Many environmentally important pollutants, including certain metals and their organic derivatives are neurotoxic. The development of the nervous system is influenced by extrinsic factors, and the perturbations caused by toxic metals often may be different in the developing nervous system than in the mature nervous system. We have previously demonstrated that lead has unique intoxicating effects in the immature nervous system: a persistent abnormal polydipsia to lithium of central nervous system origin; a defect in synaptogenesis lasting to senescence; and a persistent reduction in myelin. We will continue to utilize a multidisciplinary approach to ellucidate the neurotoxic effects of heavy metals, to investigate how such neurotoxic alterations affect the subsequent structural, chemical and functional development of the nervous system, and to determine the mechanisms of the neurotoxic action of selective toxic metals. A selected series of organometal derivatives will be used to investigate structure-neurotoxicity relationships. These studies will be pursued by investigating the uptake, distribution and fate of the neurotoxins and by determining the effect of these agents on the development and stability of neurotransmitter systems, axonal transport and myelination, and selected aspects of transport systems of the blood-brain barrier. Emphasis will be placed on those animal and in vitro models which most directly allow testing of the hypotheses that the developing nervous system is more sensitive to these agents and that consequences of such perturbations of neural development may be unique or tardive in their manifestations. Consistent with this, selected aspects of lead neurotoxicity will be investigated further. In addition, new studies will be pursued based upon our Program experience, especially those which offer rational comparisons with our earlier studies with lead. In this regard, initial plans call for examination of a selected series of organotin compounds and organolead compounds.
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