade de Ciências e Tecnologia, Universidade de Coimbra; Vitor
Rodrigues MD PhD; Henrique Carmona da Mota MD PhD, Faculdade de
Medicina, Universidade de Coimbra, Coimbra; Astrid Moura Vicente
PhD, Instituto Gulbenkian de Ciência, Oeiras,
Portugal.
*Correspondence
to first author at Hospital Pediátrico de Coimbra, Av Bissaya
Barreto, 3000-076 Coimbra, Portugal. E-mail:
guiomar@hpc.chc.min-saude.pt
Abstract:
The objective of this study was to estimate the prevalence of
autistic spectrum disorder (ASD) and identify its clinical
characterization, and medical conditions in a paediatric population
in Portugal. A school survey was conducted in elementary schools,
targeting 332 808 school-aged children in the mainland and 10 910 in
the Azores islands. Referred children were directly assessed using
the Diagnostic and Statistical Manual of Mental Disorders (4th edn),
the Autism Diagnostic Interview–Revised, and the Childhood Autism
Rating Scale. Clinical history and a laboratory investigation was
performed. In parallel, a systematic multi-source search of children
known to have autism was carried out in a restricted region. The
global prevalence of ASD per 10 000 was 9.2 in mainland, and 15.6 in
the Azores, with intriguing regional differences.
A
diversity of associated medical conditions was documented in 20%,
with an unexpectedly high rate of mitochondrial respiratory chain
disorders.
Thimerosal
induces neuronal cell apoptosis by causing cytochrome c and
apoptosis-inducing factor release from mitochondria.
International
Journal of Molecular Medicine, 2006
Yel
L, Brown LE, Su K, Gollapudi S, Gupta S.Department of Medicine,
University of California, Irvine, CA 92697, USA. lyel@uci.edu
There
is a worldwide increasing concern over the neurological risks of
thimerosal (ethylmercury thiosalicylate) which is an organic mercury
compound that is commonly used as an antimicrobial preservative. In
this study, we show that thimerosal, at nanomolar concentrations,
induces neuronal cell death through the mitochondrial pathway.
Thimerosal, in a concentration- and time-dependent manner, decreased
cell viability as assessed by calcein-ethidium staining and caused
apoptosis detected by Hoechst 33258 dye. Thimerosal-induced
apoptosis was associated with depolarization of mitochondrial
membrane, generation of reactive oxygen species, and release of
cytochrome c and apoptosis-inducing factor (AIF) from mitochondria
to cytosol. Although thimerosal did not affect cellular expression
of Bax at the protein level, we observed translocation of Bax from
cytosol to mitochondria. Finally, caspase-9 and caspase-3 were
activated in the absence of caspase-8 activation. Our data suggest
that thimerosal causes apoptosis in neuroblastoma cells by changing
the mitochondrial microenvironment.
Mitochondrial
mediated thimerosal-induced apoptosis in a human neuroblastoma cell
line (SK-N-SH).
Neurotoxicology.
2005
Humphrey
ML, Cole MP, Pendergrass JC, Kiningham KK. Department of
Pharmacology, Joan C. Edwards School of Medicine, Marshall
University, Huntington, WV 25704-9388, USA.
Environmental
exposure to mercurials continues to be a public health issue due to
their deleterious effects on immune, renal and neurological
function. Recently the safety of thimerosal, an ethyl
mercury-containing preservative used in vaccines, has been
questioned due to exposure of infants during immunization.
Mercurials have been reported to cause apoptosis in cultured
neurons; however, the signaling pathways resulting in cell death
have not been well characterized. Therefore, the objective of this
study was to identify the mode of cell death in an in vitro model of
thimerosal-induced neurotoxicity, and more specifically, to
elucidate signaling pathways which might serve as pharmacological
targets. Within 2 h of thimerosal exposure (5 microM) to the human
neuroblastoma cell line, SK-N-SH, morphological changes, including
membrane alterations and cell shrinkage, were observed. Cell
viability, assessed by measurement of lactate dehydrogenase (LDH)
activity in the medium, as well as the
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)
assay, showed a time- and concentration-dependent decrease in cell
survival upon thimerosal exposure. In cells treated for 24 h with
thimerosal, fluorescence microscopy indicated cells undergoing both
apoptosis and oncosis/necrosis. To identify the apoptotic pathway
associated with thimerosal-mediated cell death, we first evaluated
the mitochondrial cascade, as both inorganic and organic mercurials
have been reported to accumulate in the organelle. Cytochrome c was
shown to leak from the mitochondria, followed by caspase 9 cleavage
within 8 h of treatment. In addition, poly(ADP-ribose) polymerase
(PARP) was cleaved to form a 85 kDa fragment following maximal
caspase 3 activation at 24 h. Taken together these findings suggest
deleterious effects on the cytoarchitecture by thimerosal and
initiation of mitochondrial-mediated apoptosis.
Possible
Immunological Disorders in Autism: Concomitant Autoimmunity and
Immune Tolerance
The
Egyptian Journal of Immunology, 2006
Maha
I. Sh. Kawashti, Omnia R. Amin Nadia G. Rowehy
Microbiology
Department, Faculty of Medicine (For Girls), Al Azhar University,
Cairo, Egypt, Psychiatry Department, Faculty of Medicine, Cairo
University, Cairo, Egypt and Serology Lab King Fahad General
Hospital, Jeddah, K.S.A.
Abstract:
Autism is a pervasive developmental disorder that affect children
early in their life. Immunological disorders is one of several
contributing factors that have been suggested to cause autism.
Thirty autistic children aged 3-6 years and thirty non-autistic
psychologically-free siblings were studied. Circulating IgA and IgG
autoantibodies to casein and gluten dietary proteins were detected
by enzyme-immunoassays (EIA). Circulating IgG antibodies to measles,
mumps and rubella vaccine (M.M.R) and cytomeglovirus were
investigated by EIA. Results revealed high seropositivity for
autoantibodies to casein and gluten: 83.3% and 50% respectively in
autistic children as compared to 10% and 6.7% positivity in the
control group. Surprisingly, circulating anti-measles, anti-mumps
and anti-rubella IgG were positive in only 50%, 73.3% and 53.3%
respectively as compared to 100% positivity in the control group.
Anti-CMV IgG was positive in 43.3% of the autistic children as
compared to 7% in the control group. It
is concluded that, autoimmune response to dietary proteins and
deficient immune response to measles, mumps and rubella vaccine
antigens might be associated with autism, as a leading cause or a
resulting event.
Further research is needed to confirm these findings.
Pediatric
Vaccines Influence Primate Behavior, and Amygdala Growth and Opioid
Ligand Binding
Friday, May 16, 2008: IMFAR
L.
Hewitson , Obstetrics, Gynecology and Reproductive Sciences,
University of Pittsburgh, Pittsburgh, PA B. Lopresti , Radiology,
University of Pittsburgh, Pittsburgh, PA C. Stott , Thoughtful House
Center for Children, Austin, TX J. Tomko , Pittsburgh Development
Center, University of Pittsburgh, Pittsburgh, PA L. Houser ,
Pittsburgh Development Center, University of Pittsburgh, Pittsburgh,
PA E. Klein , Division of Laboratory Animal Resources, University of
Pittsburgh, Pittsburgh, PA C. Castro , Obstetrics, Gynecology and
Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA G.
Sackett , Psychology, Washington National Primate Research Center,
Seattle, WA S. Gupta , Medicine, Pathology & Laboratory
Medicine, University of California - Irvine, Irvine, CA D. Atwood ,
Chemistry, University of Kentucky, Lexington, KY L. Blue ,
Chemistry, University of Kentucky, Lexington, KY E. R. White ,
Chemistry, University of Kentucky, Lexington, KY A. Wakefield ,
Thoughtful House Center for Children, Austin,
TX
Abstract
Background:
Macaques are commonly used in pre-clinical vaccine safety testing,
but the combined childhood vaccine regimen, rather than individual
vaccines, has not been studied. Childhood vaccines are a possible
causal factor in autism, and abnormal behaviors and anomalous
amygdala growth are potentially inter-related features of this
condition.
Objectives:
The objective of this study was to compare early infant cognition
and behavior with amygdala size and opioid binding in rhesus
macaques receiving the recommended childhood vaccines (1994-1999),
the majority of which contained the bactericidal preservative
ethylmercurithiosalicylic acid (thimerosal).
Methods:
Macaques were administered the recommended infant vaccines, adjusted
for age and thimerosal dose (exposed; N=13), or saline (unexposed;
N=3). Primate development, cognition and social behavior were
assessed for both vaccinated and unvaccinated infants using
standardized tests developed at the Washington National Primate
Research Center. Amygdala growth and binding were measured serially
by MRI and by the binding of the non-selective opioid antagonist
[11C]diprenorphine, measured by PET, respectively, before (T1) and
after (T2) the administration of the measles-mumps-rubella vaccine
(MMR).
Results:
Compared
with unexposed animals, significant neurodevelopmental deficits were
evident for exposed animals in survival reflexes, tests of color
discrimination and reversal, and learning sets. Differences in
behaviors were observed between exposed and unexposed animals and
within the exposed group before and after MMR vaccination. Compared
with unexposed animals, exposed animals showed attenuation of
amygdala growth and differences in the amygdala binding of
[11C]diprenorphine. Interaction models identified significant
associations between specific aberrant social and non-social
behaviors, isotope binding, and vaccine exposure.
Conclusions:
This
animal model, which examines for the first time, behavioral,
functional, and neuromorphometric consequences of the childhood
vaccine regimen, mimics certain neurological abnormalities of
autism. The findings raise important safety issues
while
providing a potential model for examining aspects of causation and
disease pathogenesis in acquired disorders of behavior and
development.
Thimerosal
exposure in infants and neurodevelopmental disorders: An assessment
of computerized medical records in the Vaccine Safety
Datalink.
Young
HA, Geier DA, Geier MR.
The
George Washington University School of Public Health and Health
Services, Department of Epidemiology and Biostatistics, United
States.
Abstract
The
study evaluated possible associations between neurodevelopmental
disorders (NDs) and exposure to mercury (Hg) from
Thimerosal-containing vaccines (TCVs) by examining the automated
Vaccine Safety Datalink (VSD). A total of 278,624 subjects were
identified in birth cohorts from 1990-1996 that had received their
first oral polio vaccination by 3 months of age in the VSD. The
birth cohort prevalence rate of medically diagnosed International
Classification of Disease, 9th revision (ICD-9) specific NDs and
control outcomes were calculated. Exposures to Hg from TCVs were
calculated by birth cohort for specific exposure windows from
birth-7 months and birth-13 months of age. Poisson regression
analysis was used to model the association between the prevalence of
outcomes and Hg doses from TCVs.
Consistent
significantly increased rate ratios were observed for autism, autism
spectrum disorders, tics, attention deficit disorder, and emotional
disturbances with Hg exposure from TCVs.
By
contrast, none of the control outcomes had significantly increased
rate ratios with Hg exposure from TCVs. Routine childhood
vaccination should be continued to help reduce the morbidity and
mortality associated with infectious diseases, but efforts should be
undertaken to remove Hg from vaccines. Additional studies should be
conducted to further evaluate the relationship between Hg exposure
and NDs.
Glutathione,
oxidative stress and neurodegeneration
Schulz
JB, Lindenau J, Seyfried J, Dichgans J.
Neurodegeneration
Laboratory, Department of Neurology, University of Tübingen,
Germany.
Eur
J Biochem. 2000 Aug;267(16):4904-11.
Abstract
There
is significant evidence that the pathogenesis of several
neurodegenerative diseases, including Parkinson's disease,
Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral
sclerosis, may involve the generation of reactive oxygen species and
mitochondrial dysfunction.
Here,
we review the evidence for a disturbance of glutathione homeostasis
that may either lead to or result from oxidative stress in
neurodegenerative disorders. Glutathione is an important
intracellular antioxidant that protects against a variety of
different antioxidant species. An important role for glutathione was
proposed for the pathogenesis of Parkinson's disease, because a
decrease in total glutathione concentrations in the substantia nigra
has been observed in preclinical stages, at a time at which other
biochemical changes are not yet detectable. Because glutathione does
not cross the blood-brain barrier other treatment options to
increase brain concentrations of glutathione including glutathione
analogs, mimetics or precursors are discussed.
Hepatitis
B triple series vaccine and developmental disability in US children
aged 1-9 years
Carolyn
Gallagher a; Melody Goodman, Graduate Program in Public Health,
Stony Brook University Medical Center, Health Sciences Center, New
York, USA
Journal Toxicological & Environmental
Chemistry, Volume 90, Issue 5 September 2008 , pages 997 -
1008
Abstract
This study investigated the association
between vaccination with the Hepatitis B triple series vaccine prior
to 2000 and developmental disability in children aged 1–9 years (n
= 1824), proxied by parental report that their child receives early
intervention or special education services (EIS). National Health
and Nutrition Examination Survey 1999–2000 data were analyzed and
adjusted for survey design by Taylor Linearization using SAS version
9.1 software, with SAS callable SUDAAN version 9.0.1. The odds of
receiving EIS were approximately nine times as great for vaccinated
boys (n = 46) as for unvaccinated boys (n = 7), after adjustment for
confounders. This
study found statistically significant evidence to suggest that boys
in United States who were vaccinated with the triple series
Hepatitis B vaccine, during the time period in which vaccines were
manufactured with thimerosal, were more susceptible to developmental
disability than were unvaccinated boys.
IL-4
mediates the delayed neurobehavioral impairments induced by
neonatal
hepatitis B vaccination that involves the down-regulation of the IL4
receptor
in the hippocampus
Cytokine
Xiao
Wang, Junhua Yang, Zhiwei Xing, Hongyang Zhang, Yaru Wen, Fangfang
Qi, Zejie Zuo, Jie Xu, Zhibin Yao
Department
of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun
Yat-sen University, PR China
Guangdong
Province Key Laboratory of Brain Function and Disease, Zhongshan
School of Medicine, Sun Yat-sen University, PR China
ABSTRACT
We
have previously verified that neonatal hepatitis B vaccination
induced hippocampal neuroinflammation and behavior impairments in
mice. However, the exact mechanism of these effects remain unclear.
In this study, we observed that neonatal hepatitis B vaccination
induced an anti-inflammatory cytokine response lasting for 4–5
weeks in both the serum and the hippocampus, primarily indicated by
elevated IL-4 levels. Three weeks after the vaccination schedule,
however, hepatitis B vaccine (HBV)-mice showed delayed hippocampal
neuroinflammation. In periphery, IL-4 is the major cytokine induced
by this vaccine. Correlation analyses showed a positive relationship
in the IL-4 levels between serum and hippocampus in HBV-mice. Thus,
we investigated whether neonatal over-exposure to systemic IL-4
influences brain and behavior. We observed that mice injected
intraperitoneally with recombinant mouse IL-4 (mIL-4) during early
life had similar neuroinflammation and cognition impairment similar
to those induced by neonatal hepatitis B vaccination. Next, the
mechanism underlying the effects of IL-4 on brain in mice was
explored using a series of experiments. In brief,
these experiments showed that IL-4 mediates the delayed
neurobehavioral impairments induced by neonatal hepatitis B
vaccination, which involves the permeability of neonatal blood–brain
barrier and the down-regulation of IL-4 receptor. This
finding suggests that clinical events concerning neonatal IL-4
over-exposure, including neonatal hepatitis B vaccination and
allergic asthma in human infants, may have adverse implications for
brain development and cognition.
The
risk of neurodevelopmental disorders at age 10 years associated
with blood concentrations of interleukins 4 and 10 during the first
postnatal month of children born extremely preterm.
Cytokine.
2018 May 12;110:181-188. doi: 10.1016/j.cyto.2018.05.004.
Leviton
A, Joseph RM, Allred EN, Fichorova RN, O'Shea TM, Kuban KKC, Dammann
O7.
Boston
Children's Hospital and Harvard Medical School, Boston, MA, USA.
Electronic address: alan.leviton@childrens.harvard.edu.
Boston
University School of Medicine, Boston, MA, USA.
Boston
Children's Hospital and Harvard Medical School, Boston, MA, USA.
