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: 8616580
• 负责人: Allan C. Just
• 金额: $ 8.13万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616580
• 关键词: 3 year old; Accounting; Address; Affect; Age; Air; Animal Model; Base Sequence; Biological; Biological Markers; Biometry; 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; Intervention; Lead; Life; Link; Literature; Measures; Mediating; Mediation; Mentors; Metabolic; Methods; Methylation; Mexico; Modeling; Mothers; Obesity; Pattern; Pediatrics; Phase; Phenotype; Pregnancy; Process; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resolution; Risk; Sampling; Scientist; Site; Statistical Models; Techniques; Technology; Training; Umbilical Cord Blood; Urine; Validation; Work; adverse outcome; base; bisphenol A; bisulfite; cohort; density; design; endocrine disruptor exposure; epigenome; epigenomics; fetal; genome-wide; human fetus tissue; improved; in vivo; innovation; interest; member; methylome; next generation sequencing; novel; obesity in children; obesity risk; offspring; phthalates; prenatal; prenatal environmental exposure; prenatal exposure; programs; prospective; public health relevance; tool; urinary

DESCRIPTION (provided by applicant): The overarching goal of the proposed research is to investigate the association of prenatal exposure to EDCs: phthalates and BPA) with DNA methylation patterns and childhood obesity using novel epigenomic approaches. The program provides mentored training (K99) and a research phase (R00) for Allan Just PhD, an environmental epidemiologist, to become an independent academic investigator in epigenetic epidemiology. Dr. Just will receive training and guidance from a mentoring team of internationally recognized scientists with specializations in environmental and epigenetic epidemiology, pediatrics, and biostatistics, including Dr. Andrea Baccarelli, Dr. Robert Wright and Dr. Xihong Lin. Prior research has demonstrated that human prenatal exposures can alter the fetal epigenome, and animal models have shown that phthalates and BPA 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 120 children, will measure methylation in 480K 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=150), 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 members of the mentoring team. In the R00 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 contributions of the sparser, genome- wide platform with patterns found by the novel high density sequencing-based measures. This research is important because it quantifies the extent to which prenatal exposures to EDCs are associated with methylation patterns in human fetal tissue, and then links these findings to childhood obesity. Another innovation is its techniques to conduct epidemiologic studies with two different methylation technologies. The proposed work trains Dr. Just in state-of-the-art epigenomic approaches and in this way contributes to understanding of the impact of endocrine disruptors on children's health.

描述（由申请人提供）： 拟议研究的总体目标是利用新颖的表观基因组方法来调查产前接触 EDC（邻苯二甲酸盐和 BPA）与 DNA 甲基化模式和儿童肥胖之间的关系。该计划为环境流行病学家 Allan Just 博士提供指导培训 (K99) 和研究阶段 (R00)，使其成为表观遗传流行病学的独立学术研究者。 Just 博士将接受由环境和表观流行病学、儿科和生物统计学领域国际知名科学家组成的导师团队的培训和指导，其中包括 Andrea Baccarelli 博士、Robert Wright 博士和 Xihong Lin 博士。 先前的研究表明，人类产前接触可以改变胎儿表观基因组，动物模型表明邻苯二甲酸盐和 BPA 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组人类儿童的脐带血中的甲基化模式。全表观基因组甲基化微阵列（Illumina Human Mmethylation 450K BeadChip）已在 120 名儿童的脐带血 DNA 上进行检测，将测量涵盖几乎所有已知基因的 480K 个单独位点的甲基化。统计模型将这些甲基化测量值与产前 EDC 暴露和 4 岁时肥胖测量值联系起来。这些模型使用新的统计方法来进行多重比较并反映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（n=150）中进行复制，确保研究结果的一致性和普遍性。在指导团队成员领导的现有资助下，两个队列（称为 PROGRESS 和 PRISM）已经收集或正在进行所有样本和肥胖测量。在R00阶段，一种尚未应用于大规模表观遗传流行病学研究的新技术——靶向富集，将与亚硫酸氢盐处理和二代测序结合使用；这种方法将为已确定的感兴趣区域中的所有甲基化位点生成新的高分辨率测量结果。这项研究应该为检测 EDC 暴露、甲基化模式和儿童肥胖之间的关联提供更大的依据。通过将稀疏的全基因组平台的贡献与新颖的基于高密度测序的措施发现的模式进行比较，这种方法还可能有助于未来的表观遗传流行病学研究。 这项研究很重要，因为它量化了产前 EDC 暴露与人类胎儿组织甲基化模式的相关程度，然后将这些发现与儿童肥胖联系起来。另一项创新是其使用两种不同甲基化技术进行流行病学研究的技术。拟议的工作对贾斯特博士进行了最先进的表观基因组方法的培训，从而有助于了解内分泌干扰物对儿童健康的影响。