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University of New Mexico

Superfund Research Program

Mechanisms of Immune Dysregulation Produced by Uranium, Arsenic and Metal Mixtures

Project Leader: Ke Jian Liu
Grant Number: P42ES025589
Funding Period: 2017-2022
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Project Summary (2017-2022)

Native American communities in the Southwestern United States have concerns that uranium (U) and arsenic (As) exposures arising from abandoned U mine sites have increased the prevalence of metal-associated diseases including immune dysfunction. These concerns are based on environmental exposures linked to the >1,100 abandoned Cold War U waste sites and documented U and As well water contamination.

Immature pre-T (thymus) and pre-B (bone marrow) cells have been found to be extremely sensitive to As(III) and perhaps U[VI], in the form of uranyl acetate (UA), exposures. The immunotoxicity of UA has not been previously characterized. Preliminary data from the researchers suggest that UA may interact with As(III) to produce immunotoxicity via both genotoxic (DNA damage through inhibition of the enzyme poly ADP ribose polymerase inhibition), and non-genotoxic (IL-7 signaling in pre-T and pre-B cells) mechanisms in the mouse. The researchers hypothesize that immature lymphoid cells are particularly susceptible to toxicity because they lack the ability to export metals, leading to increased exposure.

The researchers at the University of New Mexico Metal Exposure and Toxicity Assessment on Tribal Lands in the Southwest Superfund Research Program Center (UNM METALS) are testing this hypothesis in mice by direct measurement of lymphoid organ metal concentrations following UA and As(III) drinking water exposures, alone and in combination. It is important to understand the mechanisms of pre-T and pre-B sensitivity to UA and As(III) exposures because these pathways could explain alterations in T- and B-cell selection that are responsible for human immune dysregulation (such as autoimmunity). These studies are providing a strong framework for interaction with two other center projects: 1) Modulation of Uranium and Arsenic Immune Dysregulation by Zinc; and 2) Immobilization of U, As, and Co-occurring Metals in Mine Wastes.

At the molecular level, UA and As(III) have been found to displace Zn, and inhibit poly ADP ribose polymerase-1 function leading to DNA damage. The researchers are currently evaluating the effects of UA on immature lymphoid cells and several potential mechanisms for UA and As(III) interactions that lead to immunotoxicity. The researchers are also investigating other environmentally relevant metal mixtures.

These studies are providing a framework for understanding how interventions, such as Zn supplementation, can be used to prevent As/U toxicity (see the Modulation of Uranium and Arsenic Immune Dysregulation by Zinc project) and perhaps other environmentally relevant metal mixtures (see the Immobilization of U, As, and Co-occurring Metals in Mine Wastes project). This work is providing critical mechanistic insights into the potential immunotoxicity of UA, its interactions with As(III), as well as other metals and, importantly, the potential for use of zinc therapy to modify immune diseases in sensitive populations who are environmentally exposed to these metals.

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