Per- and polyfluoroalkyl substances (PFAS) exposure and cardiovascular risk: lipid profile as a mediator.

BACKGROUND: In recent years, amidst the phase-out of long-chain per- and polyfluoroalkyl substances (PFAS), the true relationship between PFAS exposure and lipid metabolism or cardiovascular disease (CVD), as well as the role of lipid profiles in this association, remains unclear. METHODS: Data from 25 531 NHANES participants (age ≥ 20 years old) enrolled between 2015 and 2020 were examined. To assess links between individual PFAS and cardiovascular disease (CVD) as well as lipid measures, both logistic and multivariable linear regression analyses were performed. Nonlinear exposure-response patterns with CVD were fitted using restricted cubic splines. In addition, the combined impact of PFAS mixtures on CVD risk was investigated via Bayesian kernel machine regression (BKMR), weighted quantile sum (WQS) regression, and quantile g-computation (Q-gcomp), and mediation analyses were evaluated using causal mediation models. RESULTS: After comprehensive adjustment, each log-unit increase in PFNA, n-PFOA, n-PFOS, and Sm-PFOS was inversely associated with CVD risk. There was a significant inverse trend in the associations of n-PFOA and Sm-PFOS with CVD. PFDeA, PFHxS, PFNA, PFUA, n-PFOA, n-PFOS, and Sm-PFOS were significantly positively associated with total cholesterol (TC). PFUA was significantly negatively associated with triglycerides (TG), and specific PFAS also showed significant positive associations with low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Mixture exposure analysis indicated a significant inverse trend between PFAS mixtures and CVD, with Sm-PFOS contributing the most weight in the mixture index. Through mediation analysis, we found that total cholesterol and LDL cholesterol serve as significant intermediaries in the relationships between PFNA, n-PFOA, n-PFOS, Sm-PFOS, and cardiovascular disease. CONCLUSION: These findings imply that contemporary PFAS exposure profiles may confer differential cardiovascular effects, in part through lipid-mediated pathways, and highlight the need for continued monitoring and mechanistic studies to inform risk assessment and regulatory decisions.