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National Center For Environmental Research |  |
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Male Reproductive Toxicology GR Klinefelter 22.31.10.16 We conduct a multifaceted research program in male reproductive toxicology. Work involves (1) developing novel testing strategies, both in vivo and in vitro, in the field of epididymal toxicology; (2) developing a method to coculture epididymal epithelial cells and sperm in order to verify direct action on the epididymis; (3) studying the influence of specific proteins on sperm maturation using tandem cocultures of sperm and epididymal epithelial cells; (4) developing a method for in utero insemination to help detect alterations in fertility; (5) conducting a multivariant analysis to elucidate endpoints correlated with and predictive of toxicant-induced fertility; and (6) developing an in vitro system that permits stage dependent maturation of isolated seminiferous tubules. To date, we have identified a specific sperm protein as a candidate biomarker of fertility. Immunologic and molecular probes will be developed in order to characterize and understand the importance of this molecule and to screen for fertility defects following exposure to priority environmental chemicals. To improve the detection of endocrine-mediated effects, we quantitatively analyze two-dimensional, gel electrophoretic profiles of constitutive epididymal protein from animals exposed to environmental chemicals such as TCDD (dioxin), PCB169, and Vinclozolin. Furthermore, this analysis might provide insight into the mechanism underlying the epididymis specific decrease sperm number produced by these chemicals. The epididymal cell culture system we developed was used to demonstrate anti-androgenic action of Vinclozolin in vitro. If effects on protein synthesis and/or secretion are achieved at biologically relevant exposures, we could develop a biologically based dose-response model. Moreover, the culture system is readily amenable to human tissue application, making species extrapolation feasible. Recent research on drinking water disinfection byproducts has been responsible for an expanding program in male reproductive toxicology. Our studies have shown that both dibromoacetic and dichloracetic acid disruptspermatogenesis by inhibiting the release of sperm in the testis, which causes sperm fusion. Based on these results, studies are planned to define the mechanism of action of this and structurally related compounds. Our goal is to evaluate multiple endpoints in the semen of men exposed to a mixture of disinfection byproducts known to elicit effects in the rat. References Klinefelter G, et al: Journal of Andrology 15: 318, 1994 Klinefelter G, et al: Andrology 13: 409, 1992
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