Systems Toxicogenomics of Endocrine Disrupting Chemicals in Brain

 描述(申请人提供)：内分泌干扰物(EDCs)干扰哺乳动物荷尔蒙，可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。内分泌细胞致病的一种方式是通过引起表观基因组修饰，改变基因在特定细胞和组织中的调控方式。对人类的脑组织进行采样通常是不可行的，但血液和皮肤等其他组织可以很容易地进行采样。这提出了一个问题，即与EDC在血液和皮肤中暴露相关的表观基因组图谱是否是大脑暴露的良好替代品。这项拟议的研究将使用暴露于2，3，7，8-四氯二苯并-对二恶英(TCDD，或二恶英)的小鼠和小鼠细胞直接测试这一点。TCDD是一种EDC，影响多个组织系统，对神经发育有不利影响。小鼠将在青春期暴露于TCDD，青春期是大脑发育的关键时期。该项目的目标是了解接触TCDD如何改变三个特定脑区(皮质、下丘脑和海马体)、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，这项研究将使用遗传多样性的小鼠协作交叉参考种群来更好地反映人类种群。有些人可能比其他人更容易受到TCDD的影响，这一实验设计将捕捉到这种差异。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能够准确地反映组织中看到的表观基因组修改。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。这些结果将与可用的公共数据来源相结合，以更好地了解如何使用小鼠的表观基因组图谱来预测TCDD对人类以及在小鼠和人类的其他受影响组织中的影响。

 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.