Healthy lifestyle modifies the association between per- and polyfluoroalkyl substances and hyperlipidemia: A propensity score-matched case-control study.

The impact of per- and polyfluoroalkyl substances (PFAS) on hyperlipidemia and the potential modifying role of overall lifestyle remain underexplored. We examined six serum PFAS and a composite lifestyle score among 192 propensity score-matched case-control pairs. Individual and joint associations were evaluated using conditional logistic regression, quantile g-computation, and Bayesian kernel machine regression. A composite healthy lifestyle score was constructed based on smoking, alcohol drinking, physical activity, body shape, and diet. Per interquartile range (IQR) increase in ln-transformed concentrations, perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), and perfluoroundecanoic acid (PFUnDA) were associated with 89%, 110%, 67%, 49%, and 42% higher odds of hyperlipidemia, respectively. Mixture analyses revealed a joint positive association (OR = 1.57; 95% CI: 1.22, 2.02), driven predominantly by PFNA, the emerging alternative 6:2 Cl-PFESA, and PFHxS. Among participants with an unhealthy lifestyle (defined as a composite score ≤2 based on the population median), higher levels of PFOA, PFHxS, and PFNA were associated with significantly elevated odds of hyperlipidemia. However, for 6:2 Cl-PFESA, perfluorodecanoic acid (PFDA), and PFUnDA, these associations were generally weaker in participants adhering to a relatively healthy lifestyle, as supported by significant multiplicative interactions. Negative additive interactions were also observed for 6:2 Cl-PFESA and PFNA. Our findings demonstrate that adherence to a healthy lifestyle was associated with substantially weaker associations between 6:2 Cl-PFESA and PFDA exposures and hyperlipidemia, highlighting lifestyle modification may serve as a potential public health strategy to reduce environmental metabolic hazards.