Brigham
and Women's Hospital and Harvard Medical School, Boston, MA 02115,
USA.
University
of North Carolina School of Medicine, Chapel Hill, NC, USA.
Boston
Medical Center and Boston University School of Medicine, Boston, MA,
USA.
Tufts
University School of Medicine, Boston, MA 02111, USA; Perinatal
Neuroepidemiology Unit, Department of Gynecology and Obstetrics,
Hannover Medical School, 30623 Hannover, Germany
Abstract
BACKGROUND:
Interleukin
(IL)-4 and IL-10 are viewed mainly as anti-inflammatory cytokines.
Yet, high concentrations have also been associated with
inflammation-related diseases in newborns.
METHODS:
We
measured the concentrations of IL-4 and IL-10, as well as IL-8 and
ICAM-1 in blood specimens collected on postnatal day 21 (N = 555),
day 28 (N = 521), and both days 21 and 28 (N = 449) from
children born extremely preterm (EP) (<28 weeks gestation) who
at age 10 years had a DAS-II IQ Z-score > -2 (which
approximates a score of >70) and the following assessments,
CCC-2, and CSI-4, DAS-II, NEPSY-II, OWLS-II, SCQ, and WIAT-III.
Selected children also were assessed with the ADI-R and the ADOS-2.
We modeled the risk of low scores or dysfunctions associated with
top quartile concentrations of IL-4 and IL-10 on each day and on
both days.
RESULTS:
The
risks of low scores on the Animal Sorting and Arrows components of
the NEPSY-II, both components of the OWLS-II, and the PseudoWord and
Spelling components of the WIAT-III were heightened among children
who had top quartile concentrations of IL-4 on postnatal days 21 and
28. Children who had high concentrations of IL-10 on days 21 and 28,
individually and collectively, were at increased risk of low scores
on the WIAT-III Spelling component. High concentrations of IL-4 on
day 28 were associated with autism spectrum disorder (ASD). High
concentrations of IL-10 on day 28 were also associated with a
doubling of ASD risk, but this did not achieve statistical
significance. Top quartile concentrations of IL-4 and IL10 on both
days were not associated with increased risk of social, language, or
behavioral dysfunctions.
CONCLUSION:
Among
children born EP, those who had top quartile concentrations of IL-4
and/or IL-10 on postnatal days 21 and/or 28 were more likely than
their peers to have low scores on components of the NEPSY-II,
OWLS-II, and WIAT-III assessments, as well as identification as
having an ASD.
Induction
of metallothionein in mouse cerebellum and cerebrum with low-dose
thimerosal injection.
Minami
T, Miyata E, Sakamoto Y, Yamazaki H, Ichida S., Department of Life
Sciences, School of Science & Engineering, Kinki University,
3-4-1 Kowakae, Higashi-osaka, Osaka, 577-8502, Japan,
minamita@life.kindai.ac.jp.
Cell
Biology and Toxicology. 2009 Apr 9. [Epub ahead of
print]
Abstract
Thimerosal,
an ethyl mercury compound, is used worldwide as a vaccine
preservative. We previously observed that the mercury concentration
in mouse brains did not increase with the clinical dose of
thimerosal injection, but the concentration increased in the brain
after the injection of thimerosal with lipopolysaccharide, even if a
low dose of thimerosal was administered. Thimerosal may penetrate
the brain, but is undetectable when a clinical dose of thimerosal is
injected; therefore, the induction of metallothionein (MT) messenger
RNA (mRNA) and protein was observed in the cerebellum and cerebrum
of mice after thimerosal injection, as MT is an inducible protein.
MT-1 mRNA was expressed at 6 and 9 h in both the cerebrum and
cerebellum, but MT-1 mRNA expression in the cerebellum was three
times higher than that in the cerebrum after the injection of 12
microg/kg thimerosal. MT-2 mRNA was not expressed until 24 h in both
organs. MT-3 mRNA was expressed in the cerebellum from 6 to 15 h
after the injection, but not in the cerebrum until 24 h. MT-1 and
MT-3 mRNAs were expressed in the cerebellum in a dose-dependent
manner. Furthermore, MT-1 protein was detected from 6 to 72 h in the
cerebellum after 12 microg/kg of thimerosal was injected and peaked
at 10 h. MT-2 was detected in the cerebellum only at 10 h. In the
cerebrum, little MT-1 protein was detected at 10 and 24 h, and there
were no peaks of MT-2 protein in the cerebrum. In conclusion, MT-1
and MT-3 mRNAs but not MT-2 mRNA are easily expressed in the
cerebellum rather than in the cerebrum by the injection of low-dose
thimerosal. It is thought that the cerebellum is a sensitive organ
against thimerosal.
As
a result of the present findings, in combination with the brain
pathology observed in patients diagnosed with autism, the present
study helps to support the possible biological plausibility for how
low-dose exposure to mercury from thimerosal-containing vaccines may
be associated with autism.
Mercury
induces inflammatory mediator release from human mast
cells
Duraisamy
Kempuraj, Shahrzad Asadi, Bodi Zhang, Akrivi Manola, Jennifer Hogan,
Erika
Peterson, Theoharis C Theoharides
Journal
of Neuroinflammation 2010, 7:20
doi:10.1186/1742-2094-7-20
Abstract
Background:
Mercury is known to be neurotoxic, but its effects on the immune
system are less well known. Mast cells are involved in allergic
reactions, but also in innate and acquired immunity, as well as in
inflammation. Many patients with Autism Spectrum Disorders (ASD)
have “allergic” symptoms; moreover, the prevalence of ASD in
patients with mastocytosis, characterized by numerous hyperactive
mast cells in most tissues, is 10-fold higher than the general
population suggesting mast cell involvement. We, therefore,
investigated the effect of mercuric chloride (HgCl2) on human mast
cell activation.
Methods:
Human leukemic cultured LAD2 mast cells and normal human umbilical
cord bloodderived cultured mast cells (hCBMCs) were stimulated by
HgCl2 (0.1-10 μM) for either 10 min for beta-hexosaminidase release
or 24 hr for measuring vascular endothelial growth factor (VEGF) and
IL-6 release by ELISA.
Results:
HgCl2 induced a 2-fold increase in β-hexosaminidase release, and
also significant VEGF release at 0.1 and 1 μM (311±32 pg/106 cells
and 443±143 pg/106 cells, respectively) from LAD2 mast cells
compared to control cells (227±17 pg/106 cells, n=5, p<0.05).
Addition of HgCl2 (0.1 μM) to the proinflammatory neuropeptide
substance P (SP, 0.1 μM) had synergestic action in inducing VEGF
from LAD2 mast cells. HgCl2 also stimulated significant VEGF release
(360 ± 100 pg/106 cells at 1 μM, n=5, p<0.05) from hCBMCs
compared to control cells (182 ±57 pg/106 cells), and IL-6 release
(466±57 pg/106 cells at 0.1 μM) compared to untreated cells (13±25
pg/106 cells, n=5, p<0.05). Addition of HgCl2 (0.1 μM) to SP (5
μM) further increased IL-6 release. Conclusions: HgCl2 stimulates
VEGF and IL-6 release from human mast cells.
This
phenomenon could disrupt the blood-brain-barrier and permit brain
inflammation. As a result, the findings of the present study provide
a biological mechanism for how low levels of mercury may contribute
to ASD pathogenesis.
Brain
enlargement is associated with regression in preschool-age boys with
autism spectrum disorders
Neuroscience
Medical
Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute
and Department of Psychiatry and Behavioral Sciences, UC Davis
School of Medicine, University of California, Sacramento, CA 95817;
Departments
of Psychiatry and Biostatistics, Harvard University Schools of
Medicine and Public Health, McLean Hospital, Belmont, MA 02478; and
Department
of Radiology, UC Davis School of Medicine, University of California,
Sacramento, CA 95817
Proc
Natl Acad Sci U S A. 2011 Dec 13; 108(50): 20195–20200.
Published
online 2011 Nov 28. doi: 10.1073/pnas.1107560108
Christine
Wu Nordahl, Nicholas Lange, Deana D. Li, Lou Ann Barnett, Aaron Lee,
Michael H. Buonocore, Tony J. Simon, Sally Rogers, Sally Ozonoff,
and David G. Amarala,
ABSTRACT
Autism
is a heterogeneous disorder with multiple behavioral and biological
phenotypes. Accelerated brain growth during early childhood is a
well-established biological feature of autism. Onset pattern, i.e.,
early onset or regressive, is an intensely studied behavioral
phenotype of autism. There is currently little known, however, about
whether, or how, onset status maps onto the abnormal brain growth.
We examined the relationship between total brain volume and onset
status in a large sample of 2- to 4-y-old boys and girls with autism
spectrum disorder (ASD) [n = 53, no regression (nREG); n = 61,
regression (REG)] and a comparison group of age-matched typically
developing controls (n = 66). We also examined retrospective head
circumference measurements from birth through 18 mo of age. We
found that abnormal brain enlargement was most commonly found in
boys with regressive autism. Brain size in boys without regression
did not differ from controls. Retrospective
head circumference measurements indicate that head circumference in
boys with regressive autism is normal at birth but diverges from the
other groups around 4–6 mo of age. There were no differences in
brain size in girls with autism (n = 22, ASD; n = 24, controls).
These
results suggest that there may be distinct neural phenotypes
associated with different onsets of autism.
For boys with regressive autism, divergence in brain size occurs
well before loss of skills is commonly reported. Thus, rapid head
growth may be a risk factor for regressive autism.
Blood–brain
barrier and intestinal epithelial barrier alterations in autism
spectrum disorders
Molecular
AutismBrain, Cognition and Behavior, Published: 29 November 2016
Maria
Fiorentino, Anna Sapone, Stefania Senger, Stephanie S. Camhi, Sarah
M. Kadzielski, Timothy M. Buie, Deanna L. Kelly, Nicola Cascella and
Alessio Fasano
Abstract
Background
Autism
spectrum disorders (ASD) are complex conditions whose pathogenesis
may be attributed to gene–environment interactions. There are no
definitive mechanisms explaining how environmental triggers can lead
to ASD although the involvement of inflammation and immunity has
been suggested. Inappropriate antigen trafficking through an
impaired intestinal barrier, followed by passage of these antigens
or immune-activated complexes through a permissive blood–brain
barrier (BBB), can be part of the chain of events leading to these
disorders. Our goal was to investigate whether an altered BBB and
gut permeability is part of the pathophysiology of ASD.
Methods
Postmortem
cerebral cortex and cerebellum tissues from ASD, schizophrenia
(SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and
HC were analyzed for gene and protein expression profiles. Tight
junctions and other key molecules associated with the neurovascular
unit integrity and function and neuroinflammation were investigated.
Results
Claudin
(CLDN)-5 and -12 were increased in the ASD cortex and cerebellum.
CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8,
tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased
in the SCZ cerebellum. Differences between SCZ and ASD were observed
for most of the genes analyzed in both brain areas. CLDN-5 protein
was increased in ASD cortex and cerebellum, while CLDN-12 appeared
reduced in both ASD and SCZ cortexes. In the intestine, 75% of the
ASD samples analyzed had reduced expression of barrier-forming TJ
components (CLDN-1, OCLN, TRIC), whereas 66% had increased
pore-forming CLDNs (CLDN-2, -10, -15) compared to controls.
Conclusions
In
the ASD brain, there is an altered expression of genes associated
with BBB integrity coupled with increased neuroinflammation and
possibly impaired gut barrier integrity. While
these findings seem to be specific for ASD, the possibility of more
distinct SCZ subgroups should be explored with additional
studies.
Influence
of pediatric vaccines on amygdala growth and opioid ligand binding
in rhesus macaque infants: A pilot study
Acta
Neurobiol Exp 2010, 70: 147–164 Polish Neuroscience Society -
PTBUN, Nencki Institute of Experimental Biology
Laura
Hewitson1,2,*, Brian J. Lopresti3, Carol Stott4, N. Scott Mason3 and
Jaime Tomko1
Department
of Obstetrics and Gynecology, University of Pittsburgh School of
Medicine, Pittsburgh, PA, USA; Thoughtful House Center for Children,
Austin, TX, USA; Department of Radiology, University of Pittsburgh
School of Medicine, Pittsburgh, PA, USA; 4Independent Chartered
Scientist, Cambridge, UK;
Abstract
This
longitudinal, case-control pilot study examined amygdala growth in
rhesus macaque infants receiving the complete US childhood vaccine
schedule (1994-1999). Longitudinal structural and functional
neuroimaging was undertaken to examine central effects of the
vaccine regimen on the developing brain. Vaccine-exposed and
saline-injected control infants underwent MRI and PET imaging at
approximately 4 and 6 months of age, representing two specific
timeframes within the vaccination schedule. Volumetric analyses
showed that exposed animals did not undergo the maturational changes
over time in amygdala volume that was observed in unexposed animals.
After controlling for left amygdala volume, the binding of the
opioid antagonist [11C]diprenorphine (DPN) in exposed animals
remained relatively constant over time, compared with unexposed
animals, in which a significant decrease in [11C]DPN binding
occurred.
These
results suggest that maturational changes in amygdala volume and the
binding capacity of [11C]DPN in the amygdala was significantly
altered in infant macaques receiving the vaccine schedule. The
macaque infant is a relevant animal model in which to investigate
specific environmental exposures and structural/functional
neuroimaging during neurodevelopment.
Cultured
lymphocytes from autistic children and non-autistic siblings
up-regulate heat shock protein RNA in response to thimerosal
challenge.
Neurotoxicology.
2006 Sep;27(5):685-92. Epub 2006 Jun 16.
Walker
SJ, Segal J, Aschner M.
Department
of Physiology and Pharmacology, Wake Forest University School of
Medicine, Winston-Salem, NC 27156, USA.
swalker@wfubmc.edu
Abstract
Abstract
There
are reports suggesting that some autistic children are unable to
mount an adequate response following exposure to environmental
toxins. This potential deficit, coupled with the similarity in
clinical presentations of autism and some heavy metal toxicities,
has led to the suggestion that heavy metal poisoning might play a
role in the etiology of autism in uniquely susceptible individuals.
Thimerosal, an anti-microbial preservative previously added
routinely to childhood multi-dose vaccines, is composed of 49.6%
ethyl mercury. Based on the levels of this toxin that children
receive through routine immunization schedules in the first years of
life, it has been postulated that thimerosal may be a potential
triggering mechanism contributing to autism in susceptible
individuals. One potential risk factor in these individuals may be
an inability to adequately up-regulate metallothionein (MT)
biosynthesis in response to presentation of a heavy metal challenge.
To investigate this hypothesis, cultured lymphocytes (obtained from
the Autism Genetic Resource Exchange, AGRE) from autistic children
and non-autistic siblings were challenged with either 10 microM
ethyl mercury, 150 microM zinc, or fresh media (control). Following
the challenge, total RNA was extracted and used to query "whole
genome" DNA microarrays. Cultured lymphocytes challenged with
zinc responded with an impressive up-regulation of MT transcripts
(at least nine different MTs were over-expressed)
while
cells challenged with thimerosal responded by up-regulating numerous
heat shock protein transcripts, but not MTs. Although there were no
apparent differences between autistic and non-autistic sibling
responses in this very small sampling group, the differences in
expression profiles between those cells treated with zinc versus
thimerosal were dramatic.
Determining
cellular response, at the level of gene expression, has important
implications for the understanding and treatment of conditions that
result from exposure to neurotoxic compounds.
Sorting
out the spinning of autism: heavy metals and the question of
incidence
Acta
Neurobiol Exp 2010, 70: 165–176
Mary
Catherine DeSoto* and Robert T. Hitlan, Department of Psychology,
University of Northern Iowa, Cedar Falls, Iowa, USA
The
reasons for the rise in autism prevalence are a subject of heated
professional debate. Featuring a critical appraisal of some research
used to question whether there is a rise in cases and if rising
levels of autism are related to environmental
exposure
to toxins (Soden et al. 2007, Thompson et al. 2007, Barbaresi et al.
2009) we aim to evaluate the actual state of scientific knowledge.
