Project #1 – BioProject on Community Exposures (BP Comm) - SUMMARY With partnering Native American communities, the UNM Metals Exposure and Toxicity Assessment on Tribal Lands in the Southwest (UNM METALS) team has obtained evidence for community level exposures and health risks associated with more than 1100 abandoned uranium mine (AUM) waste sites on their tribal lands. Biomonitoring results confirm that community members are exposed to uranium and other metals beyond national norms, leading to concerns about potential impact on health. Based on published and preliminary findings, we will test the hypothesis that exposure to the unique mixtures of environmental metals associated with AUMs promotes oxidative stress and inflammatory response, processes known to promote immune dysregulation and development of numerous chronic diseases. Furthermore, we hypothesize that dietary mitigation strategies can be elucidated based on mechanisms of toxicity of specific metals and metal mixtures. In Aim 1 we will work to delineate associations between metals detected by biomonitoring, and biomarkers of oxidative stress, inflammation and immune modulation. The findings from Aim 1 are expected to provide critical information on systemic consequences of environmental metal exposures. Although uranium has been the focus of community concern, findings from the UNM METALS Environmental Projects and human biomonitoring highlight that other toxic metals are prevalent in the environment and present at elevated levels in the population. Experimental studies in Aim 2 will focus on oxidative stress generated by community- relevant metals and metal mixtures as an underlying mechanism leading to alterations in inflammatory response and immune modulation. We will select experimental endpoints and exposure patterns observed in the community to optimize human relevance of Aim 2 studies. Detailed mechanistic analyses will be performed to establish the basis for metal interactions including potential beneficial metal-metal interactions of the antioxidant metal micronutrients (zinc/Zn and selenium/Se). Studies on Zn and Se interactions with toxic metals and metal mixtures may inform tractable strategies for mitigating the adverse effects of environmental metal exposures in human populations. This project is responsive to community concerns and the outcomes are expected to 1) provide insights into biological consequences of understudied toxic metals identified in environmental samples and elevated in biospecimens from the community, 2) expand mechanistic knowledge of the impact of specific metals and metal mixtures as well as the basis for metal:metal interactions in human immune cells, and 3) experimentally test the potential of mechanism-based interventions to confer protection from environmental metal exposures. BP Comm addresses SRP mandates 1, 2 and 4: Detection and Evaluation of Effects, Risk Assessment and Risk Reduction, respectively.