Meiotic Studies of Chemicals With Estrogenic Activity

描述(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令人关注的领域，然而，由于缺乏适当的检测系统，明确描述特定物质的生殖影响的努力受到阻碍。在减数分裂研究过程中，我们群体中的小鼠无意中接触了双酚A(BPA)，这提供了证据，表明这种类似雌激素的物质破坏了哺乳动物的雌性减数分裂，增加了减数分裂不解体的风险。我们实验室的后续研究表明，两只雄性和雌性小鼠的减数分裂过程对BPA都非常敏感，因为低于目前接受的NOEL 1000倍的剂量会导致可检测到的减数分裂异常。这些发现引发了人们对双酚A对人类潜在生殖影响的严重担忧。然而，如果我们首先在动物模型中准确地定义双酚A暴露的影响，那么在人类身上进行有效的研究是最好的设计。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如何、何时以及在什么水平上在卵子发生和精子发生期间干扰哺乳动物的减数分裂。重要的是，我们将确定其他雌激素化合物(如雌二醇、二乙基己烯甾醇)是否也能产生类似的作用，从而开始阐明双酚A作用的细胞/分子机制。此外，我们将使用雌激素受体基因敲除小鼠来检验这一假设，即明显的BPA特异性减数分裂效应是通过非传统机制(即，独立于已知的雌激素受体发挥作用)介导的。最后，我们将使用一种新设计的筛选工具，包括萌芽酵母，酿酒酵母，以确定双酚A发挥作用的机制(S)。这些研究的综合数据不仅将提供有关双酚A暴露对人类潜在影响的重要见解，还将测试减数分裂研究在评估化学暴露的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.