In addition, we surveyed the empirical research on the topic of
autism and heavy metal toxins. Overall, the various causes that have
led to the increase in autism diagnosis are likely multi-faceted,
and understanding the causes is one of the most important health
topics today. We argue that scientific research does not support
rejecting the link between the neurodevelopmental disorder of autism
and toxic exposures.
Urinary
Porphyrin Excretion in Neurotypical and Autistic Children
Environ
Health Perspect. 2010 Oct;118(10):1450-7. Epub 2010 Jun 24.
Woods
JS, Armel SE, Fulton DI, Allen J, Wessels K, Simmonds PL,
Granpeesheh D, Mumper E, Bradstreet JJ, Echeverria D, Heyer NJ,
Rooney JP., Department of Environmental and Occupational Health
Sciences, University of Washington
Abstract
BACKGROUND:
Increased urinary concentrations of pentacarboxyl-, precopro- and
copro-porphyrins have been associated with prolonged mercury (Hg)
exposure in adults, and comparable increases have been attributed to
Hg exposure in children with autism (AU).
OBJECTIVES:
This study was designed to measure and compare urinary porphyrin
concentrations in neurotypical (NT) children and same-age children
with autism, and to examine the association between porphyrin levels
and past or current Hg exposure in children with autism.
METHODS:
This exploratory study enrolled 278 children 2-12 years of age. We
evaluated three groups: AU, pervasive developmental disorder-not
otherwise specified (PDD-NOS), and NT. Mothers/caregivers provided
information at enrollment regarding medical, dental, and dietary
exposures. Urine samples from all children were acquired for
analyses of porphyrin, creatinine, and Hg. Differences between
groups for mean porphyrin and Hg levels were evaluated. Logistic
regression analysis was conducted to determine whether porphyrin
levels were associated with increased risk of autism.
RESULTS:
Mean urinary porphyrin concentrations are naturally high in young
children and decline by as much as 2.5-fold between 2 and 12 years
of age. Elevated copro- (p < 0.009), hexacarboxyl- (p < 0.01)
and pentacarboxyl- (p < 0.001) porphyrin concentrations were
significantly associated with AU but not with PDD-NOS. No
differences were found between NT and AU in urinary Hg levels or in
past Hg exposure as determined by fish consumption, number of dental
amalgam fillings, or vaccines received. CONCLUSIONS:These
findings identify disordered porphyrin metabolism as a salient
characteristic of autism.
Hg
exposures were comparable between diagnostic groups, and a porphyrin
pattern consistent with that seen in Hg-exposed adults was not
apparent.
Mitochondrial
dysfunction in autism spectrum disorders: a systematic review and
meta-analysis
Molecular
Psychiatry advance online publication 25 January 2011;doi:
10.1038/mp.2010.136
D
A Rossignol and R E Frye
Abstract
A
comprehensive literature search was performed to collate evidence of
mitochondrial dysfunction in autism spectrum disorders (ASDs) with
two primary objectives. First, features of mitochondrial dysfunction
in the general population of children with ASD were identified.
Second, characteristics of mitochondrial dysfunction in children
with ASD and concomitant mitochondrial disease (MD) were compared
with published literature of two general populations: ASD children
without MD, and non-ASD children with MD. The prevalence of MD in
the general population of ASD was 5.0% (95% confidence interval 3.2,
6.9%), much higher than found in the general population (~0.01%).
The prevalence of abnormal biomarker values of mitochondrial
dysfunction was high in ASD, much higher than the prevalence of MD.
Variances and mean values of many mitochondrial biomarkers (lactate,
pyruvate, carnitine and ubiquinone) were significantly different
between ASD and controls. Some markers correlated with ASD severity.
Neuroimaging, in vitro and post-mortem brain studies were consistent
with an elevated prevalence of mitochondrial dysfunction in ASD.
Taken together, these findings suggest children with ASD have a
spectrum of mitochondrial dysfunction of differing severity.
Eighteen publications representing a total of 112 children with ASD
and MD (ASD/MD) were identified. The prevalence of developmental
regression (52%), seizures (41%), motor delay (51%),
gastrointestinal abnormalities (74%), female gender (39%), and
elevated lactate (78%) and pyruvate (45%) was significantly higher
in ASD/MD compared with the general ASD population. The prevalence
of many of these abnormalities was similar to the general population
of children with MD, suggesting that ASD/MD represents a distinct
subgroup of children with MD. Most ASD/MD cases (79%) were not
associated with genetic abnormalities, raising the possibility of
secondary mitochondrial dysfunction. Treatment studies for ASD/MD
were limited, although improvements were noted in some studies with
carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from
limitations, including small sample sizes, referral or publication
biases, and variability in protocols for selecting children for MD
workup, collecting mitochondrial biomarkers and defining MD.
Overall,
this evidence supports the notion that mitochondrial dysfunction is
associated with ASD.
Additional
studies are needed to further define the role of mitochondrial
dysfunction in ASD.
Sensitization
effect of thimerosal is mediated in vitro via reactive oxygen
species and calcium signaling.
Toxicology.
2010 July - August;274(1-3):1-9. Epub 2010 May 10.
Migdal
C, Foggia L, Tailhardat M, Courtellemont P, Haftek M, Serres
M.
Thimerosal,
a mercury derivative composed of ethyl mercury chloride (EtHgCl) and
thiosalicylic acid (TSA), is widely used as a preservative in
vaccines and cosmetic products and causes cutaneous reactions. Since
dendritic cells (DCs) play an essential role in the immune response,
the sensitization potency of chemicals was studied in vitro using
U937, a human promyelomonocytic cell line that is used as a
surrogate of monocytic differentiation and activation. Currently,
this cell line is under ECVAM (European Center for the Validation of
Alternative Methods) validation as an alternative method for
discriminating chemicals. Thimerosal and mercury derivatives induced
in U937 an overexpression of CD86 and interleukin (IL)-8 secretion
similarly to 1-chloro-2,4-dinitrobenzene (DNCB), a sensitizer used
as a positive control for DC activation. Non-sensitizers,
dichloronitrobenzene (DCNB), TSA and sodium dodecyl sulfate (SDS),
an irritant, had no effect. U937 activation was prevented by cell
pretreatment with N-acetyl-l-cysteine (NAC) but not with
thiol-independent antioxidants except vitamin E which affected CD86
expression by preventing lipid peroxidation of cell membranes.
Thimerosal, EtHgCl and DNCB induced glutathione (GSH) depletion and
reactive oxygen species (ROS) within 15min; another peak was
detected after 2h for mercury compounds only. MitoSOX, a specific
mitochondrial fluorescent probe, confirmed that ROS were essentially
produced by mitochondria in correlation with its membrane
depolarization. Changes in mitochondrial membrane permeability
induced by mercury were reversed by NAC but not by thiol-independent
antioxidants. Thimerosal and EtHgCl also induced a calcium (Ca(2+))
influx with a peak at 3h, suggesting that Ca(2+) influx is a
secondary event following ROS induction as Ca(2+) influx was
suppressed after pretreatment with NAC but not with
thiol-independent antioxidants. Ca(2+) influx was also suppressed
when culture medium was deprived of Ca(2+) confirming the
specificity of the measure.
In
conclusion, these data suggest that thimerosal induced U937
activation via oxidative stress from mitochondrial stores and
mitochondrial membrane depolarization with a primordial effect of
thiol groups.
A
cross-talk between ROS and Ca(2+) influx was demonstrated.
What's
going on? The question of time trends in autism.
Public
Health Rep. 2004 Nov-Dec;119(6):536-51.
Blaxill
MF.
Abstract
Increases in the reported prevalence of
autism and autistic spectrum disorders in recent years have fueled
concern over possible environmental causes. The author reviews the
available survey literature and finds evidence of large increases in
prevalence in both the United States and the United Kingdom that
cannot be explained by changes in diagnostic criteria or
improvements in case ascertainment. Incomplete ascertainment of
autism cases in young child populations is the largest source of
predictable bias in prevalence surveys; however, this bias has, if
anything, worked against the detection of an upward trend in recent
surveys. Comparison of autism rates by year of birth for specific
geographies provides the strongest basis for trend assessment. Such
comparisons show large recent increases in rates of autism and
autistic spectrum disorders in both the U.S. and the U.K. Reported
rates of autism in the United States increased from < 3 per
10,000 children in the 1970s to > 30 per 10,000 children in the
1990s, a 10-fold increase. In the United Kingdom, autism rates rose
from < 10 per 10,000 in the 1980s to roughly 30 per 10,000 in the
1990s. Reported rates for the full spectrum of autistic disorders
rose from the 5 to 10 per 10,000 range to the 50 to 80 per 10,000
range in the two countries. A precautionary approach suggests that
the rising incidence of autism should be a matter of urgent public
concern.
Vaccines
and Autism
Laboratory
medicine, September 2002, number 9, volume 33
Bernard
Rimland, PhD, Woody McGinnis, MD
Autism Research Institute,
San Diego, CA
Excerpt: "Vaccinations
may be one of the triggers for autism. Substantial data demonstrate
immune abnormality in many autistic children consistent with
impaired resistance to infection, activation of inflammatory
response, and autoimmunity. Impaired resistance may predispose to
vaccine injury in autism."
Theoretical
aspects of autism: Causes—A review
Journal
of Immunotoxicology, January-March 2011, Vol. 8, No. 1 , Pages
68-79
Helen
V. Ratajczak, PhD
Autism,
a member of the pervasive developmental disorders (PDDs), has been
increasing dramatically since its description by Leo Kanner in 1943.
First estimated to occur in 4 to 5 per 10,000 children, the
incidence of autism is now 1 per 110 in the United States, and 1 per
64 in the United Kingdom, with similar incidences throughout the
world. Searching information from 1943 to the present in PubMed and
Ovid Medline databases, this review summarizes results that
correlate the timing of changes in incidence with environmental
changes. Autism could result from more than one cause, with
different manifestations in different individuals that share common
symptoms. Documented causes of autism include genetic mutations
and/or deletions, viral infections, and encephalitis following
vaccination.
Therefore,
autism is the result of genetic defects and/or inflammation of the
brain. The inflammation could be caused by a defective placenta,
immature blood-brain barrier, the immune response of the mother to
infection while pregnant, a premature birth, encephalitis in the
child after birth, or a toxic environment.
Preterm
birth, vaccination and neurodevelopmental disorders: a
cross-sectional study of 6- to 12-year-old vaccinated and
unvaccinated children
Anthony
R Mawson, Azad R Bhuiyan, Brian D Ray, Binu Jacob
Department
of Epidemiology and Biostatistics, School of Public Health, Jackson
State University, Jackson, MS 39213, USA
National
Home Education Research Institute, PO Box 13939, Salem, OR 97309,
USA
J
Transl Sci 3: DOI: 10.15761/JTS.1000187, April 24, 2017
Abstract
From
about 8% to 27% of extremely preterm infants develop symptoms of
autism spectrum disorder, but the causes are not well understood.
Preterm infants receive the same doses of the recommended vaccines
and on the same schedule as term infants. The possible role of
vaccination in neurodevelopmental disorders (NDD) among premature
infants is unknown, in part because pre-licensure clinical trials of
pediatric vaccines have excluded ex-preterm infants. This paper
explores the association between preterm birth, vaccination and NDD,
based on a secondary analysis of data from an anonymous survey of
mothers, comparing the birth history and health outcomes of
vaccinated and unvaccinated homeschool children 6 to 12 years of
age. A convenience sample of 666 children was obtained, of which 261
(39%) were unvaccinated, 7.5% had an NDD (defined as a learning
disability, Attention Deficit Hyperactivity Disorder and/or Autism
Spectrum Disorder), and 7.7% were born preterm. No
association was found between preterm birth and NDD in the absence
of vaccination, but vaccination was significantly associated with
NDD in children born at term (OR 2.7, 95% CI: 1.2, 6.0). However,
vaccination coupled with preterm birth was associated with
increasing odds of NDD, ranging from 5.4 (95% CI: 2.5, 11.9)
compared to vaccinated but non-preterm children, to 14.5 (95% CI:
5.4, 38.7) compared to children who were neither preterm nor
vaccinated.
The results of this pilot study suggest clues to the epidemiology
and causation of NDD but question the safety of current vaccination
practices for preterm infants. Further research is needed to
validate and investigate these associations in order to optimize the
impact of vaccines on children’s health.
Iatrogenic
exposure to mercury after hepatitis B vaccination in preterm infants
The
Journal of Pediatrics, Volume 136, Issue 5, May 2000, Pages 679–681
Gregory
V. Stajich, PharmD, Gaylord P. Lopez, PharmD, ABAT, Sokei W. Harry,
MBBS, MPH, William R. Sexson, MD
Mercer
University, Southern School of Pharmacy, Atlanta, Georgia; Georgia
Poison Center, Grady Health System, Atlanta; Georgia Poison Center,
Georgia Health System, Atlanta and Emory University, School of
Medicine, Atlanta, Georgia.
Thimerosal,
a derivative of mercury, is used as a preservative in hepatitis B
vaccines. We measured total mercury levels before and after the
administration of this vaccine in 15 preterm and 5 term infants.
Comparison of pre- and post-vaccination mercury levels showed a
significant increase in both preterm and term infants after
vaccination. Additionally,
post-vaccination mercury levels were significantly higher in preterm
infants as compared with term infants. Because
mercury is known to be a potential neurotoxin to infants, further
study of its pharmacodynamics is warranted.
Infants
born late/moderately preterm are at increased risk for a positive
autism screen at 2 years of age.
J
Pediatr. 2015 Feb;166(2):269-75.e3. doi:
10.1016/j.jpeds.2014.10.053. Epub 2014 Dec 2.
Guy
A1, Seaton SE2, Boyle EM2, Draper ES2, Field DJ2, Manktelow BN2,
Marlow N3, Smith LK2, Johnson S4.
1Department
of Health Sciences, University of Leicester, Leicester, United
Kingdom; School of Psychology, University of Warwick, Coventry,
United Kingdom.
2Department
of Health Sciences, University of Leicester, Leicester, United
Kingdom.
3Department
of Academic Neonatology, Institute for Women's Health, University
College London, London, United Kingdom.
4Department
of Health Sciences, University of Leicester, Leicester, United
Kingdom. Electronic address: sjj19@le.ac.uk.
Abstract
OBJECTIVES:
To
assess the prevalence of positive screens using the Modified
Checklist for Autism in Toddlers (M-CHAT) questionnaire and
follow-up interview in late and moderately preterm (LMPT; 32-36
weeks) infants and term-born controls.
STUDY
DESIGN:
Population-based
prospective cohort study of 1130 LMPT and 1255 term-born infants.
Parents completed the M-CHAT questionnaire at 2-years corrected age.
Parents of infants with positive questionnaire screens were followed
up with a telephone interview to clarify failed items. The M-CHAT
questionnaire was re-scored, and infants were classified as true or
false positives. Neurosensory, cognitive, and behavioral outcomes
were assessed using parent report.
RESULTS:
Parents
of 634 (57%) LMPT and 761 (62%) term-born infants completed the
M-CHAT questionnaire. LMPT infants had significantly higher risk of
a positive questionnaire screen compared with controls (14.5% vs
9.2%; relative risk [RR] 1.58; 95% CI 1.18, 2.11). After follow-up,
significantly more LMPT infants than controls had a true positive
screen (2.4% vs 0.5%; RR 4.52; 1.51, 13.56). This remained
significant after excluding infants with neurosensory impairments
(2.0% vs 0.5%; RR 3.67; 1.19, 11.3).
CONCLUSIONS:
LMPT
infants are at significantly increased risk for positive autistic
screen.
An M-CHAT follow-up interview is essential as screening for autism
spectrum disorders is especially confounded in preterm populations.
Infants with false positive screens are at risk for cognitive and
behavioral problems.
Preterm
birth and mortality and morbidity: a population-based
quasi-experimental study.
JAMA
Psychiatry. 2013 Nov;70(11):1231-40. doi:
10.1001/jamapsychiatry.2013.2107.
D'Onofrio
BM1, Class QA, Rickert ME, Larsson H, Långström N, Lichtenstein P.
Department
of Psychological and Brain Sciences, Indiana University-Bloomington.
Abstract
IMPORTANCE:
Preterm
birth is associated with increased mortality and morbidity. However,
previous studies have been unable to rigorously examine whether
confounding factors cause these associations rather than the harmful
effects of being born preterm.
