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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Progress Reports
To better understand the effects of metals associated with abandoned uranium mines and mine waste on immune function, Debra MacKenzie, Ph.D., and her lab are conducting studies assessing the impact of single and mixed metals exposures on immune cell responses and immune regulatory pathways. In cell-based studies, the research team has found that arsenic, but not uranium, promotes an oxidative stress response, DNA damage, and cytotoxicity (Dashner-Titus and Schilz, in preparation). This is consistent with findings from RNA sequencing data from primary human CD4+ T-lymphocytes treated with arsenic, uranium, or both prior to activation. Arsenic (As) stimulated an expression of genes associated with oxidative stress and inhibited expression of genes involved in T-cell activation. Uranium exposure had no significant impact on oxidative stress markers and, in contrast to arsenic, did not interfere with T-cell activation. However, uranium modified the arsenic response suggesting that the impact of uranium may be most significant in combination with other metals (Schilz and Dashner-Titus, in preparation). This mixture effect is also observed in measures of chronic inflammation where cluster analyses show significant increases in pro-inflammatory cytokines are associated with exposure to the highest concentrations of multiple metals including cobalt (Co), manganese (Mn), molybdenum (Mo), lead (Pb), tungsten, and inorganic As and metabolites (Ong dissertation, 2019). This year, enrollment was started for Thinking Zinc, a clinical trial to investigate whether zinc dietary supplements mitigate adverse effects of metals in an exposed human population (NCT03908736). In the current year, MacKenzie and her lab have enrolled 29 participants within the first community with an additional enrollment scheduled in early 2020 and enrollment for the second community expected in mid to late 2020. Initial sample analysis is underway. The results from this study could support an avenue for intervention to improve the well-being of people during the lengthy process of environmental cleanup of mine waste.