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

项目摘要/摘要 饮用水中的砷污染仍然是世界范围内的一个主要健康威胁。一种新兴的 假说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。 特定的基因，但不改变DNA序列。更好地理解这一重要的潜在机制 砷毒性对于制定预防和治疗砷相关疾病的战略至关重要。 神经管缺陷，包括脊柱裂和无脑畸形，是常见和严重的出生缺陷。 当大脑和脊髓的胚胎前体不能正常发育时。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 假设砷对发育中的神经系统的影响是通过表观基因组来调节的。我们 建议使用容易接触到的因出生缺陷而暴露的神经系统组织进行测试 我们的假设。 在这个应用中，我们建立了一个新的基础科学-临床科学合作来确定DNA 一组患有脊髓脊膜膨出的婴儿不同组织的甲基化模式 常见和严重的神经管缺陷形式。我们的临床小组目前正在进行一项流行病学调查 孟加拉国研究确定孕妇是否通过受污染的饮用水接触砷 增加了脊髓脊膜膨出的风险。我们最近开始收集外科手术中丢弃的组织 脊髓脊膜膨出闭合，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。我们提出了一系列先导研究，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，以检查已知的在神经管缺陷中重要的候选基因的DNA甲基化 受影响婴儿的血液和神经系统组织。 这些高风险、高回报的研究将确定与砷有关的差异甲基化基因。 暴露和表型，以及检验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，如表观基因组范围的关联研究(Ewas)。这样的研究是高度 可能为预防性干预提供新的目标。

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.