PPARs, L-FABP mediate the association between Per- and polyfluoroalkyl substances and gestational diabetes: a nested case-control study.

To analyze the correlation between PFASs exposure and glucose metabolic indexes in relation to GDM risk, and to explore the mediating role of PPARs and L-FABP. Using a nested case–control study method. Blood specimens were collected during early pregnancy for quantification of PFASs, PPARs, and L-FABP. LASSO was used to select PFASs, and the selected variables were subsequently included in WQS and QGComp to analyze the relationship between PFASs and GDM. Four-way decomposition analysis and chain mediation model examined PPARs and L-FABP mediation in the PFAS-GDM association. A total of 1680 pregnant women were enrolled, of whom, 255 participants were included in the final analysis. LASSO identified seven PFASs linked to GDM risk and glucose levels. PFOA primarily drove GDM risk and elevated 2-h glucose, while PFBS predominantly influenced FPG and 1-h glucose. Mediation analysis revealed two distinct pathways: (1) a chain-mediated pathway involving FOSA-I-PPARα-L-FABP-GDM, and (2) a significant mediating effect of PPARγ in the association between HFPO-DA exposure and GDM development. Exposure to PFAS mixtures was associated with an increased risk of GDM and dysregulated glucose metabolism. Our findings highlight the mechanistic role of PPARγ in HFPO-DA-induced GDM pathogenesis, while FOSA-I appears contribute to GDM risk through sequential modulation of PPARα and L-FABP.