OBJECTIVE:
To
estimate the extent to which the associations between early
gestational age and offspring mortality and morbidity are the result
of confounding factors by using a quasi-experimental design, the
sibling-comparison approach, and by controlling for statistical
covariates that varied within families.
DESIGN,
SETTING, AND PARTICIPANTS:
A
population-based cohort study, combining Swedish registries to
identify all individuals born in Sweden from 1973 to 2008 (3,300,708
offspring of 1,736,735 mothers) and link them with multiple
outcomes.
MAIN
OUTCOMES AND MEASURES:
Offspring
mortality (during infancy and throughout young adulthood) and
psychiatric (psychotic or bipolar disorder, autism,
attention-deficit/hyperactivity disorder, suicide attempts,
substance use, and criminality), academic (failing grades and
educational attainment), and social (partnering, parenthood, low
income, and social welfare benefits) outcomes through 2009.
RESULTS:
In
the population, there was a dose-response relationship between early
gestation and the outcome measures. For
example, extreme preterm birth (23-27 weeks of gestation) was
associated with infant mortality (odds ratio, 288.1; 95%
CI, 271.7-305.5), autism (hazard ratio [HR], 3.2; 95%
CI, 2.6-4.0),
low educational attainment (HR, 1.7; 1.5-2.0), and social welfare
benefits (HR, 1.3; 1.2-1.5) compared with offspring born at term.
The associations between early gestation and mortality and
psychiatric morbidity generally were robust when comparing
differentially exposed siblings and controlling for statistical
covariates, whereas the associations with academic and some social
problems were greatly or completely attenuated in the fixed-effects
models.
CONCLUSIONS
AND RELEVANCE:
The
mechanisms responsible for the associations between preterm birth
and mortality and morbidity are outcome-specific. Associations
between preterm birth and mortality and psychiatric morbidity are
largely independent of shared familial confounds and measured
covariates, consistent with a causal inference. However, some
associations, particularly predicting suicide attempt, educational
attainment, and social welfare benefits, are the result of
confounding factors. The findings emphasize the importance of both
reducing preterm birth and providing wraparound services to all
siblings in families with an offspring born preterm.
Ancestry
of pink disease (infantile acrodynia) identified as a risk factor
for autism spectrum disorders.
goal
J
Toxicol Environ Health A. 2011 Sep 15;74(18):1185-94.
Shandley
K, Austin DW.
Swinburne
Autism Bio-Research Initiative (SABRI), Brain and Psychological
Sciences Research Centre , Swinburne University of Technology ,
Hawthorn , Victoria , Australia.
Abstract
Pink
disease (infantile acrodynia) was especially prevalent in the first
half of the 20th century. Primarily attributed to exposure to
mercury (Hg) commonly found in teething powders, the condition was
developed by approximately 1 in 500 exposed children. The
differential risk factor was identified as an idiosyncratic
sensitivity to Hg. Autismspectrum disorders (ASD) have also been
postulated to be produced by Hg. Analogous to the pink disease
experience, Hg exposure is widespread yet only a fraction of exposed
children develop an ASD, suggesting sensitivity to Hg may also be
present in children with an ASD. The objective of this study was to
test the hypothesis that individuals with a known hypersensitivity
to Hg (pink disease survivors) may be more likely to have
descendants with an ASD. Five hundred and twenty-two participants
who had previously been diagnosed with pink disease completed a
survey on the health outcomes of their descendants. The prevalence
rates of ASD and a variety of other clinical conditions diagnosed in
childhood (attention deficit hyperactivity disorder, epilepsy,
Fragile X syndrome, and Down syndrome) were compared to
well-established general population prevalence rates. The results
showed the prevalence rate of ASD among the grandchildren of pink
disease survivors (1 in 22) to be significantly higher than the
comparable general population prevalence rate (1 in 160).
The
results support the hypothesis that Hg sensitivity may be a
heritable/genetic risk factor for ASD.
Risk
Factors for Autistic Regression: Results of an Ambispective Cohort
Study.
J
Child Neurol. 2012 Jan 30. [Epub ahead of print]
Zhang
Y, Xu Q, Liu J, Li SC, Xu X., Department of Child Health Care,
Children's Hospital of Fudan University,Shanghai, China.
Abstract
A
subgroup of children diagnosed with autism experience developmental
regression featured by a loss of previously acquired abilities. The
pathogeny of autistic regression is unknown, although many risk
factors likely exist. To better characterize autistic regression and
investigate the association between autistic regression and
potential influencing factors in Chinese autistic children, we
conducted an ambispective study with a cohort of 170 autistic
subjects. Analyses
by multiple logistic regression showed significant correlations
between autistic regression and febrile seizures (OR = 3.53, 95% CI
= 1.17-10.65, P = .025),
as well as with a family history of neuropsychiatric disorders (OR =
3.62, 95% CI = 1.35-9.71, P = .011).
This
study suggests that febrile seizures and family history of
neuropsychiatric disorders are correlated with autistic
regression.
Early
Seizures Prematurely Unsilence Auditory Synapses to Disrupt
Thalamocortical Critical Period Plasticity.
Cell
Rep. 2018 May 29;23(9):2533-2540. doi: 10.1016/j.celrep.2018.04.108.
Sun
H, Takesian AE, Wang TT, Lippman-Bell JJ, Hensch TK, Jensen FE.
Department
of Neurology, Perelman School of Medicine, University of
Pennsylvania
F.M.
Kirby Neurobiology Center, Department of Neurology, Boston
Children's
Hospital, Harvard Medical School
Department
of Neuroscience, Carleton University
Abstract
Heightened
neural excitability in infancy and childhood results in increased
susceptibility to seizures. Such early-life seizures are associated
with language deficits and autism that can result from aberrant
development of the auditory cortex.
Here, we show that early-life seizures disrupt a critical period
(CP) for tonotopic map plasticity in primary auditory cortex (A1).
We show that this CP is characterized by a prevalence of "silent,"
NMDA-receptor (NMDAR)-only, glutamate receptor synapses in auditory
cortex that become "unsilenced" due to activity-dependent
AMPA receptor (AMPAR) insertion. Induction of seizures prior to this
CP occludes tonotopic map plasticity by prematurely unsilencing
NMDAR-only synapses. Further, brief treatment with the AMPAR
antagonist NBQX following seizures, prior to the CP, prevents
synapse unsilencing and permits subsequent A1 plasticity. These
findings reveal that early-life seizures modify CP regulators and
suggest that therapeutic targets for early post-seizure treatment
can rescue CP plasticity.
MMR
vaccination and febrile seizures: evaluation of susceptible
subgroups and long-term prognosis.
Vestergaard
M1, Hviid A, Madsen KM, Wohlfahrt J, Thorsen P, Schendel D, Melbye
M, Olsen J.
JAMA. 2004 Jul
21;292(3):351-7.
Abstract
CONTEXT:
The
rate of febrile seizures increases following measles, mumps, and
rubella (MMR) vaccination
but it is unknown whether the rate varies according to personal or
family history of seizures, perinatal factors, or socioeconomic
status. Furthermore, little is known about the long-term outcome of
febrile seizures following vaccination.
OBJECTIVES:
To
estimate incidence rate ratios (RRs) and risk differences of febrile
seizures following MMR vaccination within subgroups of children and
to evaluate the clinical outcome of febrile seizures following
vaccination.
DESIGN, SETTING, AND PARTICIPANTS:
A
population-based cohort study of all children born in Denmark
between January 1, 1991, and December 31, 1998, who were alive at 3
months; 537,171 children were followed up until December 31, 1999,
by using data from the Danish Civil Registration System and 4 other
national registries.
MAIN OUTCOME MEASURES:
Incidence of first
febrile seizure, recurrent febrile seizures, and subsequent
epilepsy.
RESULTS:
A total of 439,251 children (82%) received
MMR vaccination and 17,986 children developed febrile seizures at
least once; 973 of these febrile seizures occurred within 2 weeks of
MMR vaccination. The RR of febrile seizures increased during the 2
weeks following MMR vaccination (2.75; 95% confidence interval [CI],
2.55-2.97), and thereafter was close to the observed RR for
nonvaccinated children. The RR did not vary significantly in the
subgroups of children that had been defined by their family history
of seizures, perinatal factors, or socioeconomic status. At 15 to 17
months, the risk difference of febrile seizures within 2 weeks
following MMR vaccination was 1.56 per 1000 children overall (95%
CI, 1.44-1.68), 3.97 per 1000 (95% CI, 2.90-5.40) for siblings of
children with a history of febrile seizures, and 19.47 per 1000 (95%
CI, 16.05-23.55) for children with a personal history of febrile
seizures. Children with febrile seizures following MMR vaccinations
had a slightly increased rate of recurrent febrile seizures (RR,
1.19; 95% CI, 1.01-1.41) but no increased rate of epilepsy (RR,
0.70; 95% CI, 0.33-1.50) compared with children who were
nonvaccinated at the time of their first febrile
seizure.
CONCLUSIONS:
MMR
vaccination was associated with a transient increased rate of
febrile seizures
but the risk difference was small even in high-risk children. The
long-term rate of epilepsy was not increased in children who had
febrile seizures following vaccination compared with children who
had febrile seizures of a different etiology.
Common
variants associated with general and MMR vaccine–related febrile
seizures
Bjarke
Feenstra, Björn Pasternak, Frank Geller, Lisbeth Carstensen,
Tongfei Wang, Fen Huang, Jennifer L Eitson, Mads V Hollegaard,
Henrik Svanström, Mogens Vestergaard, David M Hougaard, John W
Schoggins, Lily Yeh Jan, Mads Melbye & Anders Hviid
Nature
Genetics (2014) doi:10.1038/ng.3129
Received 20 May 2014
Accepted 03 October 2014 Published online 26 October
2014
Abstract
Febrile
seizures represent a serious adverse event following measles, mumps
and rubella (MMR) vaccination.
We conducted a series of genome-wide association scans comparing
children with MMR-related febrile seizures, children with febrile
seizures unrelated to vaccination and controls with no history of
febrile seizures. Two loci were distinctly associated with
MMR-related febrile seizures, harboring the interferon-stimulated
gene IFI44L (rs273259: P = 5.9 × 10−12 versus controls, P = 1.2 ×
10−9 versus MMR-unrelated febrile seizures) and the measles virus
receptor CD46 (rs1318653: P = 9.6 × 10−11 versus controls, P =
1.6 × 10−9 versus MMR-unrelated febrile seizures). Furthermore,
four loci were associated with febrile seizures in general,
implicating the sodium channel genes SCN1A (rs6432860: P = 2.2 ×
10−16) and SCN2A (rs3769955: P = 3.1 × 10−10), a TMEM16 family
gene (ANO3; rs114444506: P = 3.7 × 10−20) and a region associated
with magnesium levels (12q21.33; rs11105468: P = 3.4 × 10−11).
Finally, we show the functional relevance of ANO3 (TMEM16C) with
electrophysiological experiments in wild-type and knockout rats.
Adverse
events following 12 and 18 month vaccinations: a population-based,
self-controlled case series analysis.
PLoS
One. 2011;6(12):e27897. Epub 2011 Dec 12.
Wilson
K, Hawken S, Kwong JC, Deeks S, Crowcroft NS, Van Walraven C, Potter
BK, Chakraborty P, Keelan J, Pluscauskas M, Manuel D. Department of
Medicine, Ottawa Hospital Research Institute, University of Ottawa,
Ottawa, Canada. kwilson@ohri.ca
Abstract
BACKGROUND:
Live
vaccines have distinct safety profiles, potentially causing systemic
reactions one to 2 weeks after administration. In the province of
Ontario, Canada, live MMR vaccine is currently recommended at age 12
months and 18 months.
METHODS:
Using
the self-controlled case series design we examined 271,495 12 month
vaccinations and 184,312 18 month vaccinations to examine the
relative incidence of the composite endpoint of emergency room
visits or hospital admissions in consecutive one day intervals
following vaccination. These were compared to a control period 20 to
28 days later. In a post-hoc analysis we examined the reasons for
emergency room visits and the average acuity score at presentation
for children during the at-risk period following the 12 month
vaccine.
RESULTS:
Four
to 12 days post 12 month vaccination, children had a 1.33
(1.29-1.38) increased relative incidence of the combined endpoint
compared to the control period, or at least one event during the
risk interval for every 168 children vaccinated. Ten to 12 days post
18 month vaccination, the relative incidence was 1.25 (95%,
1.17-1.33) which represented at least one excess event for every 730
children vaccinated. The primary reason for increased events was
statistically significant elevations in emergency room visits
following all vaccinations. There were non-significant increases in
hospital admissions.
There
were an additional 20 febrile seizures for every 100,000 vaccinated
at 12 months.
CONCLUSIONS:
There
are significantly elevated risks of primarily emergency room visits
approximately one to two weeks following 12 and 18 month
vaccination. Future studies should examine whether these events
could be predicted or prevented.
Reduced
GABAergic Action in the Autistic Brain.
Curr
Biol. 2015 Dec 16. pii: S0960-9822(15)01413-X. doi:
10.1016/j.cub.2015.11.019.
Robertson
CE1, Ratai EM2, Kanwisher N3.
1Harvard
Society of Fellows, Harvard University, Cambridge, MA 02138, USA;
McGovern Institute for Brain Research, Massachusetts Institute of
Technology, Cambridge, MA 02138, USA. Electronic address:
carolinerobertson@fas.harvard.edu.
2Athinoula
A. Martinos Center for Biomedical Imaging, Massachusetts General
Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
3McGovern
Institute for Brain Research, Massachusetts Institute of Technology,
Cambridge, MA 02138, USA.
Abstract
An
imbalance between excitatory/inhibitory neurotransmission has been
posited as a central characteristic of the neurobiology of autism
[1], inspired in part by the striking prevalence of seizures among
individuals with the disorder [2]. Evidence supporting this
hypothesis has specifically implicated the signaling pathway of the
inhibitory neurotransmitter, γ-aminobutyric acid (GABA), in this
putative imbalance: GABA receptor genes have been associated with
autism in linkage and copy number variation studies [3-7], fewer
GABA receptor subunits have been observed in the post-mortem tissue
of autistic individuals [8, 9], and GABAergic signaling is disrupted
across heterogeneous mouse models of autism [10]. Yet, empirical
evidence supporting this hypothesis in humans is lacking, leaving a
gulf between animal and human studies of the condition. Here, we
present a direct link between GABA signaling and autistic perceptual
symptomatology. We first demonstrate a robust, replicated autistic
deficit in binocular rivalry [11], a basic visual function that is
thought to rely on the balance of excitation/inhibition in visual
cortex [12-15]. Then,
using magnetic resonance spectroscopy, we demonstrate a tight
linkage between binocular rivalry dynamics in typical participants
and both GABA and glutamate levels in the visual cortex. Finally, we
show that the link between GABA and binocular rivalry dynamics is
completely and specifically absent in autism.
These results suggest a disruption in inhibitory signaling in the
autistic brain and forge a translational path between animal and
human models of the condition.
Administration
of thimerosal to infant rats increases overflow of glutamate and
aspartate in the prefrontal cortex: protective role of
dehydroepiandrosterone sulfate.
Neurochem
Res. 2012 Feb;37(2):436-47. Epub 2011 Oct 21.
Duszczyk-Budhathoki
M, Olczak M, Lehner M, Majewska MD. Marie Curie Chairs Program,
Department of Pharmacology and Physiology of Nervous System,
Institute of Psychiatry and Neurology, 02-957, Warsaw,
Poland.
Abstract
Thimerosal,
a mercury-containing vaccine preservative, is a suspected factor in
the etiology of neurodevelopmental disorders. We previously showed
that its administration to infant rats causes behavioral,
neurochemical and neuropathological abnormalities similar to those
present in autism. Here we examined, using microdialysis, the effect
of thimerosal on extracellular levels of neuroactive amino acids in
the rat prefrontal cortex (PFC). Thimerosal administration (4
injections, i.m., 240 μg Hg/kg on postnatal days 7, 9, 11, 15)
induced lasting changes in amino acid overflow: an increase of
glutamate and aspartate accompanied by a decrease of glycine and
alanine; measured 10-14 weeks after the injections. Four injections
of thimerosal at a dose of 12.5 μg Hg/kg did not alter glutamate
and aspartate concentrations at microdialysis time (but based on
thimerosal pharmacokinetics, could have been effective soon after
its injection). Application of thimerosal to the PFC in perfusion
fluid evoked a rapid increase of glutamate overflow.
