Respirable Uranyl-Vanadate-Containing Particulate Matter Derived From a Legacy Uranium Mine Site Exhibits Potentiated Cardiopulmonary Toxicity

Abstract

Exposure to windblown particulate matter (PM) arising from legacy uranium (U) mine sites in the Navajo Nation may pose a human health hazard due to their potentially high metal content, including U and vanadium (V). To assess the toxic impact of PM derived from Claim 28 (a priority U mine) compared with background PM, and consider the putative role of metal species U and V. Two representative sediment samples from Navajo Nation sites (Background PM and Claim 28 PM) were obtained, characterized in terms of chemistry and morphology, and fractioned to the respirable (≤ 10 μm) fraction. Mice were dosed with either PM sample, uranyl acetate, or vanadyl sulfate via aspiration (100 µg), with assessments of pulmonary and vascular toxicity 24 h later. Particulate matter samples were also examined for in vitro effects on cytotoxicity, oxidative stress, phagocytosis, and inflammasome induction. Claim 28 PM10 was highly enriched with U and V and exhibited a unique nanoparticle ultrastructure compared with background PM10. Claim 28 PM10 exhibited enhanced pulmonary and vascular toxicity relative to background PM10. Both U and V exhibited complementary pulmonary inflammatory potential, with U driving a classical inflammatory cytokine profile (elevated interleukin [IL]-1β, tumor necrosis factor-α, and keratinocyte chemoattractant/human growth-regulated oncogene) while V preferentially induced a different cytokine pattern (elevated IL-5, IL-6, and IL-10). Claim 28 PM10 was more potent than background PM10 in terms of in vitro cytotoxicity, impairment of phagocytosis, and oxidative stress responses. Resuspended PM10 derived from U mine waste exhibit greater cardiopulmonary toxicity than background dusts. Rigorous exposure assessment is needed to gauge the regional health risks imparted by these unremediated sites.

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

“…While this is evidence of immune modulation, these findings somewhat contrasts the findings presented by Hao et al, (2013), which observed an increase in Th2 cytokines (IL-4 and IL-10) and a decrease in Th1 cytokines (IFN-γ and TNF-α). Similarly, Zychowski et al, (2018) reported an increase in inflammatory cytokines in lung bronchoalveolar lavage fluid following acute U exposure. Future studies investigating cytokine production in immune and other tissues following drinking water U exposure will be important for understanding the immunotoxicity of U. Additionally, discrepancies between these studies highlight the importance of determining which routes and forms of U are most appropriate for use in animal models to accurately model human exposures to U.…”

Serum-borne factors alter cerebrovascular endothelial microRNA expression following particulate matter exposure near an abandoned uranium mine on the Navajo Nation

“…6 Circulating serum-borne microRNAs Highly significantly differentially expressed miRNAs (p < 0.01), as measured in the SCIP assay, were assessed in FA and CAPs serum. a-i Significantly altered (p < 0.05) microRNAs in FA and CAPs-exposed mouse serum contaminant metal mixtures, including uranium (U), arsenic (As) and vanadium (V) [4][5][6]. Metals-based exposure has been implicated in several adverse health effects, including pulmonary and cardiovascular diseases, neurological disorders and cancer [53][54][55][56].…”

“…Commercial uranium mining was active on the Navajo Nation from the 1940s-1980s during the Cold War era [1][2][3]. As a result of commercial uranium mining and insufficient remediation, many tribal communities located in the Southwestern United States are exposed to varying degrees of contaminant metal mixtures arising from abandoned uranium mines (AUMs) [4][5][6]. Exposure to metals through drinking water has been linked to adverse health outcomes [7][8][9][10], and residential proximity to AUMs is associated with an increase in circulating inflammatory biomarkers [11].…”

“…Residential proximity to AUMs is significantly associated with cumulative circulating inflammatory potential in the serum of local residents, as determined by an ex vivo mCEC cell bioassay, the serum cumulative inflammatory potential (SCIP) assay, developed in our laboratory [6,11,15,16]. The SCIP assay is used to assess mCEC cellular mRNA and protein responses to circulating serum-borne ligands following inhaled toxicant exposure or environmental insult [15][16][17][18][19][20].…”

Metal-Induced Pulmonary Fibrosis

“…Fibrotic responses in DBA/2J mice persisted 4 months following exposure, while fibrosis in C57BL/6J mice had resolved. A recent study comparing particulate toxicity from samples obtained near an abandoned, unremediated carnotite (uranium/vanadium) mine found that PM derived from mine site sediments, which evidently contained higher levels of vanadium and uranium, exhibited greater in vivo and in vitro toxicity compared to background dusts [96]. While these studies were all acute pulmonary response assessments, it was further established that vanadium, alone, can drive much of the toxicity and inflammatory outcomes.…”