Meiotic Studies of Chemicals With Estrogenic Activity

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The potential effects of man-made substances on the reproductive health of humans and other animal species is an area of increasing concern, however, efforts to clearly delineate the reproductive effects of specific substances have been hampered by the lack of a suitable assay system. The inadvertent exposure of mice in our colony to bisphenol A (BPA) during the course of meiotic studies provided evidence that this "estrogen mimic" disrupts mammalian female meiosis, increasing the risk of meiotic nondisjuntion. Subsequent investigations in our laboratory suggest that the meiotic process in both male female mice is exquisitely sensitive to BPA, as doses that are 1000-fold lower than the currently accepted NOEL induce detectable meiotic abnormalities. These findings raise serious concerns about the potential reproductive effects of BPA on humans. However, effective studies in humans can best be designed if we first accurately define the effects of BPA exposure in an animal model. The proposed studies are designed to explore these preliminary findings in depth, allowing us to determine how, when, and at what level of exposure BPA acts to disrupt mammalian meiosis during both oogenesis and spermatogensis. Importantly, we will determine whether other estrogenic compounds (e.g., estradiol, diethylstilbesterol) elicit similar effects and thereby begin to elucidate the cellular/molecular mechanisms of BPA action. Further, we will use estrogen receptor knockout mice to test the hypothesis that apparent BPA-specific meiotic effects are mediated through non-traditional mechanisms (i.e., act independently of the known estrogen receptors). Lastly, we will use a newly devised screening tool involving the budding yeast, Saccharomyces cerevisiae, to determine the mechanism(s) by which BPA exerts its effects. The combined data from these studies will not only provide important insight concerning the potential effects of BPA exposure in humans, but will test the efficacy of meiotic studies in assessing the reproductive effects of chemical exposures.