Coadministration of the neurosteroid, dehydroepiandrosterone sulfate
(DHEAS; 80 mg/kg; i.p.) prevented the thimerosal effect on glutamate
and aspartate; the steroid alone had no influence on these amino
acids. Coapplication of DHEAS with thimerosal in perfusion fluid
also blocked the acute action of thimerosal on glutamate. In
contrast, DHEAS alone reduced overflow of glycine and alanine,
somewhat potentiating the thimerosal effect on these amino acids.
Since
excessive accumulation of extracellular glutamate is linked with
excitotoxicity, our data imply that neonatal exposure to
thimerosal-containing vaccines might induce excitotoxic brain
injuries, leading to neurodevelopmental disorders.
DHEAS
may partially protect against mercurials-induced neurotoxicity.
Neonatal
Administration of Thimerosal Causes Persistent Changes in Mu Opioid
Receptors in the Rat Brain
Neurochem
Res. 2010 November; 35(11): 1840–1847.
Mieszko
Olczak, Michalina Duszczyk, Pawel Mierzejewski, Teresa Bobrowicz,
and Maria Dorota Majewska1, Department of Pharmacology and
Physiology of the Nervous System, Institute of Psychiatry and
Neurology, Sobieskiego 9 str., 02-957 Warsaw, Poland, Department of
Forensic Medicine, Medical University of Warsaw, Oczki 1 str.,
02-007 Warsaw, Poland, Department of Neuropathology, Institute of
Psychiatry and Neurology, 02-957 Warsaw, Poland, Department of
Biology and Environmental Science, University of Cardinal Stefan
Wyszynski, Wóycickiego Str. 1/3, 01-815 Warsaw,
Poland
Abstract
Thimerosal
added to some pediatric vaccines is suspected in pathogenesis of
several neurodevelopmental disorders. Our previous study showed that
thimerosal administered to suckling rats causes persistent,
endogenous opioid-mediated hypoalgesia. Here we examined, using
immunohistochemical staining technique, the density of μ-opioid
receptors (MORs) in the brains of rats, which in the second
postnatal week received four i.m. injections of thimerosal at doses
12, 240, 1,440 or 3,000 μg Hg/kg. The periaqueductal gray, caudate
putamen and hippocampus were examined. Thimerosal administration
caused dose-dependent statistically significant increase in MOR
densities in the periaqueductal gray and caudate putamen, but
decrease in the dentate gyrus, where it was accompanied by the
presence of degenerating neurons and loss of synaptic vesicle marker
(synaptophysin).
These
data document that exposure to thimerosal during early postnatal
life produces lasting alterations in the densities of brain opioid
receptors along with other neuropathological changes, which may
disturb brain development.
Unanswered
Questions: A Review of Compensated Cases of Vaccine-Induced Brain
Injury
Pace
Environmental Law Review, vol. 28, no. 2, 2011
Mary
Holland, Louis Conte, Robert Krakow and Lisa Colin
Executive
Summary
In
1986, Congress created the Vaccine Injury Compensation Program
(VICP) under the National Childhood Vaccine Injury Act (1986 Law).
This Program has original jurisdiction for children’s claims of
vaccine injury. Because almost all children receive multiple
vaccinations for daycare and school, it is critically important that
the Program provides fundamental fairness, due process and
transparency.
This
empirical investigation, published in a peer-reviewed law journal,
examines claims that the VICP compensated for vaccine-induced
encephalopathy and seizure disorder. The VICP has compensated
approximately 2,500 claims of vaccine injury since the inception of
the program. This study found 83 cases of acknowledged
vaccine-induced brain damage that include autism, a disorder that
affects speech, social communication and behavior.
In
21 published cases of the Court of Federal Claims, which administers
the VICP, the Court stated that the petitioners had autism or
described autism unambiguously. In 62 remaining cases, the authors
identified settlement agreements where Health and Human Services
(HHS) compensated children with vaccine-induced brain damage, who
also have autism or an autism spectrum disorder.
Parents
reported the existence of autism in telephone interviews and
supplied supplemental materials including medical diagnoses, school
records, and completed, standard autism screening questionnaires to
verify their reports. In 39 of the 83 cases, or 47% of the cases of
vaccine injury reviewed, there is confirmation of autism or autism
spectrum disorder beyond parental report.
This
finding of autism in compensated cases of vaccine injury is
significant. U.S. government spokespeople have been asserting no
vaccine-autism link for more than a decade. This finding calls into
question the decisions of the Court of Federal Claims in the Omnibus
Autism Proceeding in 2009 and 2010 and the statement of Health and
Human Services on its website that “HHS has never concluded in any
case that autism was caused by vaccination.”
Using
publicly available information, the investigation shows that the
VICP has been compensating cases of vaccine-induced brain damage
associated with autism for more than twenty years. This
investigation suggests that officials at HHS, the Department of
Justice and the Court of Federal Claims may have been aware of this
association but failed to publicly disclose it.
The
study calls on Congress to thoroughly investigate the VICP,
including a medical investigation of compensated claims of vaccine
injury. This investigation calls on Congress to get answers to these
critically important unanswered questions.
Integrating
experimental (in vitro and in vivo) neurotoxicity studies of
low-dose thimerosal relevant to vaccines.
Neurochem
Res.
2011
Jun;36(6):927-38. doi: 10.1007/s11064-011-0427-0. Epub 2011 Feb
25.
Dórea
JG,
Faculty of Health Sciences, Universidade de Brasília, CP 04322,
70919-970, Brasília, DF, Brazil. dorea@rudah.com.br
Abstract
There
is a need to interpret neurotoxic studies to help deal with
uncertainties surrounding pregnant mothers, newborns and young
children who must receive repeated doses of Thimerosal-containing
vaccines (TCVs). This review integrates information derived from
emerging experimental studies (in vitro and in vivo) of low-dose
Thimerosal (sodium ethyl mercury thiosalicylate). Major databases
(PubMed and Web-of-science) were searched for in vitro and in vivo
experimental studies that addressed the effects of low-dose
Thimerosal (or ethylmercury) on neural tissues and animal behaviour.
Information extracted from studies indicates that: (a) activity of
low doses of Thimerosal against isolated human and animal brain
cells was found in all studies and is consistent with Hg
neurotoxicity; (b) the neurotoxic effect of ethylmercury has not
been studied with co-occurring adjuvant-Al in TCVs; (c) animal
studies have shown that exposure to Thimerosal-Hg can lead to
accumulation of inorganic Hg in brain, and that (d) doses relevant
to TCV exposure possess the potential to affect human
neuro-development. Thimerosal at concentrations relevant for
infants' exposure (in vaccines) is toxic to cultured human-brain
cells and to laboratory animals. The persisting use of TCV (in
developing countries) is counterintuitive to global efforts to lower
Hg exposure and to ban Hg in medical products; its continued use in
TCV requires evaluation of a sufficiently nontoxic level of
ethylmercury compatible with repeated exposure (co-occurring with
adjuvant-Al) during early life.
Hepatitis
B vaccine induces apoptotic death in Hepa1-6 cells
Apoptosis.
2012 Jan 17. Hamza H, Cao J, Li X, Li C, Zhu M, Zhao S.
Key
Lab of Agricultural Animal Genetics, Breeding, and Reproduction of
Ministry of Education, College of Animal Science and Technology,
Huazhong Agricultural University, Wuhan, 430070, People's Republic
of China, Heyam68_hamza@yahoo.com.
Abstract
Vaccines
can have adverse side-effects, and these are predominantly
associated with the inclusion of chemical additives such as aluminum
hydroxide adjuvant. The objective of this study was to establish an
in vitro model system amenable to mechanistic investigations of
cytotoxicity induced by hepatitis B vaccine, and to investigate the
mechanisms of vaccine-induced cell death. The mouse liver hepatoma
cell line Hepa1-6 was treated with two doses of adjuvanted
(aluminium hydroxide) hepatitis B vaccine (0.5 and 1 μg protein per
ml) and cell integrity was measured after 24, 48 and 72 h. Hepatitis
B vaccine exposure increased cell apoptosis as detected by flow
cytometry and TUNEL assay. Vaccine exposure was accompanied by
significant increases in the levels of activated caspase 3, a key
effector caspase in the apoptosis cascade. Early transcriptional
events were detected by qRT-PCR. We report that hepatitis B vaccine
exposure resulted in significant upregulation of the key genes
encoding caspase 7, caspase 9, Inhibitor caspase-activated DNase
(ICAD), Rho-associated coiled-coil containing protein kinase 1
(ROCK-1), and Apoptotic protease activating factor 1 (Apaf-1).
Upregulation of cleaved caspase 3,7 were detected by western blot in
addition to Apaf-1 and caspase 9 expressions argues that cell death
takes place via the intrinsic apoptotic pathway in which release of
cytochrome c from the mitochondria triggers the assembly of a
caspase activation complex.
We
conclude that exposure of Hepa1-6 cells to a low dose of adjuvanted
hepatitis B vaccine leads to loss of mitochondrial integrity,
apoptosis induction, and cell death, apoptosis effect was observed
also in C2C12 mouse myoblast cell line after treated with low dose
of vaccine (0.3, 0.1, 0.05 μg/ml).
In addition In vivo apoptotic effect of hepatitis B vaccine was
observed in mouse liver.
Thimerosal
Induces Apoptosis in a Neuroblastoma Model via the cJun N-Terminal
Kinase Pathway.
Toxicological
Sciences 92 (1). 246-253
ML Herdman, A Marcelo, Y Huang, RM
Niles, Dhar S & Kiningham KK. (2006).
Department of
Pharmacology, Joan C. Edwards School of Medicine, 1542 Spring Valley
Drive, Marshall University, Huntington, WV USA
EXCERPT: In
recent years, controversy has surrounded the use of thimerosal in
vaccines as mercury is a known neurotoxin and nephrotoxin. Since the
controversy began in the late 1990's, much of the thimerosal has
been removed from vaccines administered to children in the United
States. However, it remains in some, such as the influenza vaccine,
and is added to multidose vials used in countries around the world.
Studies concentrating on thimerosal-induced neurotoxicity are
limited, and exposure guidelines, such as those set by the Food and
Drug Administration, are based on research with methylmercury.
Interestingly, some in vitro and in vivo studies suggest that
ethylmercury may react differently than methylmercury (Aschner and
Aschner, 1990; Harry et al., 2004; Magos et al., 1985). Few studies
with thimerosal have focused on determining specific signaling
pathways involved in neurotoxicity. Establishing these pathways may
be an important step in discovering methods of alleviating toxic
outcomes in patients exposed to thimerosal….Our study is the first
demonstration that thimerosal can induce the activation of JNK and
AP-1 in the SK-N-SH neuroblastoma cell line. We showed that
activation of cJun and AP-1 transcriptional activity following
thimerosal treatment does not appear to be involved in the induction
of apoptosis, as demonstrated with the studies using the cJun
dominant negative. Furthermore, we were able to show that JNK is an
essential upstream component of this pathway through the use of the
JNK inhibitor SP600125. This compound was able to attenuate
activation of downstream components of mitochondrial-mediated cell
death and subsequently protect the cells from apoptosis. These
results are significant because identifying specific signaling
pathways activated in response to thimerosal exposure presents
pharmacological targets for attenuating potential toxicity in
patients exposed to thimerosal-containing products.
Maternal
thimerosal exposure results in aberrant cerebellar oxidative stress,
thyroid hormone metabolism, and motor behavior in rat pups; sex- and
strain-dependent effects.
Cerebellum.
2012
Jun;11(2):575-86. doi: 10.1007/s12311-011-0319-5.
Sulkowski
ZL,
Chen
T,
Midha
S,
Zavacki
AM,
Sajdel-Sulkowska
EM,
Department of Psychiatry, Harvard Medical School and Brigham and
Women's Hospital, Boston, MA, USA.
Abstract
Methylmercury
(Met-Hg) and ethylmercury (Et-Hg) are powerful toxicants with a
range of harmful neurological effects in humans and animals. While
Met-Hg is a recognized trigger of oxidative stress and an endocrine
disruptor impacting neurodevelopment, the developmental
neurotoxicity of Et-Hg, a metabolite of thimerosal (TM), has not
been explored. We hypothesized that TM exposure during the perinatal
period impairs central nervous system development, and specifically
the cerebellum, by the mechanism involving oxidative stress. To test
this, spontaneously hypertensive rats (SHR) or Sprague-Dawley (SD)
rat dams were exposed to TM (200 μg/kg body weight) during
pregnancy (G10-G15) and lactation (P5-P10). Male and female neonates
were evaluated for auditory and motor function; cerebella were
analyzed for oxidative stress and thyroid metabolism. TM exposure
resulted in a delayed startle response in SD neonates and decreased
motor learning in SHR male (22.6%), in SD male (29.8%), and in SD
female (55.0%) neonates. TM exposure also resulted in a significant
increase in cerebellar levels of the oxidative stress marker
3-nitrotyrosine in SHR female (35.1%) and SD male (14.0%) neonates.
The activity of cerebellar type 2 deiodinase, responsible for local
intra-brain conversion of thyroxine to the active hormone,
3',3,5-triiodothyronine (T3), was significantly decreased in
TM-exposed SHR male (60.9%) pups. This coincided with an increased
(47.0%) expression of a gene negatively regulated by T3, Odf4
suggesting local intracerebellar T3 deficiency. Our
data thus demonstrate a negative neurodevelopmental impact of
perinatal TM exposure which appears to be both strain- and
sex-dependent.
The
rise in autism and the role of age at diagnosis.
Epidemiology.
2009
Jan;20(1):84-90. doi: 10.1097/EDE.0b013e3181902d15.
Hertz-Picciotto
I,
Delwiche
L., Department of Public Health Sciences, University of California,
Davis, California 95616, USA.
ihp@ucdavis.edu
Abstract
BACKGROUND:
Autism
prevalence in California, based on individuals eligible for
state-funded services, rose throughout the 1990s. The extent to
which this trend is explained by changes in age at diagnosis or
inclusion of milder cases has not been previously
evaluated.
METHODS:
Autism
cases were identified from 1990 through 2006 in databases of the
California Department of Developmental Services, which coordinates
services for individuals with specific developmental disorders. The
main outcomes were population incident cases younger than age 10
years for each quarter, cumulative incidence by age and birth year,
age-specific incidence rates stratified by birth year, and
proportions of diagnoses by age across birth years.
RESULTS:
Autism
incidence in children rose throughout the period. Cumulative
incidence to 5 years of age per 10,000 births rose consistently from
6.2 for 1990 births to 42.5 for 2001 births. Age-specific incidence
rates increased most steeply for 2- and 3-year olds. The proportion
diagnosed by age 5 years increased only slightly, from 54% for 1990
births to 61% for 1996 births. Changing age at diagnosis can explain
a 12% increase, and inclusion of milder cases, a 56%
increase.
CONCLUSIONS:
Autism
incidence in California shows no sign yet of plateauing. Younger
ages at diagnosis, differential migration, changes in diagnostic
criteria, and inclusion of milder cases do not fully explain the
observed increases. Other artifacts have yet to be quantified, and
as a result, the extent to which the continued rise represents a
true increase in the occurrence of autism remains unclear.
