CYTOSKELETAL TARGETS OF NEURONAL/TESTICULAR TOXICANTS

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A group of large volume, commercially important environmental and industrial toxicants - including the acrylamides, organophosphorus esters and the hexacarbons - selectively injure the nervous system and male reproductive system. Research in this laboratory, supported by ROl ES05033 entitled "Environmental/Industrial Toxicants and Testicular Injury" and funded through 08/31/93, has focused on the testicular Sertoli cell cytoskeleton as a target for these toxicants. A Research Career Development Award provides an opportunity to expand the scope of research by emphasizing a multifaceted approach to they investigation of these combined neuronal/testicular toxicants. The candidate, Kim Boekelheide, M.D., Ph.D., is Assistant Professor (tenure track} the Department of Pathology and Laboratory Medicine at Brown University. Receipt of a Research Career Development Award will relieve him of non-research-related administrative and teaching burdens which currently occupy 50% of his time. The expectation is that Dr. Boekelheide will continue to take advantage of the fine basic science research available and advance in his research career at Brown University. A manuscript recently accepted for publication in The Journal of Cell biology (M.D. Neely and K. Boekelheide, "Sertoli cell processes have axoplasmic features: an ordered microcubule distribution and an abundance high molecular weight microtubule associated protein (cycoplasmic dynein)"), describes the comparative approach taken to elucidate shared features of neuronal and testicular cytoskeletons. This proposal will continue the basic description of common cytoskeletal features and examine unique neuronal/ testicular cytoskeletal components as targets for toxicant-induced injury. The following specific hypothesis will be tested: 1) intoxication with some toxicants inhibits the function of the cytoplasmic dynein found in Sertoli cells and axons, 2) inhibition of the function of this microtubule motor blocks retrograde transport in the axon and vesicle transport in the Sertoli cell, and 3) failure of retrograde axonal transport results in a localized axonopathy with associated distal degeneration while failure of Sertoli cell vesicle transport leads to germ cell necrosis and sloughing.