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

这项拟议研究的主要目标是利用新的表观基因组学方法调查产前暴露于内分泌干扰物(内分泌干扰物：邻苯二甲酸酯和双酚A)与DNA甲基化模式和儿童肥胖的关系。该计划为环境流行病学家Allan Just博士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员。 先前的研究已经证明，人类产前暴露可以改变胎儿的表观基因组，动物模型已经表明，邻苯二甲酸酯和双酚A影响后代的甲基化和肥胖风险。这项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组人类儿童脐带血中的甲基化模式。一种表观基因组范围的甲基化微阵列(Illumina人类甲基化450K珠芯片)已经在540名儿童的脐带血DNA上进行，将测量几乎所有已知基因的48万个单独位点的甲基化。统计模型将把这些甲基化测量与产前EDC暴露和4岁时的肥胖测量联系起来。这些模型使用了新的统计方法，考虑了多重比较，并反映了基因组中甲基化位置之间的相关性。在使用相同设计的独立队列(n=180)中进行重复，确保了研究结果的一致性和可推广性。 所有样本和肥胖测量都已经在两个队列(称为PRISM和PRISM)中收集，或正在由合作者领导的现有赠款下进行。在第二阶段，一种尚未在大规模表观遗传流行病学研究中应用的新技术--靶向浓缩，将与亚硫酸氢盐治疗和下一代测序结合使用；这一方法将对已确定的感兴趣区域的所有甲基化位点产生新的高分辨率测量。这项研究应该提供更大的力量来检测EDC暴露、甲基化模式和儿童肥胖之间的联系。这种方法也可能有助于未来的表观遗传学流行病学研究，通过比较