Particulate matter (PM) exposure is a global health issue that impacts both urban and rural communities. Residential communities in the Southwestern United States have expressed concerns regarding the health impacts of fugitive PM from rural, legacy mine-sites. In addition, the recent literature suggests that exosomes may play a role in driving toxicological phenotypes following inhaled exposures. In this study, we assessed exosome-driven mechanisms and systemic health impacts following inhaled dust exposure, using a rodent model. Using an exosome inhibitor, GW4869 (10 μM), we inhibited exosome generation in the lungs of mice via oropharyngeal aspiration. We then exposed mice to previously characterized inhaled particulate matter (PM) from a legacy mine-site and subsequently assessed downstream behavioral, cellular, and molecular biomarkers in lung, serum, and brain tissue. Results indicated that CCL-2 was significantly upregulated in the lung tissue and downregulated in the brain (p < 0.05) following PM exposure. Additional experiments revealed cerebrovascular barrier integrity deficits and increased glial fibrillary acidic protein (GFAP) staining in the mine-PM exposure group, mechanistically dependent on exosome inhibition. An increased stress and anxiety response, based on the open-field test, was noted in the mine-PM exposure group, and subsequently mitigated with GW4869 intervention. Exosome lipidomics revealed 240 and eight significantly altered positive-ion lipids and negative-ion lipids, respectively, across the three treatment groups. Generally, phosphatidylethanolamine (PE) and phosphatidylcholine (PC) lipids were significantly downregulated in the PM group, compared to FA. In conclusion, these data suggest that systemic, toxic impacts of inhaled PM may be mechanistically dependent on lung-derived, circulating exosomes, thereby driving a systemic, proinflammatory phenotype.

Chronic arsenic exposures via the consumption of contaminated drinking water are clearly associated with many deleterious health outcomes, including anemia. Following exposure, trivalent inorganic arsenic (As^III) is methylated through a series of arsenic (+III oxidation state) methyltransferase (As3MT)-dependent reactions, resulting in the production of several intermediates with greater toxicity than the parent inorganic arsenicals. The extent to which inorganic vs. methylated arsenicals contribute to As^III-induced hematotoxicity remains unknown. In this study, the contribution of As3MT-dependent biotransformation to the development of anemia was evaluated in male As3mt-knockout (KO) and wild-type, C57BL/6J, mice following 60-day drinking water exposures to 1 mg/L (ppm) As^III. The evaluation of hematological indicators of anemia revealed significant reductions in red blood cell counts, hemoglobin levels, and hematocrit in As^III-exposed wild-type mice as compared to unexposed controls. No such changes in the blood of As3mt-KO mice were detected. Compared with unexposed controls, the percentages of mature RBCs in the bone marrow and spleen (measured by flow cytometry) were significantly reduced in the bone marrow of As^III-exposed wild-type, but not As3mt-KO mice. This was accompanied by increased levels of mature RBCS in the spleen and elevated levels of circulating erythropoietin in the serum of As^III-exposed wild-type, but not As3mt-KO mice. Taken together, the findings from the present study suggest that As3MT-dependent biotransformation has an essential role in mediating the hematotoxicity of As^III following drinking water exposures.