Exposure to PFOS and PFOA through drinking water is associated with greater cigarette smoke-induced COPD-like lung injury and enhanced NF-κB-related inflammatory signaling in mice.

Chronic obstructive pulmonary disease (COPD) is a major global health burden, and environmental pollutants may modify its progression. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are persistent per- and polyfluoroalkyl substances with known immunotoxic and proinflammatory effects, but their contribution to smoke-related lung injury remains unclear. Here, we investigated whether chronic PFOS or PFOA exposure was associated with greater cigarette smoke (CS)-induced COPD-like lung injury. Mice were exposed to CS for 3 months with concurrent PFOS or PFOA exposure in drinking water at the same nominal concentration (2 mg/L). Lung function, histopathology, transcriptomic profiling, and supportive in vitro assays in RAW264.7 cells were performed. Compared with CS alone, PFOS or PFOA co-exposure with CS was associated with greater pulmonary impairment, including greater alveolar destruction, enhanced airway inflammation, and more pronounced impairment of pulmonary function, as reflected by a lower forced expiratory volume in one second to forced vital capacity ratio (FEV₁/FVC). Transcriptomic and in vitro analyses were consistent with enhanced nuclear factor-κB (NF-κB)-related inflammatory signaling. These findings support a potential role for drinking-water PFAS exposure as a modifier of smoke-induced pulmonary injury.