Prenatal Exposure to Endocrine Disrupters, DNA Methylation, and Childhood Obesity

产前接触内分泌干扰物、DNA 甲基化和儿童肥胖

• 批准号: 9177788
• 负责人: Allan C. Just
• 金额: $ 24.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177788
• 关键词: 3 year old; Accounting; Address; Affect; Age; Air Pollutants; Animal Model; Base Sequence; Biological; Biological Markers; Birth; Blood specimen; Boston; Chemical Exposure; Chemicals; Child; Child Development; Child health care; Childhood; Cities; Conceptions; DNA; DNA Methylation; Data; Dependence; Development; Doctor of Philosophy; Endocrine Disruptors; Environment; Environmental Health; Epidemiologic Studies; Epidemiologist; Epidemiology; Epigenetic Process; Exposure to; Fetal Growth; Fingerprint; Funding; Future; Genes; Genome; Genomics; Goals; Grant; Health; Human; In Vitro; Individual; Infant; Instruction; Intervention; Lead; Life; Link; Literature; Measures; Mediating; Mediation; Metabolic; Metals; Methods; Methylation; Mexico; Modeling; Mothers; Obesity; Pattern; Phase; Phenotype; Pregnancy; Process; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resolution; Risk; Sampling; Site; Smoking; Statistical Models; Techniques; Technology; Umbilical Cord Blood; Urine; Validation; adverse outcome; base; bead chip; bisphenol A; bisulfite; cohort; design; endocrine disruptor exposure; epigenome; epigenomics; fetal; improved; in vivo; interest; methylation biomarker; methylation pattern; methylome; next generation sequencing; novel; obesity in children; obesity risk; offspring; phthalates; prenatal; prenatal environmental exposure; prenatal exposure; programs; prospective; tool; urinary

The overarching goal of the proposed research is to investigate the association of prenatal exposure to endocrine disrupting compounds (EDCs: phthalates and bisphenol A) with DNA methylation patterns and childhood obesity using novel epigenomic approaches. The program provides a research phase (ROO) for Allan Just PhD, an environmental epidemiologist, to become an independent academic investigator in epigenetic epidemiology. Prior research has demonstrated that human prenatal exposures can alter the fetal epigenome, and animal models have shown that phthalates and bisphenol A impact methylation and obesity risk in the offspring. The proposed research uses methylation microarrays and new sequencing-based technologies to investigate methylation patterns in the umbilical cord blood of two cohorts of human children. An epigenome-wide methylation microarray (Illumina Human Methylation 450K BeadChip), already being· conducted on umbilical cord blood DNA from 540 children, will measure methylation in 480,000 individual sites spanning almost all known genes. Statistical models will relate these methylation measures to prenatal EDC exposures and to measures of obesity at age 4. These models use new statistical approaches that account for multiple comparisons and reflect the dependence between methylation sites within the genome. Replication in an independent cohort (n=180), using the same design, assures that findings are consistent and generalizable. All samples and obesity measures are already collected or ongoing in the two cohorts (called PROGRESS and PRISM) under existing grants led by collaborators. In the second phase, a novel technique, targeted enrichment, which has not yet been applied in large-scale epigenetic epidemiologic studies, will be used in conjunction with bisulfite treatment and next generation sequencing; this approach will generate new high resolution measures of all methylation sites in identified regions of interest. This research should provide greater power to detect associations between EDC exposures, methylation patterns, and obesity in children. This approach may also contribute to future epigenetic epidemiological studies by comparing the

拟议的研究的总体目标是研究产前暴露于内分泌干扰化合物（EDCS：邻苯二甲酸盐和双苯酚A）与DNA甲基化模式和儿童期使用新型表观基因组方法的关联。该计划为环境流行病学家Allan Just Phd提供了一个研究阶段（ROO），以成为表观遗传流行病学的独立学术研究者。 先前的研究表明，人类产前暴露会改变胎儿表观基因组，动物模型表明，邻苯二甲醇和双酚会影响后代的甲基化和肥胖风险。拟议的研究使用甲基化微阵列和新的基于测序的技术来研究两个人群的脐带血中的甲基化模式。已经在540名儿童的脐带血液DNA上进行的，在脐带血液DNA上进行·甲基化的甲基化微阵列（Illumina人甲基化450k beadchip），将在480,000个跨越几乎所有已知基因的位点进行甲基化。统计模型将将这些甲基化度量与产前EDC暴露和肥胖症度量相关联。这些模型使用新的统计方法来解释多次比较，并反映了基因组内甲基化位点之间的依赖性。使用相同的设计，在独立队列中的复制（n = 180）确保发现是一致且可推广的。 在由合作者领导的现有赠款下，已经在两个队列（称为进度和棱镜）中收集或正在进行所有样本和肥胖措施。在第二阶段中，尚未在大规模表观遗传流行病学研究中应用的一种新型技术，该技术尚未应用于Bisulfite治疗和下一代测序。这种方法将对已确定的目标区域中所有甲基化位点进行新的高分辨率度量。这项研究应提供更大的能力，以检测儿童EDC暴露，甲基化模式和肥胖症之间的关联。这种方法还可以通过比较