Effects of per- and polyfluoroalkyl substances on glucose and lipid metabolism in healthy adults: The moderating role of caffeine consumption

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants associated with cardiometabolic diseases, characterized by disruptions in glucose and lipid metabolism. However, comprehensive studies assessing metabolic abnormalities, particularly novel insulin resistance (IR) indices, remain limited. Additionally, caffeine intake is a common lifestyle factor, its potential to modulate PFAS-induced metabolic disturbances remains poorly understood. This cross-sectional study investigated 3468 U.S. adults from NHANES (2007-2018) to assess associations between PFAS and glucose-lipid biomarkers, including total cholesterol (TC), triglyceride, low-density lipoprotein (LDL), high-density lipoprotein, homeostasis model assessment of IR (HOMA-IR), β-cell function (HOMA-β), and triglyceride-glucose indices (TyG, TyG-BMI), while exploring the moderating effect of caffeine intake. Among the seven PFAS analyzed, five (PFOS, PFOA, PFNA, PFDA, and PFUnA) were significantly associated with elevated TC and LDL levels in multivariable survey-weighted regression models. These PFAS compounds were also positively correlated with glucose metabolism indicators, including HOMA-β (β = 7.95, 95 % CI: 1.72, 14.18 for PFNA; β = 7.56, 95 % CI: 1.57, 13.55 for PFOA; β = 7.56, 95 % CI: 2.77, 12.35 for PFOS), the TyG index (β = 0.05, 95 % CI: 0.01, 0.08 for PFNA; β = 0.07, 95 % CI: 0.03, 0.11 for PFOA; β = 0.06, 95 % CI: 0.02, 0.10 for PFOS), and TyG-BMI (β = 1.28, 95 % CI: 0.22, 2.35 for MPAH; β = 1.24, 95 % CI: 0.24, 2.25 for PFNA; β = 2.02, 95 % CI: 1.01, 3.02 for PFOA; β = 1.78, 95 % CI: 0.54, 3.02 for PFOS). Interaction analysis revealed that caffeine intake significantly moderated PFAS associations with LDL, with stronger positive associations observed in the low caffeine intake group. These findings suggest that PFAS exposure may disrupt lipid and glucose metabolism, particularly increased LDL and IR. Caffeine may attenuate some PFAS-related lipid disturbances, underscoring the need for further investigation into its protective role.