Slow
CCL2-dependent translocation of biopersistent particles from muscle
to brain
Zakir
Khan1,2, Christophe Combadière3,4,5, François-Jérôme
Authier1,2,6, Valérie Itier1,11,2, François Lux7,8, Christopher
Exley9, Meriem Mahrouf-Yorgov1,11,2, Xavier Decrouy1,2, Philippe
Moretto10, Olivier Tillement7,8, Romain K Gherardi1,12,2,6*† and
Josette Cadusseau1,11,12,2*†
Author Affiliations
1
Inserm, U955, 8 rue du Général Sarrail, Créteil, 94010, France
2
Université Paris Est, Faculté de Médecine, 8 rue du Général
Sarrail, Créteil, 94010, France
3 Inserm, UMR-S 945, 91
Boulevard de l’Hôpital, Paris, 75013, France
4 Université
Pierre et Marie Curie, Faculté de Médecine, 11 Boulevard de
l’Hôpital, Paris, 75013, France
5 AP-HP, Groupe
Hospitalier Pitié-Salpétrière, Service d’Immunologie, 11
Boulevard de l’Hôpital, Paris, 75013, France
6 AP-HP,
Hôpital H. Mondor - A. Chenevier, Service d’Histologie, Centre de
Référence Neuromusculaire GNMH, 51 Avenue du Maréchal de Lattre
de Tassigny, Créteil, 94000, France
7 CNRS UMR 5620,
Laboratoire de Physico-Chimie des Matériaux Luminescents, 2 rue
Victor Grignard, Villeurbanne, 69622, France
8 Université
Claude Bernard Lyon 1, 2 rue Victor Grignard, Villeurbanne, 69622,
France
9 The Birchall Centre, Lennard-Jones Laboratories,
Keele University, Staffordshire, ST5 5BG, UK
10 CNRS UMR
5797, Centre d'Etudes Nucléaires de Bordeaux Gradignan, Allée du
haut Vignaud, Gradignan, 33175, France
11 Faculté des
Sciences et Technologie, UPEC, 61 Avenue du Général de Gaulle,
Créteil, France
12 IMRB Team 10, Faculté de Médecine, 8
rue du Général Sarrail, Créteil, F-94010, France
BMC
Medicine 2013, 11:99 doi:10.1186/1741-7015-11-99, 4 April
2013
Abstract
Background
Long-term biodistribution
of nanomaterials used in medicine is largely unknown. This is the
case for alum, the most widely used vaccine adjuvant, which is a
nanocrystalline compound spontaneously forming
micron/submicron-sized agglomerates. Although generally well
tolerated, alum is occasionally detected within monocyte-lineage
cells long after immunization in presumably susceptible individuals
with systemic/neurologic manifestations or autoimmune (inflammatory)
syndrome induced by adjuvants (ASIA).
Methods:
On the grounds
of preliminary investigations in 252 patients with alum-associated
ASIA showing both a selective increase of circulating CCL2, the
major monocyte chemoattractant, and a variation in the CCL2 gene, we
designed mouse experiments to assess biodistribution of
vaccine-derived aluminum and of alum-particle fluorescent surrogates
injected in muscle. Aluminum was detected in tissues by Morin stain
and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent
latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho)
were used.
Results:
Intramuscular
injection of alum-containing vaccine was associated with the
appearance of aluminum deposits in distant organs, such as spleen
and brain where they were still detected one year after injection.
Both fluorescent materials injected into muscle translocated to
draining lymph nodes (DLNs) and thereafter were detected associated
with phagocytes in blood and spleen. Particles linearly accumulated
in the brain up to the six-month endpoint; they were first found in
perivascular CD11b+ cells and then in microglia and other neural
cells. DLN ablation dramatically reduced the biodistribution.
Cerebral translocation was not observed after direct intravenous
injection, but significantly increased in mice with chronically
altered blood-brain-barrier. Loss/gain-of-function experiments
consistently implicated CCL2 in systemic diffusion of Al-Rho
particles captured by monocyte-lineage cells and in their subsequent
neurodelivery. Stereotactic particle injection pointed out brain
retention as a factor of progressive particle
accumulation.
Conclusion
Nanomaterials can be transported by
monocyte-lineage cells to DLNs, blood and spleen, and, similarly to
HIV, may use CCL2-dependent mechanisms to penetrate the brain. This
occurs at a very low rate in normal conditions explaining good
overall tolerance of alum despite its strong neurotoxic potential.
However,
continuously escalating doses of this poorly biodegradable adjuvant
in the population may become insidiously unsafe, especially in the
case of overimmunization or immature/altered blood brain barrier or
high constitutive CCL-2 production.
Blood–brain
barrier and intestinal epithelial barrier alterations in autism
spectrum disorders
Maria
Fiorentino, Anna Sapone, Stefania Senger, Stephanie S. Camhi, Sarah
M. Kadzielski, Timothy M. Buie, Deanna L. Kelly, Nicola Cascella &
Alessio Fasano
Molecular
Autism volume 7, Article number: 49 (2016)
Abstract
Background
Autism
spectrum disorders (ASD) are complex conditions whose pathogenesis
may be attributed to gene–environment interactions. There are no
definitive mechanisms explaining how environmental triggers can lead
to ASD although the involvement of inflammation and immunity has
been suggested. Inappropriate antigen trafficking through an
impaired intestinal barrier, followed by passage of these antigens
or immune-activated complexes through a permissive blood–brain
barrier (BBB), can be part of the chain of events leading to these
disorders. Our goal was to investigate whether an altered BBB and
gut permeability is part of the pathophysiology of ASD.
Methods
Postmortem
cerebral cortex and cerebellum tissues from ASD, schizophrenia
(SCZ), and healthy subjects (HC) and duodenal biopsies from ASD and
HC were analyzed for gene and protein expression profiles. Tight
junctions and other key molecules associated with the neurovascular
unit integrity and function and neuroinflammation were investigated.
Results
Claudin
(CLDN)-5 and -12 were increased in the ASD cortex and cerebellum.
CLDN-3, tricellulin, and MMP-9 were higher in the ASD cortex. IL-8,
tPA, and IBA-1 were downregulated in SCZ cortex; IL-1b was increased
in the SCZ cerebellum. Differences between SCZ and ASD were observed
for most of the genes analyzed in both brain areas. CLDN-5 protein
was increased in ASD cortex and cerebellum, while CLDN-12 appeared
reduced in both ASD and SCZ cortexes. In the intestine, 75% of the
ASD samples analyzed had reduced expression of barrier-forming TJ
components (CLDN-1, OCLN, TRIC), whereas 66% had increased
pore-forming CLDNs (CLDN-2, -10, -15) compared to controls.
Conclusions
In
the ASD brain, there is an altered expression of genes associated
with BBB integrity coupled with increased neuroinflammation and
possibly impaired gut barrier integrity.
While these findings seem to be specific for ASD, the possibility of
more distinct SCZ subgroups should be explored with additional
studies.
Thimerosal
and autism? A plausible hypothesis that should not be
dismissed.
Med
Hypotheses. 2004;62(5):788-94.
Blaxill MF, Redwood L, Bernard
S.
Abstract
The autism-mercury hypothesis first described
by Bernard et al. has generated much interest and controversy. The
Institute of Medicine (IOM) reviewed the connection between
mercury-containing vaccines and neurodevelopmental disorders,
including autism. They concluded that the hypothesis was
biologically plausible but that there was insufficient evidence to
accept or reject a causal connection and recommended a comprehensive
research program. Without citing new experimental evidence, a number
of observers have offered opinions on the subject, some of which
reject the IOM's conclusions. In a recent review, Nelson and Bauman
argue that a link between the preservative thimerosal, the source of
the mercury in childhood vaccines, is improbable. In their defense
of thimerosal, these authors take a narrow view of the original
hypothesis, provide no new evidence, and rely on selective citations
and flawed reasoning. We provide evidence here to refute the Nelson
and Bauman critique and to defend the autism-mercury hypothesis.
Autism
Spectrum Disorders in Relation to Distribution of Hazardous Air
Pollutants in the SF Bay Area
Environmental
Health Perspectives – Vol. 114 No. 9, September, 2006
Gayle
Windham, Div. of Environmental and Occupational Disease Control,
California Department of Health Services
284
ASD children & 657 controls, born in 1994 in Bay Area, were
assigned exposure levels by birth tract for 19 chemicals. Risks for
autism were elevated by 50% in tracts with the highest chlorinated
solvents and heavy metals. The highest risk compounds were mercury,
cadmium, nickel, trichloroethylene, and vinyl chloride, and the risk
from heavy metals was almost twice as high as solvents.
Excerpt:
“Our results suggest a potential association between autism and
estimated metal concentrations, and possibly solvents, in ambient
air around the birth residence.”
Environmental
mercury release, special education rates, and autism disorder: an
ecological study of Texas
Health
Place. 2006 Jun;12(2):203-9.
Palmer RF, Blanchard S, Stein Z,
Mandell D, Miller C.
University of Texas Health Science
Center, San Antonio Department of Family and Community Medicine,
7703 Floyd Curl Drive, San Antonio, Texas
Abstract
The
association between environmentally released mercury, special
education and autism rates in Texas was investigated using data from
the Texas Education Department and the United States Environmental
Protection Agency. A Poisson regression analysis adjusted for school
district population size, economic and demographic factors was used.
There was a significant increase in the rates of special education
students and autism rates associated with increases in
environmentally released mercury. On average, for each 1,000 lb of
environmentally released mercury, there was a 43% increase in the
rate of special education services and a 61% increase in the rate of
autism. The association between environmentally released mercury and
special education rates were fully mediated by increased autism
rates. This ecological study suggests the need for further research
regarding the association between environmentally released mercury
and developmental disorders such as autism. These results have
implications for policy planning and cost analysis.
Autism
spectrum disorder prevalence and proximity to industrial facilities
releasing arsenic, lead or mercury.
Sci
Total Environ. 2015 Dec 1;536:245-51. doi:
10.1016/j.scitotenv.2015.07.024. Epub 2015 Jul 25.
Dickerson
AS1, Rahbar MH2, Han I3, Bakian AV4, Bilder DA5, Harrington RA6,
Pettygrove S7, Durkin M8, Kirby RS9, Wingate MS10, Tian LH11,
Zahorodny WM12, Pearson DA13, Moyé LA 3rd14, Baio J15.
1Biostatistics/Epidemiology/Research
Design (BERD) Core, Center for Clinical and Translational Sciences
(CCTS), University of Texas Health Science Center at Houston,
Houston, TX 77030, USA. Electronic address:
Aisha.S.Dickerson@uth.tmc.edu.
2Biostatistics/Epidemiology/Research
Design (BERD) Core, Center for Clinical and Translational Sciences
(CCTS), University of Texas Health Science Center at Houston,
Houston, TX 77030, USA; Division of Epidemiology, Human Genetics,
and Environmental Sciences (EHGES), University of Texas School of
Public Health at Houston, University of Texas Health Science Center
at Houston, Houston, TX 77030, USA. Electronic address:
Mohammad.H.Rahbar@uth.tmc.edu.
3Division
of Epidemiology, Human Genetics, and Environmental Sciences (EHGES),
University of Texas School of Public Health at Houston, University
of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Electronic address: Inkyu.Han@uth.tmc.edu.
4Division
of Child Psychiatry, Department of Psychiatry, University of Utah
School of Medicine, Salt Lake City, UT 84108, USA. Electronic
address: Amanda.Bakian@hsc.utah.edu.
5Division
of Child Psychiatry, Department of Psychiatry, University of Utah
School of Medicine, Salt Lake City, UT 84108, USA. Electronic
address: Deborah.Bilder@hsc.utah.edu.
6Department
of Epidemiology, Johns Hopkins Bloomberg School of Public Health,
Baltimore, MD 21205, USA. Electronic address: rharrin5@jhu.edu.
7Mel
and Enid Zuckerman College of Public Health, University of Arizona,
Tucson, AZ 85721, USA. Electronic address: sydneyp@u.arizona.edu.
8Waisman
Center, University of Wisconsin School of Medicine and Public
Health, Madison, WI 53726, USA. Electronic address:
mdurkin@wisc.edu.
9Department
of Community and Family Health, College of Public Health, University
of South Florida, Tampa, FL 33612, USA. Electronic address:
rkirby@health.usf.edu.
10Department
of Health Care Organization and Policy, School of Public Health,
University of Alabama at Birmingham, Birmingham, AL 35205, USA..
Electronic address: mslay@uab.edu.
11National
Center on Birth Defects and Developmental Disabilities, Centers for
Disease Control and Prevention, Atlanta, GA 30333, USA. Electronic
address: bsr4@cdc.gov.
12Department
of Pediatrics, Rutgers New Jersey Medical School, Newark, NJ 07103,
USA. Electronic address: zahorodn@njms.rutgers.edu.
13Department
of Psychiatry and Behavioral Sciences, University of Texas Medical
School, Houston, TX 77054, USA. Electronic address:
Deborah.A.Pearson@uth.tmc.edu.
14Division
of Biostatistics, University of Texas School of Public Health at
Houston, Houston, TX 77030, USA. Electronic address:
Lemuel.A.Moye@uth.tmc.edu.
15National
Center on Birth Defects and Developmental Disabilities, Centers for
Disease Control and Prevention, Atlanta, GA 30333, USA. Electronic
address: xzb1@cdc.gov.
Abstract
Prenatal
and perinatal exposures to air pollutants have been shown to
adversely affect birth outcomes in offspring and may contribute to
prevalence of autism spectrum disorder (ASD). For
this ecologic study, we evaluated the association between ASD
prevalence, at the census tract level, and proximity of tract
centroids to the closest industrial facilities releasing arsenic,
lead or mercury
during the 1990s. We used 2000 to 2008 surveillance data from five
sites of the Autism and Developmental Disabilities Monitoring (ADDM)
network and 2000 census data to estimate prevalence. Multi-level
negative binomial regression models were used to test associations
between ASD prevalence and proximity to industrial facilities in
existence from 1991 to 1999 according to the US Environmental
Protection Agency Toxics Release Inventory (USEPA-TRI). Data for
2489 census tracts showed that after adjustment for demographic and
socio-economic area-based characteristics, ASD prevalence was higher
in census tracts located in the closest 10th percentile compared of
distance to those in the furthest 50th percentile (adjusted RR=1.27,
95% CI: (1.00, 1.61), P=0.049). The
findings observed in this study are suggestive of the association
between urban residential proximity to industrial facilities
emitting air pollutants and higher ASD prevalence.
Inflammatory
Responses to Trivalent Influenza Virus Vaccine Among Pregnant
Women
Vaccine.
2011 Nov 8;29(48):8982-7. doi: 10.1016/j.vaccine.2011.09.039. Epub
2011 Sep 22.
Christian LM, Iams JD, Porter K, Glaser
R.
Department of Psychiatry, The Ohio State University
Medical Center, Columbus, OH
Abstract
Objective
In the
U.S., seasonal trivalent influenza vaccination (TIV) is currently
universally recommended for all pregnant women. However, data on the
maternal inflammatory response to vaccination is lacking and would
better delineate the safety and clinical utility of immunization. In
addition, for research purposes, vaccination has been used as a mild
immune trigger to examine in vivo inflammatory responses in
nonpregnant adults. The utility of such a model in pregnancy is
unknown. Given the clinical and empirical justifications, the
current study examined the magnitude, time course, and variance in
inflammatory responses following seasonal influenza virus
vaccination among pregnant women.
Methods
Women were assessed
prior to and at one day (n=15), two days (n=10), or approximately
one week (n=21) following TIV. Serum interleukin (IL)-6, tumor
necrosis factor (TNF)-α, C-reactive protein (CRP), and macrophage
migration inhibitory factor (MIF) were determined by high
sensitivity immunoassay.
Results
Significant increases in CRP
were seen at one and two days post-vaccination (ps <.05). A
similar effect was seen for TNF-α, for which an increase at two
days post-vaccination approached statistical significance (p = .06).
There was considerable variability in magnitude of response;
coefficients of variation for change at two days post-vaccination
ranged from 122% to 728%, with the greatest variability in IL-6
responses at this timepoint.
Conclusions
Trivalent influenza
virus vaccination elicits a measurable inflammatory response among
pregnant women. There is sufficient variability in response for
testing associations with clinical outcomes. As adverse perinatal
health outcomes including preeclampsia and preterm birth have an
inflammatory component, a tendency toward greater inflammatory
responding to immune triggers may predict risk of adverse outcomes,
providing insight into biological mechanisms underlying risk. The
inflammatory response elicited by vaccination is substantially
milder and more transient than seen in infectious illness, arguing
for the clinical value of vaccination. However, further research is
needed to confirm that the mild inflammatory response elicited by
vaccination is benign in pregnancy
Elevated
maternal C-reactive protein and autism in a national birth
cohort.
