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Perinatal Exposures, Tissue- and Cell-specific Epigenomics, & Lifecourse Outcomes

围产期暴露、组织和细胞特异性表观基因组学、

基本信息

批准号：
9545289
负责人：
Dana Dolinoy
金额：
$ 119.09万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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/9545289
关键词：
Adult Affect Age-Months Animal Model Animals Behavior Bioinformatics Biological Availability Biological Markers Blood Brain Breast Cell Nucleus Cell Separation Cells Chemicals Child Complex DNA DNA Methylation Data Development Diet Diethylhexyl Phthalate Disease Disease Outcome Dose Ectoderm Endoderm Environmental Exposure Environmental Health Epidemiology Epigenetic Process Epithelial Cells Exposure to Feces Female Fluorescence Funding Gene Expression Genes Genetic Transcription Germ Layers Hair Hair Cells Health Heritability Human Hyperactive behavior Kidney Laboratory Animals Lead Leukocytes Life Liver Liver neoplasms Malignant Neoplasms Maps Measurement Mediating Mesoderm Metabolic Metabolic syndrome Methylation Michigan Modification Motor Mus Mutate National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Environmental Health Sciences Neurons Obesity Outcome Perinatal Perinatal Exposure Peripheral Phenotype Population Proximal Kidney Tubules Proxy Research Resources Saliva Sample Size Sampling Sex Characteristics Source Specificity Stem cells Testing Time Tissues Toxicant exposure Tumor Pathology Universities bisphenol A cell type disorder prevention disorder risk environmental change epidemiology study epigenome epigenomics exposed human population frontal lobe genome-wide analysis human disease human tissue imprint methylation pattern methylome mouse model neurodevelopment next generation sequencing nutrition peripheral blood phthalates public health relevance sex stem toxicant transcriptome transcriptomics tumor

项目摘要

DESCRIPTION (provided by applicant): Toxicant exposures early in life adversely affect health outcomes in both animals and humans, in part due to epigenetic mechanisms (e.g. DNA methylation). Studies also indicate that exposures' impact on the epigenome can be tissue and even cell specific. Yet, epigenetic epidemiology analysis of toxicants is often limited to biologically available or "surrogate" (e.g. blood, saliva) samples, which serve as proxies for epigenetic status in tissues targeted by exposures. While methylation of peripheral DNA may not mirror that of all tissues, it has been used as a biomarker associated with both disease and exposures. Using bisphenol A and phthalates (e.g. DEHP) as representative toxicants, our overall objective is to utilize mouse models to evaluate tissue- and cell-specific epigenetic alterations associated with perinatal exposures and disease outcomes, including tissues not feasibly assessed in humans. We leverage resources by utilizing tissues funded as part of the Michigan NIEHS/EPA-funded Children's Environmental Health P01 Center in which epigenetic analysis in target tissues focuses on candidate metastable epialleles and imprinted genes, two sets of loci most vulnerable to environmental changes. Within TaRGET II U01, we will extend analysis genome- wide to 11 tissue and cell types to map DNA methylation (5mC), hydroxymethylation (5hmC), and gene expression in an effort to inform epigenetic epidemiology studies with an environmental focus. We use sample sizes powered to detect sex differences and conduct methylome and transcriptome analyses immediately following perinatal exposure at post-natal day 22 in target tissues from the three germ layers (brain & breast from ectoderm, kidney from mesoderm, & liver from endoderm) and in surrogate tissues of human relevance (hair, peripheral blood leukocytes, & stool), as well as longitudinally at 8 months of age to identify exposure- dependent epigenetic changes that persist into adulthood. Capitalizing on our team's expertise in cell-specific epigenetics, we also include 4 purified cell populations to furthr compare target cells to surrogates. Ultimately, we seek to identify a subset of tissue-independent labile genes, which represent regions of the epigenome vulnerable early in life, and may be interrogated, with the use of surrogate tissues.