Interdisciplinary approaches for understanding the metabolic effects of arsenic and manganese

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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.