| Tri-ortho-cresyl phosphate (TOCP) is a known neurotoxic organophosphorus compound widely used in industry, primarily as a heat exchange medium, a flame retardant, and a plasticizer. It causes so-called organophosphorus compound induced delayed neurotoxicity (OPIDN) in humans and other sensitive species. The toxicity to the reproductive system was heretofore unknown. The studies described in this dissertation were designed to examine the effects of TOCP on the male reproductive system and identify targets of toxicity and elucidate potential mechanisms of action.; Initial studies in roosters indicated TOCP causes pathology in seminiferous tubule germ cells consisting of vacuoles, detached spermatid heads, and decreases in vas deferens sperm motility. Esterase activities known to be susceptible to TOCP (nonspecific esterase and neurotoxic esterase), were similarly inhibited in testis. Lack of pathology following parathion administration argued for a non-cholinergic mechanism of toxicity. Subsequent studies focused exclusively on the male Fischer 344 rat, the test animal of choice for assessment of reproductive toxicity.; Subchronic daily administration of TOCP for 63 days (the length of the seminiferous epithelial cycle plus transit time of sperm to the vas deferens), resulted in dose-dependent decreases in sperm motility, numbers, density/distal cauda, and esterase activities. There was a simultaneous increase in sperm morphology abnormalities, and histopathological lesions in the seminiferous epithelium (detached spermatid heads, vacuoles, and residual bodies). Electron microscopic documentation of the time course of lesion onset and development, showed Sertoli cell endoplasmic reticulum dilation following three days of 150 mg TOCP/kg/d administration. Sertoli cells appeared to have lost supporting cytoarchitectural framework responsible for maintaining cell structure integrity. Leydig cell nonspecific esterase was inhibited (demonstrated by both biochemical and histochemical assays), however no changes in testosterone or ultrastructure were recorded. Likewise, serum luteinizing and follicle stimulating hormone levels were not affected.; A Mg('++)-dependent, Ca('++)-independent decrease in phosphorylation of testis cytosolic proteins in the molecular weight range of 50-60k, 90k, and 200k was observed. This was seen as early as 24 hours following a single 1000 mg/kg dose.; Recovery experiments indicated the TOCP-induced testicular lesion is an irreversible event at the doses administered. (Abstract shortened with permission of author.)... |
