Male Germline Development and Estrogenic Exposures

 描述（由申请方提供）：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增加的结果。该项目是我们实验室最近对小鼠和绵羊进行的研究的结果，这些研究发现了外源性雌激素诱导的新表型：我们发现睾丸发育期间的暴露会影响成年雄性的减数分裂前期事件，显着且永久地降低暴露个体的减数分裂重组水平。因为重组是雄性减数分裂的基本特征，并且降低水平低于特定阈值（即，每个同源染色体对一次交换）导致细胞死亡，这种新的睾丸表型与暴露于外源性雌激素对男性生育力产生不利影响的假设一致。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。我们初步研究中使用的暴露窗口与雄性生殖系的表观遗传重编程相一致。此外，由于重组的影响是永久性的，并且当暴露的雄性生殖细胞移植到对照睾丸中时，表型是明显的，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性雌激素减数分裂影响的发育窗口和易受影响的细胞类型，并通过表征暴露导致的生殖系表观遗传修饰来验证这一假设。重要的是，在这些研究中使用的重组表型提供了一种新的，敏感的，定量的方法来测量暴露的影响精子发生的一个重要方面，并跟踪跨代的影响。

 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.