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
• 负责人: David Lawrence Aylor
• 金额: $ 56.52万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9567637
• 关键词: ATAC-seq; Adolescence; Affect; Alleles; Behavior; Bioinformatics; Biopsy Specimen; Blood; Brain; Brain region; Cell Culture Techniques; Cells; Chemical Exposure; Chemicals; Chromatin; Commerce; Computer Simulation; Cultured Cells; DNA Methylation; Data; Data Set; Data Sources; Development; Diagnosis; Dioxins; Disease; Dose; Embryo; Endocrine Disruptors; Endocrine disruption; Environment; Epigenetic Process; Experimental Designs; Exposure to; Fibroblasts; Gene Expression; Genes; Genetic; Genetic Variation; Genome; Genotype; Goals; Hazardous Chemicals; Health; Hippocampus (Brain); Hormones; Human; Hybrids; Hypothalamic structure; In Vitro; Individual; Inheritance Patterns; Leukocytes; Link; Malignant Neoplasms; Measures; Modeling; Modification; Molecular; Molecular Biology; Mouse Strains; Mus; Neurologic; Neurologic Effect; Neurosecretory Systems; Neurotoxins; Outcome; Persons; Poison; Population; Population Heterogeneity; Publishing; Reproducibility; Research; Resources; Sampling; Skin; System; Testing; Tetrachlorodibenzodioxin; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxicity Tests; Toxicogenetics; Toxicogenomics; Toxicology; Toxin; Variant; base; brain tissue; cell type; cognitive disability; environmental chemical exposure; epigenetic profiling; epigenome; epigenomics; experimental study; functional genomics; gene environment interaction; head-to-head comparison; in vivo; inter-individual variation; motor disorder; mouse model; neurotoxicity; novel strategies; outcome prediction; peripheral blood; population based; public health relevance; relating to nervous system; repository; reproductive; response; screening; sperm cell; transcriptome sequencing; transgenerational epigenetic inheritance

 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。