Mol
Psychiatry. 2013 Jan 22. doi: 10.1038/mp.2012.197.
Brown AS,
Sourander A, Hinkka-Yli-Salomäki S, McKeague IW, Sundvall J, Surcel
HM.
Department of Psychiatry, Columbia University College of
Physicians and Surgeons, New York State Psychiatric Institute, New
York, NY, USA, Department of Epidemiology, Columbia University
Mailman School of Public Health, New York, NY, USA.
Abstract
Autism
is a complex neuropsychiatric syndrome with a largely unknown
etiology. Inflammation during pregnancy may represent a common
pathway by which infections and other insults increase risk for the
disorder. Hence, we investigated the association between early
gestational C-reactive protein (CRP), an established inflammatory
biomarker, prospectively assayed in maternal sera, and childhood
autism in a large national birth cohort with an extensive serum
biobank. Other strengths of the cohort included nearly complete
ascertainment of pregnancies in Finland (N=1.2 million) over the
study period and national psychiatric registries consisting of
virtually all treated autism cases in the population. Increasing
maternal CRP levels, classified as a continuous variable, were
significantly associated with autism in offspring. For maternal CRP
levels in the highest quintile, compared with the lowest quintile,
there was a significant, 43% elevated risk. This finding suggests
that maternal inflammation may have a significant role in autism,
with possible implications for identifying preventive strategies and
pathogenic mechanisms in autism and other neurodevelopmental
disorders.Molecular Psychiatry advance online publication, 22
January 2013; doi:10.1038/mp.2012.197.
What
is regressive autism and why does it occur? Is it the consequence of
multi-systemic dysfunction affecting the elimination of heavy metals
and the ability to regulate
neural temperature?
N
Am J Med Sci. 2009 July; 1(2): 28–47.
Graham E.
Ewing
Montague Healthcare, Nottingham United
Kingdom
Abstract
There is a compelling argument that the
occurrence of regressive autism is attributable to genetic and
chromosomal abnormalities, arising from the overuse of vaccines,
which subsequently affects the stability and function of the
autonomic nervous system and physiological systems. That sense
perception is linked to the autonomic nervous system and the
function of the physiological systems enables us to examine the
significance of autistic symptoms from a systemic perspective.
Failure of the excretory system influences elimination of heavy
metals and facilitates their accumulation and subsequent
manifestation as neurotoxins: the long-term consequences of which
would lead to neurodegeneration, cognitive and developmental
problems. It may also influence regulation of neural hyperthermia.
This article explores the issues and concludes that sensory
dysfunction and systemic failure, manifested as autism, is the
inevitable consequence arising from subtle DNA alteration and
consequently from the overuse of vaccines.
Neurologic
adverse events following vaccination
Prog
Health Sci 2012, Vol 2 , No1
Sienkiewicz D.*, Kułak W.,
Okurowska-Zawada B., Paszko-Patej G.
Department of Pediatric
Rehabilitation of the Medical University of Bialystok,
Poland
Abstract
The present review summarizes data on
neurological adverse events following vaccination in the relation to
intensity, time of onset, taking into account the immunological and
non-immunological mechanisms. The authors described the
physiological development of the immune system and the possible
immune system responses following vaccination. Toxic property of
thimerosal - a mercury-containing preservative used in some vaccines
was presented. The neurological complications after vaccination were
described. The role of vaccination in the natural course of
infectious diseases and the current immunizations schedule in Poland
was discussed.
Discussion
by Sienkiewicz et. al.:
"Among
the "major" neurological complications, usually
manifesting more than 48 hours after vaccination and which might be
the cause of permanent damage to the central nervous system (CNS),
the following are listed: seizures - especially if there is no
increase in body temperature, hypotonic-hyporesponsive episodes,
postvaccinal encephalitis, postvaccinal encephalopathy [6, 8-11] and
autism [10, 12-14]."
Immunological
and autoimmune considerations of Autism Spectrum Disorders.
J
Autoimmun. 2013 Jul 15. pii: S0896-8411(13)00073-5. doi:
10.1016/j.jaut.2013.05.005.
Gesundheit B, Rosenzweig JP, Naor
D, Lerer B, Zachor DA, Procházka V, Melamed M, Kristt DA, Steinberg
A, Shulman C, Hwang P, Koren G, Walfisch A, Passweg JR, Snowden JA,
Tamouza R, Leboyer M, Farge-Bancel D, Ashwood P.
Jerusalem,
Israel.
Abstract
Autism Spectrum Disorders (ASD) are a
group of heterogeneous neurodevelopmental conditions presenting in
early childhood with a prevalence ranging from 0.7% to 2.64%. Social
interaction and communication skills are impaired and children often
present with unusual repetitive behavior. The condition persists for
life with major implications for the individual, the family and the
entire health care system. While the etiology of ASD remains
unknown, various clues suggest a possible association with altered
immune responses and ASD. Inflammation in the brain and CNS has been
reported by several groups with notable microglia activation and
increased cytokine production in postmortem brain specimens of young
and old individuals with ASD. Moreover several laboratories have
isolated distinctive brain and CNS reactive antibodies from
individuals with ASD. Large population based epidemiological studies
have established a correlation between ASD and a family history of
autoimmune diseases, associations with MHC complex haplotypes, and
abnormal levels of various inflammatory cytokines and immunological
markers in the blood. In addition, there is evidence that antibodies
that are only present in some mothers of children with ASD bind to
fetal brain proteins and may be a marker or risk factor for ASD.
Studies involving the injection of these ASD specific maternal serum
antibodies into pregnant mice during gestation, or gestational
exposure of Rhesus monkeys to IgG subclass of these antibodies, have
consistently elicited behavioral changes in offspring that have
relevance to ASD. We will summarize the various types of studies
associating ASD with the immune system, critically evaluate the
quality of these studies, and attempt to integrate them in a way
that clarifies the areas of immune and autoimmune phenomena in ASD
research that will be important indicators for future research.
Identification
of Unique Gene Expression Profile in Children with Regressive Autism
Spectrum Disorder (ASD) and Ileocolitis
PLoS
ONE 8(3): e58058. doi:10.1371/journal.pone.0058058
Walker SJ,
Fortunato J, Gonzalez LG, Krigsman A
Abstract
Gastrointestinal
symptoms are common in children with autism spectrum disorder (ASD)
and are often associated with mucosal inflammatory infiltrates of
the small and large intestine. Although distinct histologic and
immunohistochemical properties of this inflammatory infiltrate have
been previously described in this ASDGI group, molecular
characterization of these lesions has not been reported. In this
study we utilize transcriptome profiling of gastrointestinal mucosal
biopsy tissue from ASDGI children and three non-ASD control groups
(Crohn's disease, ulcerative colitis, and histologically normal) in
an effort to determine if there is a gene expression profile unique
to the ASDGI group. Comparison of differentially expressed
transcripts between the groups demonstrated that non-pathologic
(normal) tissue segregated almost completely from inflamed tissue in
all cases. Gene expression profiles in intestinal biopsy tissue from
patients with Crohn's disease, ulcerative colitis, and ASDGI, while
having significant overlap with each other, also showed distinctive
features for each group. Taken
together, these results demonstrate that ASDGI children have a
gastrointestinal mucosal molecular profile that overlaps
significantly with known inflammatory bowel disease (IBD), yet has
distinctive features that further supports the presence of an
ASD-associated IBD variant, or, alternatively, a prodromal phase of
typical inflammatory bowel disease.
Although we report qPCR confirmation of representative
differentially expressed transcripts determined initially by
microarray, these findings may be considered preliminary to the
extent that they require further confirmation in a validation
cohort.
Early
Disruption of the Microbiome Leading to Decreased Antioxidant
Capacity and Epigenetic Changes: Implications for the Rise in Autism
Front.
Cell. Neurosci., 15 August 2018 |
https://doi.org/10.3389/fncel.2018.00256
Rebecca
S. Eshraghi, Richard C. Deth, Rahul Mittal, Mayank Aranke, Sae-In S.
Kay4, Baharak Moshiree and Adrien A. Eshraghi
Currently,
1 out of every 59 children in the United States is diagnosed with
autism. While initial research to find the possible causes for
autism were mostly focused on the genome, more recent studies
indicate a significant role for epigenetic regulation of gene
expression and the microbiome. In this review article, we
examine the connections between early disruption of the developing
microbiome and gastrointestinal tract function, with particular
regard to susceptibility to autism. The biological mechanisms that
accompany individuals with autism are reviewed in this manuscript
including immune system dysregulation, inflammation, oxidative
stress, metabolic and methylation abnormalities as well as
gastrointestinal distress.
We propose that these autism-associated biological mechanisms may be
caused and/or sustained by dysbiosis, an alteration to the
composition of resident commensal communities relative to the
community found in healthy individuals and its redox and epigenetic
consequences, changes that in part can be due to early use and
over-use of antibiotics across generations. Further studies are
warranted to clarify the contribution of oxidative stress and gut
microbiome in the pathophysiology of autism. A better understanding
of the microbiome and gastrointestinal tract in relation to autism
will provide promising new opportunities to develop novel treatment
modalities.
Methylomic
analysis of monozygotic twins discordant for autism spectrum
disorder and related behavioural traits
Mol Psychiatry.
2014 Apr;19(4):495-503. doi: 10.1038/mp.2013.41. Epub 2013 Apr 23.
Wong
CC1, Meaburn EL2, Ronald A2, Price TS3, Jeffries AR1, Schalkwyk LC1,
Plomin R1, Mill J4.
1
King's College London, MRC Social, Genetic and Developmental
Psychiatry Centre, Institute of Psychiatry, De Crespigny Park,
London, UK.
2
1] King's College London, MRC Social, Genetic and Developmental
Psychiatry Centre, Institute of Psychiatry, De Crespigny Park,
London, UK [2] Department of Psychological Sciences, Birkbeck,
University of London, London, UK.
3
1] King's College London, MRC Social, Genetic and Developmental
Psychiatry Centre, Institute of Psychiatry, De Crespigny Park,
London, UK [2] Institute of Translational Medicine and Therapeutics,
School of Medicine, University of Pennsylvania, PA, USA.
4
1] King's College London, MRC Social, Genetic and Developmental
Psychiatry Centre, Institute of Psychiatry, De Crespigny Park,
London, UK [2] University of Exeter Medical School, Exeter
University, St Luke's Campus, Exeter, UK.
Abstract
Autism
spectrum disorder (ASD) defines a group of common, complex
neurodevelopmental disorders. Although the aetiology of ASD has a
strong genetic component, there is considerable monozygotic (MZ)
twin discordance indicating a role for non-genetic factors. Because
MZ twins share an identical DNA sequence, disease-discordant MZ twin
pairs provide an ideal model for examining the contribution of
environmentally driven epigenetic factors in disease. We performed a
genome-wide analysis of DNA methylation in a sample of 50 MZ twin
pairs (100 individuals) sampled from a representative population
cohort that included twins discordant and concordant for ASD,
ASD-associated traits and no autistic phenotype. Within-twin and
between-group analyses identified numerous differentially methylated
regions associated with ASD. In addition, we report significant
correlations between DNA methylation and quantitatively measured
autistic trait scores across our sample cohort. This study
represents the first systematic epigenomic analyses of MZ twins
discordant for ASD and implicates a role for altered DNA methylation
in autism.
"Exerpt
These
findings concur with mounting data suggesting that environmentally
mediated effects on the epigenome may be relatively common and
important for disease."
Correlations
between gene expression and mercury levels in blood of boys with and
without autism.
Neurotox
Res. 2011 Jan;19(1):31-48. doi: 10.1007/s12640-009-9137-7. Epub 2009
Nov 24.
Stamova
B1, Green PG, Tian Y, Hertz-Picciotto I, Pessah IN, Hansen R, Yang
X, Teng J, Gregg JP, Ashwood P, Van de Water J, Sharp FR.
Department
of Neurology, University of California at Davis Medical Center,
Sacramento, CA 95817, USA. boryana.stamova@ucdmc.ucdavis.edu
Abstract
Gene
expression in blood was correlated with mercury levels in blood of
2- to 5-year-old boys with autism (AU) compared to age-matched
typically developing (TD) control boys. This was done to address the
possibility that the two groups might metabolize toxicants, such as
mercury, differently. RNA was isolated from blood and gene
expression assessed on whole genome Affymetrix Human U133 expression
microarrays. Mercury levels were measured using an inductively
coupled plasma mass spectrometer. Analysis of covariance (ANCOVA)
was performed and partial correlations between gene expression and
mercury levels were calculated, after correcting for age and batch
effects. To reduce false positives, only genes shared by the ANCOVA
models were analyzed. Of the 26 genes that correlated with mercury
levels in both AU and TD boys, 11 were significantly different
between the groups (P(Diagnosis*Mercury) ≤ 0.05). The expression
of a large number of genes (n = 316) correlated with mercury levels
in TD but not in AU boys (P ≤ 0.05), the most represented
biological functions being cell death and cell morphology.
Expression of 189 genes correlated with mercury levels in AU but not
in TD boys (P ≤ 0.05), the most represented biological functions
being cell morphology, amino acid metabolism, and antigen
presentation. These data and those in our companion study on
correlation of gene expression and lead levels show that AU and TD
children display different correlations between transcript levels
and low levels of mercury and lead. These findings might suggest
different genetic transcriptional programs associated with mercury
in AU compared to TD children.
Abnormal
immune response to brain tissue antigen in the syndrome of
autism.
Am
J Psychiatry. 1982 Nov;139(11):1462-5.
Weizman A, Weizman R,
Szekely GA, Wijsenbeek H, Livni E.
Abstract
Cell-mediated
immune response to human myelin basic protein was studied by the
macrophage migration inhibition factor test in 17 autistic patients
and a control group of 11 patients suffering from other mental
diseases included in the differential diagnosis of the syndrome of
autism. Of the 17 autistic patients, 13 demonstrated inhibition of
macrophage migration, whereas none of the nonautistic patients
showed such a response. The
results indicate the existence of a cell-mediated immune response to
brain tissue in the syndrome of autism.
Detection
and sequencing of measles virus from peripheral mononuclear cells
from patients with inflammatory bowel disease and autism.
Dig
Dis Sci. 2000 Apr;45(4):723-9.
Kawashima H, Mori T, Kashiwagi
Y, Takekuma K, Hoshika A, Wakefield A.
Department of
Paediatrics, Tokyo Medical University, Japan.
Abstract
It
has been reported that measles virus may be present in the intestine
of patients with Crohn's disease. Additionally, a new syndrome has
been reported in children with autism who exhibited developmental
regression and gastrointestinal symptoms (autistic enterocolitis),
in some cases soon after MMR vaccine. It is not known whether the
virus, if confirmed to be present in these patients, derives from
either wild strains or vaccine strains. In order to characterize the
strains that may be present, we have carried out the detection of
measles genomic RNA in peripheral mononuclear cells (PBMC) in eight
patients with Crohn's disease, three patients with ulcerative
colitis, and nine children with autistic enterocolitis. As controls,
we examined healthy children and patients with SSPE, SLE, HIV-1 (a
total of eight cases). RNA was purified from PBMC by Ficoll-paque,
followed by reverse transcription using AMV; cDNAs were subjected to
nested PCR for detection of specific regions of the hemagglutinin
(H) and fusion (F) gene regions. Positive samples were sequenced
directly, in nucleotides 8393-8676 (H region) or 5325-5465 (from
noncoding F to coding F region). One of eight patients with Crohn
disease, one of three patients with ulcerative colitis, and three of
nine children with autism, were positive. Controls were all
negative. The sequences obtained from the patients with Crohn's
disease shared the characteristics with wild-strain virus. The
sequences obtained from the patients with ulcerative colitis and
children with autism were consistent with being vaccine strains.
The results were concordant with the exposure history of the
patients. Persistence of measles virus was confirmed in PBMC in some
patients with chronic intestinal inflammation.
Mechanisms
of aluminum adjuvant toxicity and autoimmunity in pediatric
populations
Lupus.
