Association between serum perfluoroalkyl substances and COPD risk: population evidence and in vitro validation.
BACKGROUND Per- and polyfluoroalkyl substances are characterized by environmental persistence, bioaccumulation potential, and multi-organ toxicity. Given their ubiquitous presence in the environment and human serum, concerns regarding respiratory health risks are growing, particularly due to scarce evidence on environmental etiologies of chronic obstructive pulmonary disease in never-smokers. This study aimed to investigate the mechanistic role of these substances in chronic obstructive pulmonary disease through a population-computational-experimental paradigm, with specific focus on lipid-metabolic mediation. METHODS Data from the National Health and Nutrition Examination Survey (2007-2018) were analyzed using weighted quantile sum regression and quantile-based g-computation to assess mixture exposure effects. Mediation analysis was performed to evaluate the triglyceride-glucose index as a metabolic intermediate pathway. Network toxicology and molecular docking analyses were conducted to identify core protein targets. Human bronchial epithelial cells were exposed to perfluorooctanoic acid to validate target gene expression and downstream pathway activation. RESULTS Mixture exposure showed a significant positive association with chronic obstructive pulmonary disease risk. Perfluorooctanesulfonic acid and perfluorooctanoic acid were the primary toxicity contributors. The association remained robust among never-smokers. The triglyceride-glucose index significantly mediated the exposure-disease relationship (mediation proportion: 6.6%-7.8%). SRC, EGFR, PPARG, and MMP9 were identified as core targets. Experimental validation confirmed that perfluorooctanoic acid altered expression of these targets, activating inflammation and remodeling pathways. CONCLUSIONS These substances disrupt pulmonary homeostasis through concurrent molecular activation and lipid-metabolic disturbance, evidenced by triglyceride-glucose index mediation. This dual mechanism provides new evidence for chronic obstructive pulmonary disease prevention in never-smokers and identifies potential metabolic intervention targets.