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University of New Mexico

Superfund Research Program

Modulation of Uranium and Arsenic Immune Dysregulation by Zinc

Project Leader: Debra MacKenzie
Co-Investigators: Laurie G. Hudson, Esther Erdei
Grant Number: P42ES025589
Funding Period: 2017-2022

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Project Summary (2017-2022)

With partnering Native American communities, the University of New Mexico Metal Exposure and Toxicity Assessment on Tribal Lands in the Southwest Superfund Research Program Center (UNM METALS) 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. The researchers’ published and preliminary work shows that certain metals interact with key cellular targets to disrupt zinc-dependent protein function. The researchers are testing the hypothesis that metals disrupt multiple classes of zinc binding proteins known to regulate immune responses, and that supplemental zinc will mitigate immunotoxicity resulting from metal exposures.

In Aim 1 the researchers are investigating the immunotoxic effects and underlying mechanisms of U, As, and environmentally relevant metal mixtures, and whether the immunotoxic effects are reduced by supplemental zinc in cell and mouse models. Aim 2 is testing whether dietary zinc supplementation will decrease biomarkers of immune dysregulation in exposed populations in partnership with affected communities. The work is innovative by combining exposure information and biomonitoring data from exposed populations with mechanistic studies in experimental models.

To date, there are no significant, community-based health studies describing both exposure and immunologic outcome measures in these impacted Tribal communities. The researchers are proposing a novel hypothesis that metals exposures disrupt multiple classes of Zn binding proteins critical for immune function leading to immune dysregulation, and that supplemental Zn will mitigate metal toxicity.

This study represents the first human intervention (clinical trial) based on zinc supplementation to mitigate the adverse effects of mixed metal exposures. The project is well integrated with the environmental science and engineering projects to inform distinct metals exposures for experimental studies, and the Mechanisms of Immune Dysregulation Produced by Uranium, Arsenic and Metal Mixtures project to share mechanistic data and model systems. This study works closely with the Community Engagement and Research Translation Cores for community input and reporting results back to the communities, and the Biostatistics and Data Management Core for research support.

The outcomes from these studies will be significant by testing metals and metals mixtures of concern to communities to elucidate impact on and mechanisms of immune dysregulation as detected in exposed populations, and testing the feasibility of a mechanism-based intervention to alleviate the adverse effects of metals exposures. The proposed intervention is also sympathetic with the culture as it uses a natural element to restore balance to a perturbed system.

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