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.

描述（由适用提供）：生命早期的毒物暴露会不利地影响动物和人类的健康结果，部分原因是表观遗传机制（例如DNA甲基化）。研究还表明，暴露对表观基因组的影响可能是组织，甚至是细胞的特异性。然而，对有毒物质的表观遗传流行病学分析通常仅限于生物学上可用或“替代”（例如血液，唾液）样本，这些样本是通过暴露靶向的组织中表观遗传状态的代理。虽然外周DNA的甲基化可能不能反映所有组织的甲基化，但它已被用作与疾病和暴露相关的生物标志物。使用双苯酚A和邻苯二甲酸盐（例如DEHP）代表有毒物质，我们的总体目标是利用小鼠模型来评估与围产期暴露和疾病结果相关的组织和细胞特异性的表观遗传学改变，包括在人类中无法得到可行评估的组织。我们通过利用作为密歇根州NIEHS/EPA资助的儿童环境卫生P01中心资助的时间安排来利用资源，在该中心中，目标时间的表观遗传分析侧重于候选亚稳态的epialleles和Indranded Genes，这是两组在环境变化中最容易受到影响的基因座。在目标II U01中，我们将将分析基因组扩展到11种组织和细胞类型，以绘制DNA甲基化（5MC），羟甲基化（5HMC）和基因表达，以努力以环境重点为表观遗传学的流行病学研究提供信息。我们使用动力的样品量来检测性别差异，并在产后第22天的周围暴露后立即进行甲基甲基甲基甲基和转录组分析，并在三个细菌层的目标时机（来自过胚层的脑和乳房，来自中胚层的脑和乳腺年龄识别持续到成年的暴露依赖性表观遗传变化。利用我们团队在细胞特异性表观遗传学方面的专业知识，我们还包括4个纯化的细胞群，以将靶细胞与替代物进行比较。最终，我们试图确定一部分非依赖性标签基因，该基因代表了表观基因组早期脆弱的区域，并且可以使用替代组织的使用，并可能受到询问。