Serum perfluoroalkyl and polyfluoroalkyl substances and the risk of cardiometabolic diseases: Unraveling the mediating role of inflammatory markers

The persistence and biotoxicity of perfluoroalkyl and polyfluoroalkyl substances (PFASs) have raised concerns about cardiometabolic diseases (CMDs). Inflammation is thought to underlie the pathology of various CMDs. We aimed to comprehensively assess the risk of CMDs associated with PFASs and quantify the mediating effects of two kinds of inflammatory markers. Nine PFASs, a direct marker (high-sensitivity C-reactive protein [hs-CRP]), and an indirect marker (serum ferritin [SF]) were analyzed. A total of 12 CMDs of five types were defined based on 15 cardiometabolic biomarkers. The PFAS mixture had significant adverse effects on hypercholesterolemia (HC; OR = 1.20, 95% CI: 1.03-1.39), high low-density lipoprotein cholesterol (high LDL-C; OR = 1.13, 95% CI: 1.01-1.30), hypertension (OR = 1.10, 95% CI: 1.03-1.19), and hyperuricemia (OR = 1.31, 95% CI: 1.16-1.48) in the quantile-based g-computation (QGC) model, with PFNA and PFTrDA contributing the most. PFHxS was found to significantly impact all five types of CMDs simultaneously. The exposure-response analysis exhibited complex nonlinear patterns, with significant heterogeneity across diseases. Both inflammatory markers significantly mediated the effects of multiple PFASs on CMDs, with SF contributing a higher proportion of the mediating effects for obesity, dyslipidemia, and hyperuricemia. The highest mediation proportion reached 85.78% for abdominal obesity (FDR = 0.024). These results suggest that inflammation may serve as a key pathological mechanism linking PFAS exposure to CMDs, highlighting the potential value of SF as an iron status and indirect inflammatory marker in assessing PFAS-related cardiometabolic health risks.