The proposed research is designed to investigate the role of calmodulin, a calcium binding protein, in the mechanism of toxic action of xenobiotics with particular reference to chlordecone and its metabolite, chlordecone alcohol. The research, as outlined would evaluate the interaction of these neurotoxicants with synaptic function in rodent brain. Neurochemical and biochemical evaluation of the effects of these neurotoxicants on brain function would provide valuable information on the alterations of synaptic function. As established in past experimentation, proper functioning of the central nervous system is dependent on proper neurotransmission. Neurotransmission is dependent on proper synthesis, release, binding and uptake/reuptake of several neurotransmitters such as dopamine, norepinephrine, serotonin, acetylcholine and gamma aminobutyric acid. Interaction of toxicants with these neuronal processes will result in the dysfunction of the central nervous system. Calmodulin has been shown to regulate various biochemical events associated with synaptic function. The effects of chlordecone and its metabolism of chloredecone alcohon on calmodulin dependent neurotransmitter synthesis, neurotransmitter release, protein phosphorylation, protein kinase and membrane bound transport enzymes which are critical to the synaptic function will be determined. Such multifaceted studies, as proposed, should extend existing knowledge regarding the specific effects of chlordecone interaction with the central nervous system. Once the mechanism of toxic action of chlordecone and its metabolite, chlordecone alcohol, is understood then development of proper therapeutic measures would be possible. Such therapeutic measures would be invaluable in the treatment of humans exposed to these and related environmental chemicals. The test animal will be gerbils whose ability to convert chlordecone to chlordecone alcohol parallels the ability of humans to make this conversion.
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