Development of a fish model for epigenetic & multigenerational contaminant effect

表观遗传鱼类模型的开发

• 批准号: 8191628
• 负责人: KRISTINE L WILLETT
• 金额: $ 20.59万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-12 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191628
• 关键词: Address; Adult; Affect; Age; Animal Model; Area; Aromatic Polycyclic Hydrocarbons; Barker Hypothesis; Benzo(a)pyrene; Biological Markers; Birth Rate; Build-it; Chemicals; Chorion; DNA; Dependence; Development; Developmental Biology; Disadvantaged; Disease; Disease susceptibility; Embryo; Endocrine Disruptors; Endocrine disruption; Environmental Exposure; Environmental Pollutants; Environmental Pollution; Environmental Risk Factor; Epigenetic Process; Exposure to; Fertility; Fishes; Functional disorder; Generations; Genes; Goals; Health; Human; Investigation; Knowledge; Low Birth Weight Infant; Malignant Childhood Neoplasm; Mammals; Measures; Mediating; Medicine; Methylation; Modeling; Molecular; Molecular Target; Mothers; National Institute of Environmental Health Sciences; Outcome; Pathology; Pathway interactions; Perinatal Exposure; Phenotype; Physiological; Population; Premature Birth; Protocols documentation; Reproduction; Research; Risk; Screening procedure; Specificity; Staging; Technology; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxicology; Work; Zebrafish; base; cognitive function; cost; design; drug development; experience; insight; medical specialties; mutant; offspring; reproductive; reproductive success; sex; small molecule

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.

描述(由申请人提供)：该项目的总体目标是建立斑马鱼作为研究发育过程中暴露于环境毒物的多代和表观遗传后果的更快和相关的模型。由于其快速发育、繁殖力和相对较低的养殖成本，鱼类是研究环境污染物暴露的多代和跨代表观遗传影响的唯一适合但未得到充分利用的模型。苯并[a]芘是一种与环境相关的致癌和内分泌干扰化合物，对哺乳动物造成多代影响，它的影响将是这项研究的重点。多环芳烃(PAHs)和BaP一样，与早产、低出生体重和暴露在环境中的母亲的后代患上儿童期癌症有关。然而，在与这些环境暴露相关的生殖、发育和多代/跨代影响的分子机制方面存在着重大的知识差距。我们假设父母暴露于BaP将对生殖产生不利影响，改变基因特异性和全球甲基化状态，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，我们希望确定暴露于苯并苯后改变的新途径，并评估表观遗传学改变的关键时间段、组织特异性和性别依赖性。最重要的是，我们将验证斑马鱼的模型，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，为成人疾病的胎儿基础和多代毒性影响奠定基础。 与公共卫生相关：现在有了一种新的认识，即在关键发育阶段发挥作用的环境因素会增加成人疾病的风险，而且这种疾病易感性可以通过多代或跨代传递。鱼类是一种非常适合但未得到充分利用的模式生物，用于测试环境污染物暴露的多代和表观遗传后果。这项提议将使用斑马鱼来探索与环境相关的内分泌干扰物苯并[a]芘的多代毒性机制。