Systems Toxicogenomics of Endocrine Disrupting Chemicals in Brain

脑内内分泌干扰化学物质的系统毒物基因组学

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Endocrine disrupting chemicals (EDCs) interfere with mammalian hormones, and can cause myriad adverse health effects, including developmental effects, neurological effects, reproductive effects, and cancer. One way that EDCs cause disease is by causing epigenomic modifications that change how genes are regulated in specific cells and tissues. It is often not feasible to sample brain tissue in humans, but other tissues lik blood and skin can be readily sampled. This raises the question of whether epigenomic profiles associated with EDC exposure in blood and skin are good surrogates for exposure in brain. The proposed research will test this directly using mice and mouse cells exposed to 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD, or dioxin). TCDD is an EDC that affects multiple tissue systems and has adverse neurodevelopmental effects. Mice will be exposed to TCDD during adolescence, a critical time for brain development. The project's objective is to understand how TCDD exposure alters epigenomic profiles in three specific brain regions (cortex, hypothalamus, and hippocampus), peripheral blood leukocytes, and skin. Comparing these samples will reveal robust epigenomic signatures of TCDD exposure. Importantly, the study will use the genetically diverse mouse Collaborative Cross reference population to better reflect human populations. Some individuals may be more susceptible to TCDD exposure than others, and this experimental design will capture that variation. In parallel, mouse primary cells will be exposed to TCDD in vitro to determine if cell-based systems can accurately reflect the epigenomic modifications seen in tissues. If so, cell-based systems will have many applications for research and for screening potentially hazardous chemicals. The results will be integrated with available public data sources to better understand how mouse epigenomic profiles can be used to predict TCDD effects in humans, and in other affected tissues in mouse and humans.
 描述(由申请人提供):内分泌干扰化学品(EDCs)干扰哺乳动物激素,并可能导致无数不良健康影响,包括发育影响、神经影响、生殖影响和癌症。内分泌干扰物引起疾病的一种方式是引起表观基因组修饰,改变基因在特定细胞和组织中的调节方式。在人类中对脑组织进行取样通常是不可行的,但其他组织如血液和皮肤可以很容易地进行取样。这就提出了一个问题,即与血液和皮肤中EDC暴露相关的表观基因组谱是否是脑中暴露的良好替代物。这项拟议中的研究将直接使用暴露于2,3,7,8-四氯二苯并二恶英(TCDD或二恶英)的小鼠和小鼠细胞来测试这一点。TCDD是一种EDC,可影响多个组织系统,并对神经发育产生不良影响。小鼠将在青春期暴露于TCDD,这是大脑发育的关键时期。该项目的目标是了解TCDD暴露如何改变三个特定大脑区域(皮层,下丘脑和海马),外周血白细胞和皮肤的表观基因组图谱。比较这些样本将揭示TCDD暴露的强大表观基因组特征。重要的是,该研究将使用遗传多样性小鼠协作交叉参考群体,以更好地反映人类群体。有些人可能比其他人更容易受到TCDD暴露的影响,本实验设计将捕捉这种变化。同时,小鼠原代细胞将在体外暴露于TCDD,以确定基于细胞的系统是否可以准确地反映组织中观察到的表观基因组修饰。如果是这样的话,基于细胞的系统将在研究和筛选潜在危险化学品方面有许多应用。研究结果将与现有的公共数据源相结合,以更好地了解小鼠表观基因组图谱如何用于预测TCDD对人类以及小鼠和人类其他受影响组织的影响。

项目成果

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David Lawrence Aylor其他文献

David Lawrence Aylor的其他文献

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{{ truncateString('David Lawrence Aylor', 18)}}的其他基金

A New Model for Elucidating the Genetic Mechanisms of Hybrid Male Sterility in House Mice
阐明家鼠杂交雄性不育遗传机制的新模型
  • 批准号:
    10709906
  • 财政年份:
    2022
  • 资助金额:
    $ 63.26万
  • 项目类别:
A New Model for Elucidating the Genetic Mechanisms of Hybrid Male Sterility in House Mice
阐明家鼠杂交雄性不育遗传机制的新模型
  • 批准号:
    10592916
  • 财政年份:
    2022
  • 资助金额:
    $ 63.26万
  • 项目类别:
Systems Toxicogenomics of Endocrine Disrupting Chemicals in Brain
脑内内分泌干扰化学物质的系统毒物基因组学
  • 批准号:
    9567637
  • 财政年份:
    2016
  • 资助金额:
    $ 63.26万
  • 项目类别:
Epigenetics, environmental exposure, and reproduction in the Collaborative Cross
协同杂交中的表观遗传学、环境暴露和繁殖
  • 批准号:
    8831815
  • 财政年份:
    2014
  • 资助金额:
    $ 63.26万
  • 项目类别:
Epigenetics, environmental exposure, and reproduction in the Collaborative Cross
协同杂交中的表观遗传学、环境暴露和繁殖
  • 批准号:
    9063160
  • 财政年份:
    2014
  • 资助金额:
    $ 63.26万
  • 项目类别:
Epigenetics, environmental exposure, and reproduction in the Collaborative Cross
协同杂交中的表观遗传学、环境暴露和繁殖
  • 批准号:
    8478110
  • 财政年份:
    2012
  • 资助金额:
    $ 63.26万
  • 项目类别:
Epigenetics, environmental exposure, and reproduction in the Collaborative Cross
协同杂交中的表观遗传学、环境暴露和繁殖
  • 批准号:
    8281087
  • 财政年份:
    2012
  • 资助金额:
    $ 63.26万
  • 项目类别:
System Genetics of Male Infertility in the Collaborative Cross
合作杂交中男性不育的系统遗传学
  • 批准号:
    8003213
  • 财政年份:
    2010
  • 资助金额:
    $ 63.26万
  • 项目类别:
System Genetics of Male Infertility in the Collaborative Cross
合作杂交中男性不育的系统遗传学
  • 批准号:
    8205432
  • 财政年份:
    2010
  • 资助金额:
    $ 63.26万
  • 项目类别:

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