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）： 拟议的研究的总体目标是使用新型的表观基因组方法研究产前暴露与EDCS：邻苯二甲酸酯和BPA）与DNA甲基化模式和儿童肥胖的关联。该计划提供了指导的培训（K99）和一个研究阶段（R00），艾伦·贾斯（Allan Just Phd）（环境流行病学家）成为表观遗传学流行病学的独立学术研究者。 Dr. Just Dr.将获得由国际认可的科学家团队的培训和指导，这些科学家在环境和表观遗传学流行病学，儿科和生物统计学方面具有专业知识，包括Andrea Baccarelli博士，Robert Wright博士和Xihong Lin博士。 先前的研究表明，人类产前暴露会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个人群的脐带血中的甲基化模式。已经在120名儿童的脐带血液DNA上进行的，在脐带血DNA上已经进行了整个表观基因组甲基化微阵列（Illumina Human甲基化450K Beadchip），将测量几乎所有已知基因的480K个体位点的甲基化。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 = 150）确保发现是一致且可推广的。在由指导团队成员领导的现有赠款下，所有样本和肥胖措施已经收集或持续在两个队列中（称为进度和棱镜）。在R00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型技术将与Bisulfite治疗和下一代测序一起使用。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将稀疏，基因组平台的贡献与新型高密度测序措施发现的模式进行比较，从而有助于未来的表观遗传流行病学研究。 这项研究很重要，因为它量化了对EDC的产前暴露与人类胎儿组织中的甲基化模式相关的程度，然后将这些发现与儿童肥胖联系起来。另一个创新是其通过两种不同的甲基化技术进行流行病学研究的技术。拟议的工作仅采用最先进的表观基因组方法来训练博士，通过这种方式，有助于理解内分泌破坏者对儿童健康的影响。