Abstract
Perfluorinated compounds (PFCs) are persistent environmental pollutants with near-universal human exposure, yet their respiratory health impacts during adolescence remain insufficiently explored. This investigation evaluated single and combined effects of serum PFCs on pulmonary function and respiratory morbidity in a nationally representative adolescent cohort (n = 976, ages 12-19 years) utilizing 2007-2012 NHANES data. Advanced analytical approaches including multivariable regression, mixture modeling (BKMR and WQS), and mediation analysis were employed to assess associations with spirometric parameters (FEV1, FVC, FEV1/FVC) and respiratory symptoms while examining inflammatory and oxidative stress pathways. Computational approaches integrating network toxicology and molecular docking identified key protein targets. Analytical results demonstrated significant associations between specific PFC congeners (PFOA, PFHS, PFOS) and pulmonary function measures, with age-stratified effects observed for wheezing symptoms. Mixture analyses revealed PFOA as the predominant contributor to observed respiratory effects, partially mediated through oxidative stress pathways (6.8-8.2% mediation). Molecular investigations identified critical signaling nodes (INS, AKT1, TP53, TNF, IL6, ALB and PPARγ) potentially linking PFC exposure to respiratory outcomes. These findings provide mechanistic insights into PFC-induced pulmonary effects during adolescence, highlighting the need for continued investigation of these environmentally persistent compounds' impact on developing respiratory systems. The integrated epidemiological-computational approach demonstrates the utility of combining population-level data with mechanistic modeling to elucidate environmental health effects.