Revealing the Link Between Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Stroke: A Comprehensive Epidemiological and Network Toxicology Perspective.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants associated with cardiovascular disease; however, their association with stroke risk remains insufficiently characterized. Critical knowledge gaps remain regarding the dose-response relationships, mixture effects, and biological pathways potentially linking PFAS to cerebrovascular disease. We initially screened 50,912 U.S. adults from NHANES (2003-2012) and included eligible participants to examine associations between serum PFAS concentrations, including PFOA, PFOS, PFHxS, and PFNA, and self-reported stroke. Weighted generalized linear models assessed exposure-response relationships and weighted quantile sum (WQS) regression were used to evaluate PFAS mixture effects. Causal mediation analysis quantified the contributions of serum lipids (total cholesterol [TC] and LDL-cholesterol) to the PFAS-stroke associations. Individual PFAS showed positive associations with stroke. Near-linear dose-response curves suggested no apparent thresholds for PFOA, PFHxS, and PFNA (all P for trend < 0.01), while PFOS exhibited a threshold effect at 3.73 ng/mL (95% CI: 3.15-4.28). WQS regression indicated that PFAS mixtures were positively associated with stroke risk (OR = 1.52; 95% CI: 1.17-1.97), with PFOS contributing the largest mixture weight (0.39). Mediation analyses indicated TC and LDL mediated 2.07-11.22% of the PFAS-stroke associations (P mediation < 0.05). This study establishes PFAS exposure, particularly PFOS-dominated mixtures, may represent an environmental correlate of stroke risk, with lipid dysregulation potentially contributing to this association. Strategies aimed at reducing PFOS exposure may help mitigate the potential cerebrovascular burden associated with PFAS exposure.