# Metabolic and Neurocognitive Impacts of Military-Associated Toxicant Exposures

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2024 · —

## Abstract

Arsenic is a widespread environmental toxicant contaminating the drinking water of over 100 million
individuals globally. Importantly, veterans experience additional exposures from their service, including
historical chemical weapons use, contaminated military bases, ordinance disposal, burn pits, oil fires, and the
extensive use of arsenic-based pesticides (Agent Blue) in Vietnam. Arsenic is associated with multiple
conditions enriched in the veteran population, including neurocognitive disorders like anxiety,
depression, and PTSD; however, the full impact of arsenic exposure on veterans’ health remains grossly
underappreciated. Thus, understanding the links between arsenic and veterans’ health as well as the
mechanisms by which arsenic promotes disease development may illuminate novel therapeutic approaches to
reduce the considerable burden of mental health disorders among America’s veterans. Our data indicate that
one mechanism of arsenic-induced neurocognitive dysfunction is via depletion of brain
docosahexaenoic acid (DHA), an essential fatty acid critical for normal brain development and function.
Indeed, arsenic exposure and low DHA consumption are both independently associated with
neuropsychiatric disorders. In addition, mechanistic studies show that arsenic and DHA exert opposing
actions on multiple pathways regulating neurocognitive function. Because of DHA’s central role in neuronal
health, approaches for enhancing brain DHA levels are needed; however, traditional DHA supplements fail
to deliver DHA across the blood brain barrier (BBB). In contrast, our novel DHA delivery approach using
lysophosphatidylcholine-linked DHA (LPC-DHA) exploits a unique transporter at the BBB (Mfsd2a),
allowing for brain DHA enrichment and improvements in neurocognition. Whether LPC-DHA can address
arsenic neurotoxicity arising from military service is unknown. In Specific Aim 1, we will use a mouse model to
characterize the impact of military-associated arsenic exposure on neurocognitive function across domains
of learning/memory and anxiety/depression, with a focus on behaviors regulated by the amygdala,
hippocampus, and prefrontal cortex. We will also examine critical mechanisms of arsenic neurotoxicity.
Finally, we will assess the capacity of LPC-DHA to rescue arsenic-induced neurobehavioral abnormalities.
Evidence for such rescue would suggest that LPC-DHA may be a novel treatment for mitigating historical
arsenic exposure, such as among Vietnam veterans exposed to Agent Blue. Better than treatment, however,
would be prevention. Since serving in combat areas increases exposures to multiple environmental toxicants
that induce oxidative stress and may adversely affect mental health through brain DHA depletion, it is critical to
know whether service members can be protected from the adverse effects of these exposures. In Specific
Aim 2, we will interrogate the supposition that LPC-DHA supplementation during exposure prevents arsenic-
induced neurocogniti...

## Key facts

- **NIH application ID:** 10701417
- **Project number:** 1I01BX006108-01A1
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Robert M Sargis
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701417

## Citation

> US National Institutes of Health, RePORTER application 10701417, Metabolic and Neurocognitive Impacts of Military-Associated Toxicant Exposures (1I01BX006108-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10701417. Licensed CC0.

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