Inflammation mediates the association between per- and polyfluoroalkyl substance exposure and kidney function:...

Exposure to legacy per- and polyfluoroalkyl substance (PFAS) has been positively associated with impaired kidney function; however, evidence regarding PFAS isomers and emerging PFAS, as well as the underlying mechanisms, remains limited. PFAS isomers were defined as linear and branched structural forms of the same compound; legacy PFAS as historically produced compounds (e.g., PFOS and PFHxS); and emerging PFAS as newer replacement chemicals, including 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA). This study integrated epidemiological analyses and animal experiments to examine associations between PFAS exposure, systemic inflammation, and kidney function. In the epidemiological analysis, both legacy and emerging PFAS were associated with reduced estimated glomerular filtration rate (eGFR), and mediation analysis indicated that systemic inflammation partially explained these associations. For example, each one-unit increase in log-transformed 6:2 Cl-PFESA concentration was associated with lower eGFR (β = -1.56; 95 % CI: -2.37 to -0.74), with white blood cell count mediating 7.91 % of the Cl-PFESA-eGFR association. Isomer-specific effects were observed: linear PFOS and PFHxS showed stronger associations with inflammatory markers than their branched counterparts, while eGFR did not differ by isomer. Weighted quantile sum regression identified 6:2 Cl-PFESA as the largest contributor to reduced eGFR within the PFAS mixture (weight = 0.321). In mice, Cl-PFESA exposure resulted in increases in serum creatinine compared with the control group (2.70-fold in the 400 μg/L group; P < 0.01). Tumor necrosis factor-α was strongly correlated with serum creatinine (r = 0.949; P < 0.01) and mediated 58.41 % of the Cl-PFESA-creatinine association.