# Interdisciplinary approaches for understanding the metabolic effects of arsenic and manganese

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $636,066

## Abstract

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 poli...

## Key facts

- **NIH application ID:** 10064382
- **Project number:** 1R01ES030945-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Mary Gamble
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $636,066
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064382

## Citation

> US National Institutes of Health, RePORTER application 10064382, Interdisciplinary approaches for understanding the metabolic effects of arsenic and manganese (1R01ES030945-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10064382. Licensed CC0.

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