Epigenetics, environmental exposure, and reproduction in the Collaborative Cross

描述(由申请人提供) 这项研究是一种系统遗传学方法，旨在描述遗传变异、表观遗传调控、基因表达、男性生殖生理和环境暴露之间的复杂关系。为了实现这一目标，研究人员将利用各种近交系小鼠品系和合作杂交的力量，合作杂交是具有系统遗传学理想特性的小鼠参考种群。为了确定基因与环境(GxE)的相互作用，研究人员将用强大的雌激素己烯雌酚(DES)扰乱生殖系统，并将暴露人群和对照人群的表型相同。研究人员将测量DNA甲基化、mRNA表达和生殖特征，目的是在基因组功能的三个水平上模拟遗传效应和GxE。这项研究将产生关于生殖系统潜在的遗传网络、DES在分子水平上的功能以及DES敏感性的基因的新的生物学知识。 公共卫生相关性：内分泌干扰物(EDCs)用于许多消费品，大多数人经常接触到低水平的EDCs。小鼠被用来展示EDC暴露如何对生殖系统造成不利影响，但这些研究中使用的小鼠通常在基因上是相同的。由于研究人员知道遗传学是人类对环境暴露的敏感性的重要决定因素，他们建议在一种新的可用小鼠资源中研究EDC对生殖的影响，该资源具有与人类相似的遗传变异量。

DESCRIPTION (provided by applicant) The proposed research is a systems genetics approach to characterize the complex relationships between genetic variation, epigenetic regulation, gene expression, male reproductive physiology, and environmental exposure. To accomplish this goal, the investigators will leverage the power of diverse inbred mouse strains and the Collaborative Cross, a mouse reference population that has ideal properties for systems genetics. To identify gene-by-environment (GXE) interactions, the investigators will perturb the reproductive system with the powerful estrogen diethylstilbestrol (DES) and phenotype identical exposed and control populations. The investigators will measure DNA methylation, mRNA expression, and reproductive traits with the purpose of modeling genetic effects and GXE across three levels of genome function. This research will produce new biological knowledge of the genetic networks underlying the reproductive system, DES function at the molecular level, and genes underlying DES sensitivity. Public Health Relevance: Endocrine disrupting chemicals (EDCs) are used in many consumer products and most people are exposed to low levels of EDCs regularly. Mice have been used to show how EDC exposure can cause adverse effects on the reproductive system, but the mice used in these studies are usually genetically identical. Since the investigators know genetics are an important determinant of sensitivity to environmental exposures in humans, they propose to study EDC effects on reproduction in a newly available mouse resource that has a human-like amount of genetic variation.