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...