Interdisciplinary approaches for understanding the metabolic effects of arsenic and manganese

项目摘要 砷暴露困扰着全球70多个国家和地区的1.4亿人，其中包括美国和 会导致癌症和许多其他慢性疾病。慢性接触锰(Mn)，一种已知的 神经毒素通过受污染的饮用水困扰着包括美国在内的50多个国家，并可能相互作用 与AS暴露于某些结果。此外，可执行的饮用水标准和生物标志物 缺乏锰暴露。迫切需要确定处于危险中的个人的战略。尽管多年来 研究表明，砷暴露导致不良健康后果的机制仍不清楚。 明白了。需要创新的方法来表征砷和锰暴露的代谢影响- 发病前-开始更好地了解潜在的机制，最终确定 处于危险中的个人。无机砷一旦被摄入，就会被S-腺苷蛋氨酸甲基化，形成 一甲基(MMAS)和二甲基砷(DMAS)在促进尿砷消除的过程中。甲基 合成SAM需要来自叶酸的基团。在我们最近完成的随机、双盲、 孟加拉国的安慰剂对照叶酸临床试验(FACT)，我们证明了补充FA 显著增加甲基化为DMAS，从而降低血液AS和血液MMA，一种有毒的 中级的。我们建议利用来自事实的数据和生物样本来使用新型超高 分辨代谢组学(HRM)分析以确定与AS相关的代谢物和代谢途径 暴露、暴露减少、甲基化以及锰暴露的独立和联合影响。 独特的事实研究设计包括提供具有/不具有FA补充的As去除过滤器(400 或800微克/天×12或24周)。这一设计允许我们识别和验证新的代谢物和途径 因砷暴露和砷甲基化情况而改变(目标1a)；锰暴露(目标1b)；以及砷的减少 暴露(目标2a)。目标2b-c使我们能够通过FA治疗确定持久性/可逆性，包括 补充FA促进AS甲基化的剂量依赖性增加；以及联合暴露的影响 至MN(目标2d)。在与山上代谢组学中心主任沃克博士的一项新合作中。西奈半岛，我们 将把FACT的严格RCT方法--确定人类因果关系的最佳设计--与 我们的人力资源管理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- 以及依赖持续时间的方法，以增强我们研究结果的严谨性。在Aim 3a中，在与 哥伦比亚大学的Kioumortzoglou博士，我们将使用新颖和健壮的模式识别方法来识别 受砷和锰暴露影响的特定代谢模式。AIM 3b将使用分层建模 全面量化砷和锰对目标1和目标2确定的途径的影响。 这项研究可能为有关AS流行地区FA强化计划的政策决策提供参考，并可能 确定砷和锰暴露的生物标志物，这些生物标志物可能为饮用水标准的决策提供信息。

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.