Minimal uranium immunotoxicity following a 60-day drinking water exposure to uranyl acetate in male and female C57BL/6J mice

Abstract

Historical uranium (U) mining in the Southwestern United States resulted in significant environmental contamination throughout this region and presents a significant risk of chronic metal exposure and toxicity for communities living in close proximity to mine waste sites. Uranium exposure is associated with numerous deleterious health effects including immune dysfunction; however, its effects on the immune system have yet to be fully characterized. We recently published that drinking water exposure to U, in the form of uranyl acetate (UA), results in overall low tissue retention of U (<0.01%), with very little accumulation in immune organs (blood, bone marrow, spleen, and thymus) of male and female mice. In the present study we characterized the immunotoxicity of U, in the form of UA, following a 60-day drinking water exposure to 5 and 50 ppm in male and female C57BL/6J mice. The following immunotoxicity endpoints were evaluated: hematology, immune tissue weights and total cell recoveries, immunophenotying of the spleen and thymus, and immune cell function (lymphocyte mitogenesis and T-dependent antibody response). Uranium exposure had subtle impacts on the immune endpoints evaluated, likely due to low U accumulation at these sites. The only significant alterations were a slight decrease in the percentages of splenic natural killer T-cells and macrophages in exposed male mice. Despite minimal immunological effects, this study highlights the importance of investigating toxicological endpoints in both sexes and developing accurate animal models that model epidemiological exposures in the future.

Co-exposure of sodium arsenite and uranyl acetate differentially alters gene expression in CD3/CD28 activated CD4+ T-cells

“…Of importance to note is that uranyl acetate treatment alone did not significantly alter the expression of in the selected genes from any of the 3 donors tested, indicating that uranyl acetate alone may not exert a direct effect on gene expression at the doses used but may only show an effect in combination with other metals. Previous studies in animal models suggest that uranyl acetate has little impact on CD4+ T-cells [ 60 ] and that uranyl acetate is not cytotoxic or able to induce oxidative stress or DNA damage in Jurkat T-cells [ 42 ], supporting the lack of gene expression changes observed by uranyl acetate treatment in our study. Less variability was observed between donor 1 and donor 3 where in most genes the directionality of results was similar with slightly different magnitudes.…”

“…The results indicate that while uranyl acetate alone did not significantly alter global gene expression during T-cell activation in a controlled experimental system, changes in biological processes and pathways involved in T-cell activation and immune response are induced when in the presence of both low dose sodium arsenite and the mixture. This is supported by results indicating no alterations in T-cell subsets or function in mice exposed to uranium for 60 days [ 60 ]. In contrast, there is evidence indicating that populations exposed to uranium exhibit altered immune cell counts and function [ 16 , 19 , 26 ].…”

Exposures to uranium and arsenic alter intraepithelial and innate immune cells in the small intestine of male and female mice

“…The effects of U exposure on T cell development in the thymus have not been extensively studied, but our previous studies show very little U exposure at this site and no effects on T cell subsets following drinking water exposures in male and female mice (Bolt et al, 2018;Bolt et al, 2019). Therefore, rather than impacting T cell development in the thymus, it is more feasible that U produces effects locally in the gut either through direct toxicity to IELs or through indirect effects on innate immune cell populations or the microbiome.…”