Our objective is to elucidate mechanisms by which environmental polychlorinated biphenyls (PCBs) impair reproductive function. Emphasis is placed on the effects of PCBs on hormone-secreting cells of the reproductive system. It is hypothesized that PCBs can affect reproductive function in two different ways - by acting as anti-estrogens or estrogens and/or by exerting toxic effects directly on endocrine cells of the reproductive system. In our studies, PCBs will first be tested both in vitro and in vivo to determine whether they possess any anti-estrogenic or estrogenic activity. Studies will then be conducted using cell cultures 1) to test the direct effect of these PCBs on the viability of gonadotrophs, lactotrophs, Leydig cells, and granulosa cells; 2) to assess whether pre- exposure to PCBs in vivo sensitizes cells to the toxic effects of PCBs in vitro; 3) to determine whether PCB-induced cell death involves apoptosis using the techniques of acridine orange and propidium iodide staining of nuclei, DNA electrophoresis, Apoptag labeling of 3'-OH DNA ends, and flow cytometry; and 4) to determine whether PCBs act directly on endocrine cells to alter basal and hormone-stimulated luteinizing hormone, follicle- stimulating hormone, prolactin,a nd testosterone release using radioimmunoassay and plaque assays. In additional experiments, PCBs will be administered to adult male rats to investigate effects on testicular, epididymal, and male accessory gland weights and histology; testicular sperm production and epididymal sperm storage; sperm morphology; and hormone secretion. PCBs will then be administered to female rats to determine effects on estrous cyclicity, ovulation, and secretion of reproductive hormones. The possibility that termination of treatment with PCBs reverses the effects of PCBs also will be investigated. Finally, the effects of multigenerational exposure to PCBs on reproductive processes will be studied. Results from these investigations should not only provide important insight into our understanding of the manner in which PCB environmental pollutants act to interfere with reproductive processes but should also begin to define the mechanisms by which these effects are mediated.
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