The hexacarbons, acrylamides and carbon disulfide are all industrial compounds produced in large quantity which pose a serious health risk due to their induction of a similar toxic syndrome consisting of nervous system dysfunction and testicular atrophy following subchronic workplace or environmental exposure. This laboratory has identified abnormalities in microtubule assembly resulting from intoxication of rats with the biologically active n-hexane metabolite 2,5-hexanedione and has associated these microtubule abnormalities with the induction of testicular atrophy. Based on these preliminary observations, we propose the following hypothesis for the pathogenesis of testicular injury induced by this class of toxicants: after metabolic activation, the hexacarbons, acrylamides and carbon disulfide produce crosslinks between lysyl Epilson-amine groups of tubulin; crosslinked tubulin subunits nucleate microtubule formation; the presence of additional toxicant induced nucleating centers within cells alters the number and length of cytoplasmic microtubules; testicular atrophy results because of the unique dependence of the seminiferous tubule upon Sertoli cell cytoskeletal integrity for the maintenance of spermatogenesis and testicular homeostasis. This hypothesis will be tested with a Gamma-diketone treatment protocol which controls for systemic and nervous system toxicity allowing identification of biochemical and morphological events specific for testicular atrophy. The reversibility of the testicular injury will be determined. The nature of the underlying tubulin modification which results in abnormal microtubule assembly will be elucidated. Tissue culture and immunologic techniques will be developed to allow early assessment of additional compounds which may induce testicular atrophy by Sertoli cell cytoskeletal disruption.
|Boekelheide, K; Anthony, D C; Giangaspero, F et al. (1988) Aliphatic diketones: influence of dicarbonyl spacing on amine reactivity and toxicity. Chem Res Toxicol 1:200-3|