Development of a fish model for epigenetic & multigenerational contaminant effect

表观遗传鱼类模型的开发

基本信息

批准号：
8319336
负责人：
KRISTINE L WILLETT
金额：
$ 17.88万
依托单位：
UNIVERSITY OF MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-12 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8319336
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

项目摘要

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.

描述（由申请人提供）：该项目的总体目标是建立斑马鱼作为一种更快，相关的模型，以研究发展对环境有毒物质的发展的多代和表观遗传后果。由于它们的快速发展，繁殖力和相对较低的培养成本，FISH是一种独特但未充分利用的模型，用于研究环境污染物暴露的多代和跨代，表观遗传效应。苯并[a] pyrene的作用是与环境相关的致癌和内分泌破坏化合物，从而在哺乳动物中引起多代作用，这将是这项研究的重点。多环芳烃（PAHS）（如BAP）与早产，低出生体重和童年癌症有关，与裸露的母亲的后代有关。然而，与这些环境暴露相关的生殖，发育和多/跨代作用的分子机制中存在显着的知识差距。我们假设父母接触BAP将对繁殖，改变基因特异性和全球甲基化状态并引起可量化的病理。重要的是，我们期望这些效果可以保留在随后的F1，F2和F3代中。通过我们的实验计划，我们期望确定通过BAP暴露改变的新途径，并评估表观遗传变化的关键时间，组织特异性和性依赖性。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，这些生物标志物将能够用于进一步筛选其他化学物质作为成人疾病和多代毒性作用的胎儿基础。