Development of a fish model for epigenetic & multigenerational contaminant effect

描述（由申请人提供）：本项目的总体目标是建立斑马鱼作为一个更快和相关的模型来研究发育暴露于环境毒物的多代和表观遗传后果。由于鱼类的快速发育、繁殖力和相对较低的养殖成本，它们是研究环境污染物暴露的多代和跨代表观遗传效应的独特适合模型，但尚未得到充分利用。苯并[a]芘是一种与环境有关的致癌和内分泌干扰化合物，会对哺乳动物造成多代影响，其影响将是本研究的重点。与BaP一样，多环芳烃（PAHs）与暴露于环境中的母亲的后代早产、低出生体重和儿童癌症有关。然而，在与这些环境暴露相关的生殖、发育和多/跨代效应的分子机制方面存在着重大的知识缺口。我们假设父母接触BaP会对生殖产生不利影响，改变基因特异性和全局甲基化状态，并导致可量化的病理。重要的是，我们预计这些影响可以在随后的F1、F2和F3代中保留下来。通过我们的实验计划，我们希望确定BaP暴露改变的新途径，并评估表观遗传变化的关键时间段、组织特异性和性别依赖性。最重要的是，我们将验证斑马鱼模型，并确定关键的生物标志物，这些标志物将能够用于进一步筛选其他化学物质，以确定成人疾病的胎儿基础和多代毒性效应。

DESCRIPTION (provided by applicant): The overall goal of this project is to establish zebrafish as a faster and relevant model to study multigenerational and epigenetic consequences of developmental exposure to environmental toxicants. Because of their rapid development, fecundity and relatively lower culture cost, fish are a uniquely suited but underutilized model to study multi- and trans-generational, epigenetic effects of environmental contaminant exposure. Effects of benzo[a]pyrene an environmentally relevant carcinogenic and endocrine disrupting compound that causes multigenerational effects in mammals will be the focus of this study. Polycyclic aromatic hydrocarbons (PAHs), like BaP, are implicated in preterm deliveries, low birth weights, and childhood cancers in offspring of exposed mothers. However, a significant knowledge gap exists in the molecular mechanisms for reproductive, developmental and multi/trans-generational effects associated with these environmental exposures. We hypothesize that parental exposure to BaP will adversely affect reproduction, alter gene specific and global methylation status, and cause quantifiable pathologies. Importantly, we expect that these effects could be preserved in subsequent F1, F2 and F3 generations. With our experimental plan we expect to identify new pathways altered by BaP exposure and assess critical time periods, tissue specificities, and sex dependence for epigenetic changes. Most importantly we will validate the zebrafish model and identify critical biomarkers that will be able to be used to further screen other chemicals for the fetal basis of adult disease and multigenerational toxic effects. PUBLIC HEALTH RELEVANCE: There is a new appreciation that environmental factors that act during key developmental stages can increase the risk of developing adult disease, and that this disease susceptibility can be passed on multi- or transgenerationally. Fish are a well suited, but underutilized, model organism for testing the multigenerational and epigenetic consequences of environmental contaminant exposure. This proposal will use zebrafish to probe mechanisms of multigenerational toxicity of an environmentally relevant endocrine disruptor benzo[a]pyrene.