Examining tissue-specific DNA methylation after prenatal exposure to arsenic among infants with spina bifida

脊柱裂婴儿产前暴露于砷后检查组织特异性 DNA 甲基化

• 批准号: 9978432
• 负责人: Maitreyi Mazumdar
• 金额: $ 28.04万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-16 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978432
• 关键词: Address; Affect; Anencephaly and spina bifida X linked; Arsenic; Bangladesh; Basic Science; Birth Rate; Blood; Brain; Candidate Disease Gene; Cells; Chronic; Chronic lung disease; Clinical; Clinical Sciences; Collaborations; Congenital Abnormality; DNA; DNA Methylation; DNA Sequence; Data; Development; Diabetes Mellitus; Disease; Embryo; Environmental Exposure; Epigenetic Process; Exposure to; Folic Acid; Future; Gene Expression; Genes; Genetic Predisposition to Disease; Genetic Transcription; Goals; Health; Human; Individual; Infant; Intake; Intervention; Investigation; Kidney Cortex Necrosis; Live Birth; Low Birth Weight Infant; Malignant neoplasm of lung; Mediating; Meningomyelocele; Methods; Mothers; Nervous system structure; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Neural tube; Neuroepithelial Tissue; Nucleotides; Nutritional; Operative Surgical Procedures; Outcome; Pattern; Peripheral Nervous System Diseases; Phenotype; Pilot Projects; Population; Pregnancy; Premature Birth; Prevalence; Preventive Intervention; Resolution; Risk; Sampling; Series; Severities; Spinal Cord; Spinal Dysraphism; Swab; Testing; Tissues; Toxic effect; bisulfite sequencing; contaminated drinking water; design; drinking water; epidemiology study; epigenome; epigenome-wide association studies; high reward; high risk; innovation; methylation pattern; nervous system disorder; neural plate; neurotoxicity; nutrition; prenatal; prenatal exposure; prevent; protective effect; skin lesion; transcriptome sequencing; whole genome

PROJECT SUMMARY/ABSTRACT Arsenic contamination in drinking water continues to be a major health threat worldwide. An emerging hypothesis is that arsenic acts via the epigenome, the multitude of compounds that affect DNA transcription of specific genes but do not alter DNA sequence. Better understanding of this important potential mechanism of arsenic toxicity is essential to design strategies to prevent and treat arsenic-related diseases. Neural tube defects, including spina bifida and anencephaly, are common and severe birth defects that occur when the embryonic precursors to the brain and spinal cord do not properly develop. Neural tube defects are increasingly considered to be among the sequelae of arsenic exposure. In this R21 application, we test the hypothesis that arsenic's effects on the developing nervous system are mediated through the epigenome. We propose to use readily accessible nervous system tissue that is exposed as a result of the birth defect to test our hypotheses. In this application, we establish a new basic science-clinical science collaboration to determine DNA methylation patterns from various tissues from a human population of infants with myelomeningocele, a common and severe form of neural tube defect. Our clinical group is currently conducting an epidemiological study in Bangladesh to determine whether maternal arsenic exposure through contaminated drinking water increases the risk of myelomeningocele. We have recently started collecting discarded tissue from surgical closure of the myelomeningocele, and these samples provide a unique opportunity to investigate tissue- specific epigenetic patterns. We propose a series of pilot studies that will whole genome bisulfite sequencing (WGBS), a new and innovative method that enables investigation of DNA methylation at a single-nucleotide resolution, to examine DNA methylation in candidate genes known to be important in neural tube defects in the blood and nervous system tissue of affected infants. These high risk, high reward studies will identify genes that are differentially methylated in relation to arsenic exposure and phenotype, as well as test the hypothesis that neuroepithelial tissue provides a unique window into the study of human neural tube defects. These studies will also provide important preliminary data for future collaborative projects such as epigenome-wide association studies (EWAS). Such studies are highly likely to provide new targets for preventive interventions.

项目概要/摘要 饮用水中的砷污染仍然是全世界的主要健康威胁。一个新兴的 假设是砷通过表观基因组发挥作用，表观基因组是影响 DNA 转录的多种化合物。 特定基因，但不改变 DNA 序列。更好地理解这一重要的潜在机制 砷毒性对于设计预防和治疗砷相关疾病的策略至关重要。 神经管缺陷，包括脊柱裂和无脑畸形，是常见且严重的出生缺陷 当大脑和脊髓的胚胎前体没有正常发育时。神经管缺陷是 越来越多地被认为是砷暴露的后遗症之一。在此 R21 应用程序中，我们测试了 假设砷对发育中的神经系统的影响是通过表观基因组介导的。我们 建议使用因出生缺陷而暴露的易于接近的神经系统组织进行测试 我们的假设。 在此应用中，我们建立了新的基础科学-临床科学合作来确定 DNA 患有脊髓脊膜膨出的婴儿人群的各种组织的甲基化模式 常见且严重的神经管缺陷形式。我们的临床小组目前正在进行流行病学调查 孟加拉国开展的一项研究旨在确定孕产妇是否通过受污染的饮用水接触砷 增加脊髓脊膜膨出的风险。我们最近开始收集手术中废弃的组织 脊髓脊膜膨出的闭合，这些样本提供了一个独特的机会来研究组织- 特定的表观遗传模式。我们提出了一系列试点研究，将全基因组亚硫酸氢盐测序 (WGBS)，一种新的创新方法，能够研究单核苷酸的 DNA 甲基化 分辨率，检查已知对神经管缺陷很重要的候选基因中的 DNA 甲基化 受影响婴儿的血液和神经系统组织。 这些高风险、高回报的研究将识别与砷相关的差异甲基化基因 暴露和表型，以及测试神经上皮组织提供独特窗口的假设 进入人类神经管缺陷的研究。这些研究还将提供重要的初步数据 未来的合作项目，例如全表观基因组关联研究（EWAS）。此类研究具有很高的 可能为预防性干预措施提供新的目标。