PROJECT SUMMARY (Project 1: Chen) Chronic exposure to arsenic (As), commonly found in mine tailings particulate matters (mt-PMs), heightens the risk of lung diseases. This risk is notably elevated for those living near contaminated sites due to continuous exposure from inhaling dust and consuming tainted water or food. Additionally, environmental stressors, such as mold, intensify these risks. At present, there is limited data about the mechanisms and effects of these exposures, especially regarding nonmalignant lung diseases. In previously published research, we found that As inhibited the production of major mucins, essential components for mucociliary clearance (MCC), in differentiated human airway epithelial cells (HAECs). Moreover, mouse models exposed to inhaled synthetic arsenic-containing dusts (sACDs) and real-life mt-PMs showed reduced CC16 expression, another crucial MCC component. A decrease in CC16, a significant biomarker, is correlated with impaired lung function in various diseases. Importantly, As appeared to repress retinoic acid (RA) signaling, leading to the downregulation of both mucins and CC16. In our preliminary studies for this proposal, we extended the previous findings by revealing that As-exposed HAECs underwent a process of de-differentiation. This change resulted in the repression of several secretory and ciliated cell markers, suggesting a pronounced MCC deficiency (MCCD) and a compromised epithelial barrier. Notably, all-trans retinoic acid (t-RA) could counteract As's effects, underscoring the significance of the RAR/RXR signaling pathway. Furthermore, Nrf2's involvement was essential for RAR/RXR degradation, and a deficiency in CC16 rendered mice more susceptible to mold exposure. Based on these insights, we hypothesize that As exposure induces MCCD in the airway epithelium through a crosstalk between Nrf2 and RAR/RXR. This dysfunction likely weakens the protective barrier, increasing susceptibility to environmenta