Meiotic Studies of Chemicals With Estrogenic Activity

描述（由申请人提供）：人造物质对人类和其他动物物种生殖健康的潜在影响是一个日益受到关注的领域，然而，由于缺乏合适的分析系统，明确描述特定物质生殖影响的努力受到阻碍。在减数分裂研究过程中，我们的群体中的小鼠无意中暴露于双酚A （BPA）提供了证据，证明这种“雌激素模拟物”破坏了哺乳动物雌性减数分裂，增加了减数分裂不分离的风险。我们实验室的后续研究表明，雄性和雌性小鼠的减数分裂过程对BPA非常敏感，因为比目前公认的NOEL低1000倍的剂量会诱发可检测到的减数分裂异常。这些发现引起了人们对BPA对人类生殖的潜在影响的严重关注。然而，如果我们首先在动物模型中准确地定义BPA暴露的影响，就可以最好地设计有效的人体研究。拟议的研究旨在深入探索这些初步发现，使我们能够确定BPA在卵子发生和精子发生过程中如何，何时以及在何种水平上破坏哺乳动物减数分裂。重要的是，我们将确定其他雌激素化合物（如雌二醇、己烯雌酚）是否会产生类似的效果，从而开始阐明BPA作用的细胞/分子机制。此外，我们将使用雌激素受体敲除小鼠来验证bpa特异性减数分裂效应是通过非传统机制介导的假设（即，独立于已知的雌激素受体）。最后，我们将使用一种新设计的筛选工具，包括出芽酵母，酿酒酵母，来确定BPA发挥其作用的机制。这些研究的综合数据不仅将提供BPA对人体潜在影响的重要见解，而且将检验减数分裂研究在评估化学品暴露对生殖影响方面的有效性。

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.