2012 Feb;21(2):223-30. doi: 10.1177/0961203311430221.
L
Tomljenovic, CA Shaw
Neural Dynamics Research Group,
Department of Ophthalmology and Visual Sciences, University of
British Columbia, Vancouver, BC, Canada
Departments of
Ophthalmology and Visual Sciences and Experimental Medicine and the
Graduate Program in Neuroscience, University of British Columbia,
Vancouver, BC, Canada
Lucija Tomljenovic, Post-doctoral
fellow, Neural Dynamics Research Group, Department of Ophthalmology
and Visual Sciences, University of British Columbia
Abstract
Immune
challenges during early development, including those
vaccine-induced, can lead to permanent detrimental alterations of
the brain and immune function. Experimental evidence also shows that
simultaneous administration of as little as two to three immune
adjuvants can overcome genetic resistance to autoimmunity. In some
developed countries, by the time children are 4 to 6 years old, they
will have received a total of 126 antigenic compounds along with
high amounts of aluminum (Al) adjuvants through routine
vaccinations. According to the US Food and Drug Administration,
safety assessments for vaccines have often not included appropriate
toxicity studies because vaccines have not been viewed as inherently
toxic. Taken together, these observations raise plausible concerns
about the overall safety of current childhood vaccination programs.
When assessing adjuvant toxicity in children, several key points
ought to be considered: (i) infants and children should not be
viewed as “small adults” with regard to toxicological risk as
their unique physiology makes them much more vulnerable to toxic
insults; (ii) in adult humans Al vaccine adjuvants have been linked
to a variety of serious autoimmune and inflammatory conditions
(i.e., “ASIA”), yet children are regularly exposed to much
higher amounts of Al from vaccines than adults; (iii) it is often
assumed that peripheral immune responses do not affect brain
function. However,
it is now clearly established that there is a bidirectional
neuro-immune cross-talk that plays crucial roles in immunoregulation
as well as brain function. In turn, perturbations of the
neuro-immune axis have been demonstrated in many autoimmune diseases
encompassed in “ASIA” and are thought to be driven by a
hyperactive immune response; and (iv) the same components of the
neuro-immune axis that play key roles in brain development and
immune function are heavily targeted by Al adjuvants.
In summary, research evidence shows that increasing concerns about
current vaccination practices may indeed be warranted. Because
children may be most at risk of vaccine-induced complications, a
rigorous evaluation of the vaccine-related adverse health impacts in
the pediatric population is urgently needed.
Etiology
of autism spectrum disorders: Genes, environment, or both?
OA
Autism 2014 Jun 10;2(2):11
C Shaw, S Sheth, D Li, L
Tomljenovic
University of British Columbia, Vancouver, British
Columbia, Canada
Introduction
Thus
far, most of the research on both neurodevelopmental and
neurodegenerative disorders has been focused on finding the presumed
underlying genetic causes, while much less emphasis has been put on
potential environmental factors. While some forms of autism are
clearly genetic, the fact remains that heritability factors cannot
adequately explain all reported cases nor their drastic increase
over the last few decades. In particular, studies on twins have now
shown that common environmental factors account for 55% of their
risk for developing autism while genetic susceptibility explains
only 37% of cases. Because the prenatal environment and early
postnatal environment are shared between twins and because overt
symptoms of autism emerge around the end of the first year of life,
it is likely that at least some of the environmental factors
contributing to the risk of autism exert their deleterious
neurodevelopmental effect during this early period of life. Indeed,
evidence has now emerged showing that autism may in part result from
early-life immune insults induced by environmental xenobiotics. One
of the most common xenobiotic with immuno-stimulating as well as
neurotoxic properties to which infants under two years of age are
routinely exposed worldwide is the aluminum (Al) vaccine adjuvant.
In this review we discuss the mechanisms by which Al can induce
adverse neurological and immunological effects and how these may
provide important clues of Al’s putative role in autism. Because
of the tight connection between the development of the immune and
the central nervous system, the possibility that
immune-overstimulation in early infancy via vaccinations may play a
role in neurobehavioural disorders needs to be carefully considered.
Conclusion
There
is now sufficient evidence from both human and animal studies
showing that cumulative exposure to aluminium adjuvants is not as
benign as previously assumed. Given that vaccines are the only
medical intervention that we attempt to deliver to every living
human on earth and that by far the largest target population for
vaccination are healthy children, a better appreciation and
understanding of vaccine adjuvant risks appears warranted.
Thiol-modulated
mechanisms of the cytotoxicity of thimerosal and inhibition of DNA
topoisomerase II alpha.
Chem
Res Toxicol. 2008 Feb;21(2):483-93.
Wu X, Liang H, O'Hara KA,
Yalowich JC, Hasinoff BB.
Faculty of Pharmacy, University of
Manitoba, 50 Sifton Road, Winnipeg, Manitoba, R3T 2N2,
Canada.
Abstract
Thimerosal is an organic mercury compound
that is widely used as a preservative in vaccines and other solution
formulations. The use of thimerosal has caused concern about its
ability to cause neurological abnormalities due to mercury
accumulation during a normal schedule of childhood vaccinations.
While the chemistry and the biological effects of methylmercury have
been well-studied, those of thimerosal have not. Thimerosal reacted
rapidly with cysteine, GSH, human serum albumin, and single-stranded
DNA to form ethylmercury adducts that were detectable by mass
spectrometry. These results indicated that thimerosal would be
quickly metabolized in vivo because of its reactions with protein
and nonprotein thiols. Thimerosal
also potently inhibited the decatenation activity of DNA
topoisomerase II alpha, likely through reaction with critical free
cysteine thiol groups.
Thimerosal, however, did not act as a topoisomerase II poison and
the lack of cross-resistance with a K562 cell line with a decreased
level of topoisomerase II alpha (K/VP.5 cells) suggested that
inhibition of topoisomerase II alpha was not a significant mechanism
for the inhibition of cell growth. Depletion
of intracellular GSH with buthionine sulfoximine treatment greatly
increased the K562 cell growth inhibitory effects of thimerosal,
which showed that intracellular glutathione had a major role in
protecting cells from thimerosal.
Pretreatment of thimerosal with glutathione did not, however, change
its K562 cell growth inhibitory effects, a result consistent with
the rapid exchange of the ethylmercury adduct among various
thiol-containing cellular reactants. Thimerosal-induced single and
double strand breaks in K562 cells were consistent with a rapid
induction of apoptosis. In conclusion, these studies have elucidated
some of the chemistry and biological activities of the interaction
of thimerosal with topoisomerase II alpha and protein and nonprotein
thiols and with DNA.
Topoisomerases
facilitate transcription of long genes linked to autism
Nature
(2013) doi:10.1038/nature12504
Received 17 January 2013 Accepted
24 July 2013 Published online 28 August 2013
Ian F. King,
Chandri N. Yandava, Angela M. Mabb, Jack S. Hsiao, Hsien-Sung
Huang, Brandon L. Pearson, J. Mauro Calabrese, Joshua Starmer,
Joel S. Parker, Terry Magnuson, Stormy J. Chamberlain, Benjamin D.
Philpot & Mark J. Zylka
Abstract
Topoisomerases are
expressed throughout the developing and adult brain and are mutated
in some individuals with autism spectrum disorder (ASD). However,
how topoisomerases are mechanistically connected to ASD is unknown.
Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor,
dose-dependently reduces the expression of extremely long genes in
mouse and human neurons, including nearly all genes that are longer
than 200 kilobases. Expression of long genes is also reduced after
knockdown of Top1 or Top2b in neurons, highlighting that both
enzymes are required for full expression of long genes. By mapping
RNA polymerase II density genome-wide in neurons, we found that this
length-dependent effect on gene expression was due to impaired
transcription elongation. Interestingly, many high-confidence ASD
candidate genes are exceptionally long and were reduced in
expression after TOP1 inhibition. Our
findings suggest that chemicals and genetic mutations that impair
topoisomerases could commonly contribute to ASD and other
neurodevelopmental disorders.
Aluminum
in the central nervous system (CNS): toxicity in humans and animals,
vaccine adjuvants, and autoimmunity.
Immunol
Res. 2013 Jul;56(2-3):304-16.
Shaw CA, Tomljenovic
L.
Abstract
We have examined the neurotoxicity of aluminum
in humans and animals under various conditions, following different
routes of administration, and provide an overview of the various
associated disease states. The literature demonstrates clearly
negative impacts of aluminum on the nervous system across the age
span. In adults, aluminum exposure can lead to apparently
age-related neurological deficits resembling Alzheimer's and has
been linked to this disease and to the Guamanian variant, ALS-PDC.
Similar outcomes have been found in animal models. In addition,
injection of aluminum adjuvants in an attempt to model Gulf War
syndrome and associated neurological deficits leads to an ALS
phenotype in young male mice. In young children, a highly
significant correlation exists between the number of pediatric
aluminum-adjuvanted vaccines administered and the rate of autism
spectrum disorders. Many of the features of aluminum-induced
neurotoxicity may arise, in part, from autoimmune reactions, as part
of the ASIA syndrome.
Transcriptomic
Analyses of Neurotoxic Effects in Mouse Brain After Intermittent
Neonatal Administration of Thimerosal.
Toxicol
Sci. 2014 Apr 4.
Li X1, Qu F, Xie W, Wang F, Liu H, Song S,
Chen T, Zhang Y, Zhu S, Wang Y, Guo C, Tang TS.
Abstract
Thimerosal
is a vaccine antimicrobial preservative which has long been
suspected an iatrogenic factor possibly contributing to
neurodevelopmental disorders including autism. The association
between infant vaccine thimerosal exposure and autism remains an
open question. Although thimerosal has been removed from mandatory
childhood vaccines in the United States, thimerosal-preserved
vaccines are still widely used outside of the United States
especially in developing countries. Notably, thimerosal-containing
vaccines are being given to the newborns within the first 12-24 h
after birth in some countries. To examine the possible neurotoxic
effects of early neonatal exposure to a higher level of thimerosal,
FVB mice were subcutaneously injected with thimerosal-mercury at a
dose which is 20× higher than that used for regular Chinese infant
immunization during the first 4 months of life. Thimerosal-treated
mice exhibited neural development delay, social interaction
deficiency, and inclination of depression. Apparent
neuropathological changes were also observed in adult mice
neonatally treated with thimerosal. High-throughput RNA sequencing
of autistic-behaved mice brains revealed the alternation of a number
of canonical pathways involving neuronal development, neuronal
synaptic function, and the dysregulation of endocrine system.
Intriguingly, the elevation of anterior pituitary secreting hormones
occurred exclusively in male but not in female thimerosal-treated
mice, demonstrating for the first time the gender bias of
thimerosal-mercury toxicity with regard to endocrine system. Our
results indicate that higher dose of neonatal thimerosal-mercury
(20× higher than that used in human) is capable of inducing
long-lasting substantial dysregulation of neurodevelopment, synaptic
function, and endocrine system, which could be the causal
involvements of autistic-like behavior in mice.
Self-organized
criticality theory of autoimmunity.
PLoS
One. 2009 Dec 31;4(12):e8382. doi: 10.1371/journal.pone.0008382.
Tsumiyama
K1, Miyazaki Y, Shiozawa S.
Department
of Biophysics, Kobe University Graduate School of Health Science,
Kobe, Japan.
Abstract
BACKGROUND:
The
cause of autoimmunity, which is unknown, is investigated from a
different angle, i.e., the defect in immune 'system', to explain the
cause of autoimmunity.
METHODOLOGY/PRINCIPAL
FINDINGS:
Repeated
immunization with antigen causes systemic autoimmunity in mice
otherwise not prone to spontaneous autoimmune diseases.
Overstimulation of CD4(+) T cells led to the development of
autoantibody-inducing CD4(+) T (aiCD4(+) T) cell which had undergone
T cell receptor (TCR) revision and was capable of inducing
autoantibodies. The aiCD4(+) T cell was induced by de novo TCR
revision but not by cross-reaction, and subsequently overstimulated
CD8(+) T cells, driving them to become antigen-specific cytotoxic T
lymphocytes (CTL). These CTLs could be further matured by antigen
cross-presentation, after which they caused autoimmune tissue injury
akin to systemic lupus erythematosus (SLE).
CONCLUSIONS/SIGNIFICANCE:
Systemic
autoimmunity appears to be the inevitable consequence of
over-stimulating the host's immune 'system' by repeated immunization
with antigen, to the levels that surpass system's self-organized
criticality.
Can
Awareness of Medical Pathophysiology in Autism Lead to Primary Care
Autism Prevention Strategies?
Elizabeth Mumper, MD, FAAP
N A J Med Sci.
2013;6(3):134-144. DOI:
10.7156/najms.2013.0603134
Abstract
Emerging research
suggests that the timing of environmental factors in the presence of
genetic predispositions has influenced the increase in autism
spectrum disorders over the past several decades. A review of the
medical literature suggests that autism may be impacted by
environmental toxicants, breastfeeding duration, gut flora
composition, nutritional status, acetaminophen use, vaccine
practices and use of antibiotics and/or frequency of infections. The
author reports her retrospective clinical research in a general
pediatric practice (Advocates for Children), which shows a modest
trend toward lower prevalence of autism than her previous pediatric
practice or recent CDC data. Out of 294 general pediatrics patients
followed since 2005 there were zero new cases of autism (p value
0.014). Given the prevalence of autism for that cohort of 1 in 50
children in the United States, it is important to consider
implementing strategies in primary care practice that could
potentially modify environmental factors or affect the timing of
environmental triggers contributing to autism.
Autism:
a novel form of mercury poisoning
Medical
Hypotheses (2001) 56(4), 462–471, 2001 Harcourt Publishers Ltd
doi:
10.1054/mehy.2000.1281,
S.
Bernard, A. Enayati, L. Redwood, H. Roger, T. Binstock
ARC
Research, Cranford, New Jersey, USA
Summary
Autism is a syndrome characterized by impairments in social
relatedness and communication, repetitive behaviors, abnormal
movements, and sensory dysfunction. Recent epidemiological studies
suggest that autism may affect 1 in 150 US children. Exposure to
mercury can cause immune, sensory, neurological, motor, and
behavioral dysfunctions similar to traits defining or associated
with autism, and the similarities extend to neuroanatomy,
neurotransmitters, and biochemistry. Thimerosal, a preservative
added to many vaccines, has become a major source of mercury in
children who, within their first two years, may have received a
quantity of mercury that exceeds safety guidelines. A review of
medical literature and US government data suggests that: (i) many
cases of idiopathic autism are induced by early mercury exposure
from thimerosal; (ii) this type of autism represents an unrecognized
mercurial syndrome; and (iii) genetic and non-genetic factors
establish a predisposition whereby thimerosal’s adverse effects
occur only in some children.
[Autistic
syndrome (Kanner) and vaccination against smallpox (author's
transl)].
Eggers C.
Klin Padiatr. 1976
Mar;188(2):172-80. [Article in German]
Abstract
3-4
weeks following an otherwise uncomplicated first vaccination against
smallpox a boy, then aged 15 months and last seen at the age of 5
1/2 years, gradually developed a complete Kanner syndrome. The
question whether vaccination and early infantile autism might be
connected is being discussed. A causal relationship is considered
extremely unlikely. But vaccination
is recognized as having a starter function for the onset of
autism.
Autistic
disturbances of affective contact.
Nervous Child 2,
217-250 (1943)
Kanner L.
Johns Hopkins University
“Case
3. Richard M. was referred to the Johns Hopkins Hospital on February
5, 1941, at 3 years, 3 months of age, with the complaint of deafness
because he did not talk and did not respond to questions.”
“Following
smallpox vaccination at 12 months, he had an attack of diarrhea and
fever, from which he recovered in somewhat less than a week.”
“In
September, 1940, the mother, in commenting on Richard's failure to
talk, remarked in her notes: I can't be sure just when he stopped
the imitation of words sounds. It seems that he has gone backward
mentally gradually for the last two years.”
Richard
M:
November 1937 – Born
November
1938 – Vaccinated with Smallpox vaccine
September 1940 –
Mother reports developmental regression beginning approximately two
years previously
February 1941 – Referred to Hopkins for
evaluation
1943 – Becomes the third child to be described
as autistic by Leo Kanner in his disorder defining paper, the first
paper published on autism.
