Associations of per- and polyfluoroalkyl substances (PFAS) exposure with arterial stiffness: Evidence from NHANES 2011–2018

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants linked to various diseases, yet their association with arterial stiffness remains unclear. Using data from 5209 U.S. adults in the National Health and Nutrition Examination Survey (2011–2018), the association between PFAS exposure and estimated pulse wave velocity (ePWV) was investigated via multiple statistical approaches. In single-exposure models, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS), but not perfluorononanoic acid (PFNA), were significantly associated with elevated ePWV. PFOS exhibited a nonlinear dose-response relationship. However, mixture analyses (Weighted Quantile Sum regression and Quantile G-computation models) detected no significant overall mixture effect. Exploratory component rankings and an Extreme Gradient Boosting model interpreted with SHapley Additive exPlanations consistently identified PFOS as the predominant driver. Exploratory mediation analyses suggested that oxidative stress (serum uric acid and gamma-glutamyl transferase [GGT]) and mineral homeostasis (serum calcium) may serve as potential mediating pathways, although the nonspecific signals for uric acid, and inconsistent GGT findings across PFAS congeners warrant cautious interpretation. Subgroup analyses indicated greater susceptibility in females and partnered individuals. Overall, these findings provide hypothesis-generating evidence for potential pathways and offer exploratory insights for prevention, while also highlighting the need for future studies employing more direct measures.