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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

批准号：
9098205
负责人：
David Lawrence Aylor
金额：
$ 63.26万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
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/9098205
关键词：
ATAC-seq Accounting 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)Histocompatibility Testing Hormones Human Hybrids Hypothalamic structure In Vitro Individual Inheritance Patterns Leukocytes Life Link Malignant Neoplasms Measures Modeling Modification Molecular Molecular Biology Mouse Strains Mus Neurologic Neurosecretory Systems Neurotoxins Outcome Persons Poison Population Population Heterogeneity Primary Cell Cultures Publishing Research Resources Sampling Shapes Skin System Testing 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 functional genomics gene environment interaction head-to-head comparison in vivo inter-individual variation motor disorder mouse model neurotoxicity novel strategies peripheral blood population based public health relevance relating to nervous system repository reproductive research study response screening sperm cell transcriptome sequencing transgenerational epigenetic inheritance

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）：内分泌干扰化学物质（EDC）会干扰哺乳动物激素，并可能对健康造成多种不利影响，包括发育影响、神经系统影响、生殖影响和癌症。 EDC 引起疾病的一种方式是引起表观基因组修饰，从而改变基因在特定细胞和组织中的调节方式。对人类脑组织进行采样通常是不可行的，但可以轻松对血液和皮肤等其他组织进行采样。这就提出了一个问题：与血液和皮肤中 EDC 暴露相关的表观基因组谱是否可以作为大脑中 EDC 暴露的良好替代指标。拟议的研究将直接使用暴露于 2,3,7,8-四氯二苯并-对二恶英（TCDD 或二恶英）的小鼠和小鼠细胞进行测试。 TCDD 是一种影响多个组织系统并对神经发育产生不良影响的 EDC。小鼠将在青春期接触 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（皮质、下丘脑和海马）、外周血白细胞和皮肤的表观基因组谱。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的小鼠协作交叉参考群体来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，这个实验设计将捕捉到这种变化。与此同时，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反映组织中观察到的表观基因组修饰。如果是这样，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。结果将与现有的公共数据源相结合，以更好地了解如何使用小鼠表观基因组图谱来预测 TCDD 对人类以及小鼠和人类其他受影响组织的影响。