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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：
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
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/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

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.