Male Germline Development and Estrogenic Exposures

 描述(由申请人提供)：男性生育力下降和生殖道异常发生率增加被认为是环境暴露于具有雌激素活性的化学品的结果。这个项目是我们实验室最近对小鼠和绵羊进行的研究的结果，发现了外源雌激素诱导的一种新的表型：我们发现，在睾丸发育期间暴露影响成年男性的减数分裂前期事件，显著和永久性地降低暴露个体的减数分裂重组水平。由于重组是男性减数分裂的基本特征，低于特定阈值的水平(即每对同源染色体一次交换)会导致细胞死亡，这种新的睾丸表型与暴露于外源雌激素对男性生育不利的假设是一致的。此外，由于重组创造了遗传多样性，我们的发现具有重要的进化意义。在我们的初步研究中使用的暴露窗口与雄性生殖系的表观遗传重新编程相一致。此外，由于重组的影响是永久性的，当来自暴露的男性的生殖细胞被移植到对照睾丸中时，表型明显，我们假设雌激素暴露直接作用于发育中的睾丸的生殖细胞，改变精原干细胞的表观基因组。我们将通过定义睾丸易受外源雌激素减数分裂影响的发育窗口(S)和易受影响的细胞类型(S)，并通过表征暴露导致的生殖系的表观遗传修饰来检验这一假设。重要的是，这些研究中使用的重组表型提供了一种新的、敏感的和定量的方法来测量暴露对精子发生的关键方面的影响，并跟踪世代之间的影响。

 DESCRIPTION (provided by applicant): Declining male fertility and an increased incidence of reproductive tract abnormalities have been postulated to be a consequence of increasing environmental exposure to chemicals with estrogenic activity. This project is an outgrowth of recent studies of mice and sheep in our laboratory that have uncovered a new phenotype induced by exogenous estrogens: We have found that exposures during testis development affect the events of meiotic prophase in the adult male, significantly and permanently reducing levels of meiotic recombination in the exposed individual. Because recombination is an essential feature of male meiosis, and decreasing levels below a specific threshold (i.e., one exchange per homologous chromosome pair) results in the demise of the cell, this new testicular phenotype is consistent with the hypothesis that exposure to exogenous estrogens adversely affects male fertility. In addition, because recombination creates genetic diversity, our findings have important evolutionary implications. The exposure windows used in our preliminary studies coincide with the epigenetic reprogramming of the male germline. In addition, because the effect on recombination is permanent and the phenotype is evident when germ cells from exposed males are transplanted into a control testis, we hypothesize that estrogenic exposures act directly on the germ cells of the developing testis, altering the epigenome of the spermatogonial stem cell. We will test this hypothesis by defining the developmental window(s) during which the testis is susceptible to the meiotic effects of exogenous estrogens and the cell type(s) that are vulnerable, and by characterizing the epigenetic modifications of the germline that result from exposure. Importantly, the recombination phenotype used in these studies provides a novel, sensitive, and quantitative approach to measuring the effects of exposures on an essential aspect of spermatogenesis and for tracking effects across generations.