Male Germline Development and Estrogenic Exposures

男性生殖细胞发育和雌激素暴露

基本信息

批准号：
8853165
负责人：
Patricia Hunt
金额：
$ 34.58万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-22 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8853165
关键词：
Adult Affect Biological Assay Cell Death Cell Lineage Cell Transplantation Cells Chemicals Chromosome Pairing Chromosomes Cultured Cells DNA Methylation Data Defect Development Endocrine Disruptors Environmental Exposure Epigenetic Process Estrogen Receptors Estrogens Event Evolution Exposure to Fertility Generations Genetic Genetic Recombination Genetic Variation Genome Germ Cells Goals Gonadal structure Haploidy Histone H3 Human In Vitro Inbred Strains Mice Incidence Individual Knock-out Laboratories Maps Measures Mediating Meiosis Meiotic Recombination Modification Mouse Strains Mus Newborn Infant Phenotype Post-Translational Protein Processing Process Production Prophase Receptor Gene Resistance Seminal fluid Sheep Somatic Cell Sorting - Cell Movement Spermatogenesis Stem cells System Techniques Testicular Dysgenesis Syndrome Testing Testis Transplantation bisulfite sequencing cell type epigenome epigenomics estrogenic activity germline stem cells imprint male next generation novel prenatal public health relevance receptor reproductive research study tool trait

项目摘要

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.

描述（由申请人提供）：男性生育能力下降和生殖道异常发生率增加被认为是环境中暴露于具有雌激素活性的化学物质增加的结果。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。揭示了外源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男性减数分裂前期的事件，显着且永久地降低暴露个体的减数分裂重组水平。重组是雄性减数分裂的一个基本特征，并且将水平降低到特定阈值以下（即每个同源染色体对一次交换）会导致细胞死亡，这种新的睾丸表型与暴露于外源雌激素产生不利影响的假设是一致的此外，由于重组产生了遗传多样性，因此我们的初步研究中使用的暴露窗口与雄性种系的表观遗传重编程是一致的，因为对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，表型是明显的，我们发现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，我们将通过定义来检验这一假设。睾丸易受外源雌激素和易受伤害的细胞类型的减数分裂影响的发育窗口，并通过表征因暴露而产生的种系的表观遗传修饰。这些研究中使用的重组表型提供了一种新颖、灵敏和定量的方法来测量暴露对精子发生的一个重要方面的影响并跟踪各代人的影响。