Interdisciplinary approaches for understanding the metabolic effects of arsenic and manganese

项目摘要 砷（As）暴露困扰着全球70多个国家的1.4亿人，包括美国，和 导致癌症和许多其他慢性疾病。长期接触锰（Mn）， 神经毒素，通过受污染的饮用水困扰50多个国家，包括美国，并且可以相互作用 在某些结果中，此外，可执行的饮用水标准和生物标志物 锰暴露不足。迫切需要制定战略，以确定处于危险之中的个人。尽管经过多年的 研究表明，砷暴露导致不良健康结果的机制仍然很差 明白需要创新的方法来表征As和Mn暴露的代谢效应- 在疾病发作之前-开始更好地了解潜在的机制，最终确定 处于危险中的个人。一旦摄入，无机As通过S-腺苷甲硫氨酸（SAM）进行甲基化， 单甲基砷（MMA）和二甲基砷（DMAs）在促进尿砷消除的过程中起作用。甲基 来自叶酸的基团是SAM合成所必需的。在我们最近完成的随机，双盲， 在孟加拉国的一项安慰剂对照叶酸临床试验（FACT）中，我们证明了FA补充剂 显着增加作为甲基化的DMA，从而降低血液中的As和血液中的MMA，一个有毒的 中间体我们建议利用FACT的数据和生物样本，采用新的超高- 分辨率代谢组学（HRM）分析，以确定与As相关的代谢物和代谢途径 暴露、砷暴露减少、砷甲基化以及锰暴露的独立和联合效应。 独特的FACT研究设计包括提供含/不含FA补充剂的As去除过滤器（400 或800 µg/d × 12或24周）。这种设计使我们能够识别和验证新的代谢物和途径 通过As暴露和As甲基化谱（Aim 1a）、Mn暴露（Aim 1b）和As减少改变 暴露（目标2a）。目的2b-c使我们能够通过FA治疗确定持久性/可逆性，包括以下因素的影响： FA补充促进的As甲基化的剂量依赖性增加;以及共同暴露的影响 至Mn（目标2d）。在与步行者博士的新合作中，他是Mt.西奈半岛，我们 将结合联合收割机的事实，严格的随机对照试验方法-最好的设计，以确定因果关系的人类-与 我们的HRM平台可以查询数千种代谢物和大多数代谢途径。我们将使用剂量- 和持续时间依赖的方法来增强我们发现的严谨性。在目标3a中，与 博士在哥伦比亚的Kioumourtzoglou，我们将使用新的和强大的模式识别方法来识别 特定的代谢模式受到As和Mn暴露的影响。Aim 3b将使用分层建模 全面量化As和Mn对目标1和2中确定的途径的影响。的调查结果 这项研究可以为砷流行地区FA强化计划的决策提供信息， 确定砷和锰暴露的生物标志物，可以为饮用水标准的决定提供信息。

Project Summary Arsenic (As) exposure afflicts >140 million people in 70+ countries worldwide, including the U.S., and contributes to cancer and many other chronic diseases. Chronic exposure to manganese (Mn), a known neurotoxin, through contaminated drinking water afflicts 50+ countries, including the U.S., and may interact with As exposure for some outcomes. Furthermore, enforceable drinking water standards and biomarkers of Mn exposure are lacking. Strategies to identify individuals at risk are urgently needed. Despite years of research, the mechanisms by which As exposure leads to adverse health outcomes remains poorly understood. Innovative approaches are needed to characterize metabolic effects of As and Mn exposures – prior to disease onset – to begin to better understand the underlying mechanisms, ultimately to identify individuals at risk. Once ingested, inorganic As undergoes methylation by S-adenosylmethionine (SAM) to form mono- (MMAs) and di-methyl (DMAs) arsenicals in a process that facilitates urinary As elimination. Methyl groups from folate are required for SAM synthesis. In our recently completed randomized, double-blind, placebo-controlled folic acid clinical trial (FACT) in Bangladesh, we demonstrated that FA supplementation significantly increased As methylation to DMAs and thereby lowered blood As and blood MMAs, a toxic intermediate. We propose to leverage data and biological samples from FACT to employ novel ultra high- resolution metabolomics (HRM) analyses to identify metabolites and metabolic pathways associated with As exposure, As exposure reduction, As methylation and the independent and joint effects of Mn exposure. The unique FACT study design includes provision of As-removal filters with/without FA supplementation (400 or 800 µg/d × 12 or 24 weeks). This design permits us to identify and validate novel metabolites and pathways altered by As exposure and As methylation profiles (Aim 1a); Mn exposure (Aim 1b); and reduction in As exposure (Aim 2a). Aims 2b-c allow us to identify persistence/reversibility by FA treatment, including effects of dose-dependent increases in As methylation facilitated by FA supplementation; and the impact of co-exposure to Mn (Aim 2d). In a new collaboration with Dr. Walker, Director of the Metabolomics Center at Mt. Sinai, we will combine FACT’s rigorous RCT approach–the best possible design to determine causality in humans–with our HRM platform that interrogates thousands of metabolites and most metabolic pathways. We will use dose- and duration-dependent approaches to enhance the rigor of our findings. In Aim 3a, in a new collaboration with Dr. Kioumourtzoglou at Columbia, we will use novel and robust pattern recognition approaches to identify specific metabolic patterns that are impacted by As and Mn exposures. Aim 3b will use hierarchical modeling to comprehensively quantify the As and Mn impacts on the pathways identified in Aims 1 and 2. The findings of this study may inform policy decisions regarding FA fortification programs in As-endemic areas and may identify biomarkers of As and Mn exposure that may inform decisions on drinking water standards.