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August 12, 2010
Cal State Long Beach Biochemist's Research Supports Premise That
Chemical Plasticizers May Contribute to Autism and Alzheimer's Disease
Who knew that brine shrimp—the tiny creatures popularly known as “Sea-Monkeys”—could reveal problems with chemicals found in plastics or even contribute to potential treatments for neurological conditions such as Alzheimer’s disease and autism?
Roger Acey, a professor of biochemistry at California State University, Long Beach (CSULB), and students in his lab have been studying the biology and genetics of embryonic development, using brine shrimp, Artemia salina, as a biological model. He is particularly interested in how environmental contaminants affect development.
“I think all baby boomers understand Sea-Monkeys,” Acey explained. “As kids, you could order them from suppliers advertising in comic books and grow them at home.” Artemia have long been used in scientific research and remain popular in science education at school and home. The shrimp grow up to three-quarters of an inch long and can live for some time once hatched.
Acey’s lab initially looked at how exposing the shrimp to toxic metals like copper, mercury, cadmium, etc., could affect their development. While continuing this successful work, which led to discovery of a shrimp protein that can capture metals, Acey took his ongoing research with Artemia in another direction.
“We began looking at plasticizers and how they might affect embryonic development,” he said. “We started looking at phthalate esters—compounds that give plastic bottles their malleability. They’re found in PVC (polyvinyl chloride), blood bags, plastic tubing, cosmetics and children’s toys, and are well known environmental contaminants. They have been reported to be teratogens (causing birth defects), carcinogens and endocrine disruptors. Endocrine disruptors are compounds that resemble the structure of estrogens and mimic the activity of these hormones. There are examples of populations of fish that are essentially all female due to phthalate ester contamination. Most recently, phthalate esters have been implicated in Type II diabetes.
“We made a series of phthalate esters (phthalates) with increasing the carbon chain lengths and started looking at the effect of these compounds on developing shrimp,” he continued. “Diethyl and dimethyl are non-toxic; di-n-propyl was slightly toxic; but di-n-butyl (DBP), which is the most commonly found phthalate, turns out to be the most toxic.”
As the shrimp develop, they produce an enzyme that metabolizes the DBP, he said. “At first, we called the enzyme DBPase. As soon as the shrimp hatch and begin to develop, DPBase activity increases dramatically. If you expose the shrimp to phthalate during the early period of development, they died. If you expose the shrimp to the phthalate later in development, the compound is no longer toxic. The idea is that there is a well-defined period of development when the embryos are sensitive to the phthalate. Therefore, we began looking for a specific biochemical event that was impacted by the DBP.” He has since identified DBPase as butyrylcholinesterase.
He noted that the shrimp were being affected by DBP at the point where their nervous system was beginning to develop, adding that shrimp have a cholinergic nervous system similar to humans in that they both use a chemical neurotransmitter called acetylcholine.
He and his students have since used umbilical cord stem cells to study the role of butyrylcholinesterase in developing neurons and the effect of DBP. “After the stem cells are activated and begin to develop into a neuron, the DBP becomes toxic. We think what is happening is that the DBP prevents the butyrylcholinesterase from performing its normal biological function. We’re currently in the process of determining the exact function of the enzyme," Acey said.
Acey is interested in how plasticizers might be connected to the dramatic rise in autism and Alzheimer’s disease. A recent study has shown that rat fetuses exposed to DBP develop symptoms characteristic of autism. "If you think about it, this suggests compounds that interact with butyrylcholinesterase could induce neurological problems,” he said.
That led him to consider another plasticizer, bisphenol A, commonly called BPA, which is being widely studied for its possible toxicity. Acey’s group has shown that BPA is an inhibitor of butyrylcholinesterase. “Again, the concern is that since this compound interacts with butyrylcholinesterase, it may have a pronounced effect on neuron development,” he said. Acey believes every effort should be made to prevent exposure of pregnant women and infants to these types of compounds.
“Interestingly, the level of brain butyrylcholinesterase is significantly increased in Alzheimer’s patients,” he said. Current therapeutics used in the treatment of Alzheimer’s disease target butyrylcholinesterase, so he and CSULB Professor Ken Nakayama are collaborating on further examining the biochemistry of this enzyme and its possible connections to Alzheimer’s disease.
“Dr. Nakayama, an organic chemist, had a series of compounds he wanted tested on an enzyme from bacteria,” Acey said. “I suggested we test his compounds on butyrylcholinesterase. The results of the experiments revealed that the compounds are potent inhibitors of butyrylcholinesterase and, as such, are potential therapeutics for the treatment of Alzheimer’s disease. Alzheimer’s patients lose their cognitive functions as a result of the decrease in the level of a specific neurotransmitter. Compounds that inhibit butyrylcholinesterase result in an increase in the level of neurotransmitters —the compounds responsible for memory— and the patients begin to recover their memory.”
They’ve applied for a patent for the compounds and are preparing to write a grant proposal to fund further studies to demonstrate whether the compounds can cross the blood-brain barrier. Acey remarked that some autistic children are responding to certain Alzheimer’s drugs, so the hope is that these compounds might someday be the basis for new medications to treat both conditions.
Acey’s research has been funded by grants from CSULB, the March of Dimes, the National Institutes of Health, and the California State University Program for Education and Research in Biotechnology (CSUPERB).
To learn more about Acey’s research, visit http://chemistry.csulb.edu/roger-acey.html.