Epigenetics, environmental exposure, and reproduction in the Collaborative Cross

描述（由申请人提供） 拟议的研究是一个系统遗传学的方法来表征遗传变异，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，研究人员将利用不同近交系小鼠品系和协作杂交的力量，协作杂交是一种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，研究人员将干扰生殖系统与强大的雌激素己烯雌酚（DES）和表型相同的暴露和对照人群。 研究人员将测量DNA甲基化、mRNA表达和生殖性状，目的是在三个基因组功能水平上对遗传效应和GXE进行建模。这项研究将产生新的生物学知识的遗传网络的生殖系统，DES功能在分子水平上，和基因的DES敏感性。 公共卫生相关性：内分泌干扰物（EDCs）用于许多消费品中，大多数人经常接触低水平的EDCs。 小鼠已被用于显示EDC暴露如何对生殖系统造成不良影响，但这些研究中使用的小鼠通常在遗传上是相同的。由于研究人员知道遗传学是人类对环境暴露敏感性的重要决定因素，他们建议在一种新的小鼠资源中研究EDC对生殖的影响，这种小鼠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.