# Project 4 - Biomedical Project 2 - BP2 - Mechanisms of Immune Dysregulation Produced by Uranium, Arsenic and Metal Mixtures

> **NIH NIH P42** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $215,498

## Abstract

Project 4 - Biomedical Project 2 – BP2 - Project Summary 
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 
>1100 abandoned Cold War U waste sites and documented U and As well water contamination. Immature pre- 
T (thymus) and pre-B (bone marrow) 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. 
We provide preliminary data that UA interacts with As(III) to produce immunotoxicity via both genotoxic (DNA 
damage through PARP inhibition), and non-genotoxic (IL-7 signaling in pre-T and pre-B cells) in the mouse. 
We also hypothesize that immature lymphoid cells lack the ability to export metals, leading to increased 
exposures. In the present studies we will test this hypothesis by direct measurement of lymphoid organ 
concentrations following UA and As(III) exposures, alone and in combination, following drinking water 
exposures. It is important to understand the mechanisms of pre-T and pre-B sensitivity to UA and AsIII 
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 provide a strong framework for 
interaction with BP-1 and EP-1. At the molecular level, UA and As(III) have been found to displace Zn, and 
inhibit PARP-1 function leading to DNA damage. Although the UA may not have strong immunotoxicity on its 
own, there appears to be important synergy with UA and As(III). The bases for these interactions are not well 
understood. The proposed studies will evaluate several potential mechanism for UA and As(III) interactions. 
We also propose to investigate other environmentally relevant metal mixtures. These studies also provide a 
framework for understanding how interventions, such as Zn supplementation, can be used to prevent 
arsenic/uranium toxicity (BP-1) and perhaps other environmentally relevant metal mixtures (EP-1). The 
proposed studies will provide 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.

## Key facts

- **NIH application ID:** 9903356
- **Project number:** 5P42ES025589-04
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Scott W Burchiel
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $215,498
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903356

## Citation

> US National Institutes of Health, RePORTER application 9903356, Project 4 - Biomedical Project 2 - BP2 - Mechanisms of Immune Dysregulation Produced by Uranium, Arsenic and Metal Mixtures (5P42ES025589-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9903356. Licensed CC0.

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