Integrating lipid metabolomics and epidemiology: A mediation analysis of blood lipids between per- and polyfluoroalkyl substances (PFAS) and renal impairment.

Exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to renal impairment, but evidence on mixed PFAS exposure in the general Chinese population and the underlying mechanisms remains limited. This study therefore investigated the associations between PFAS exposure and renal function and evaluated the potential mediating role of blood lipids. Serum levels of legacy and emerging PFAS, renal function parameters, and blood lipid profiles were measured in 1370 adult residents from Zhejiang Province, China; additionally, 452 lipid metabolites were quantified in a subset of 316 participants. Using multiple linear regression, restricted cubic splines (RCS), and mixture exposure models, we found that PFAS mixture exposure was associated with reduced renal function, with eGFR decreases ranging from 2.2% to 2.9% per quartile increase across models, and PFOA as a predominant contributor. Mediation analyses further revealed that elevated total cholesterol, low-density lipoprotein cholesterol, and disturbances in fatty acids and phospholipids mediated 6.3% to 65.9% of the association between PFAS exposure and renal function decline. Collectively, these findings suggest that mixed PFAS exposure, particularly to PFOA and PFHpA, may induce impaired renal function, with increased blood lipids playing an important mediating role.