Objective: To analyze the correlation between exposure to various Per- and polyfluoroalkyl substances (PFASs) and glucose metabolic indexes in relation to the risk of gestational diabetes mellitus (GDM), and to explore the mediating role of PPARs and L-FABP in this association. Methods: Using a nested case-control study method, study participants were recruited from a maternal and child healthcare hospital between January 2022 and June 2023. Blood samples were collected during early pregnancy, and a 75g oral glucose tolerance test (OGTT) was performed at 24-28 weeks of gestation. The concentration of serum PFASs was measured by SPE-UPLC-MS/MS, while PPARα, PPARγ, and L-FABP levels were determined using double-antibody sandwich ELISA. LASSO regression was used to select PFASs variables for the model, and the selected variables were subsequently included in weighted quantile sum (WQS) regression to analyze the relationship between mixed PFASs exposure and GDM. A four-way decomposition analysis was employed to assess the mediating and interaction effects of PPARs, and L-FABP in the relationship between PFASs exposure and GDM. Results: A total of 1680 pregnant women were enrolled, of whom, 255 participants (85 GDM cases and 170 controls) were included in the final analysis. Using LASSO regression, seven PFASs significantly associated with GDM risk and blood glucose levels were identified: PFOA, PFBA, PFBS, PFDA, PFTeDA, FOSA-I, and HFPO-DA. PFOA emerged as the primary driver of both GDM risk and elevated 2-hour postprandial blood glucose levels, while PFBS predominantly influenced fasting plasma glucose (FPG) and 1-hour postprandial glucose levels. 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. Conclusion: 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.

Per- and Polyfluoroalkyl Substances, Gestational Diabetes Mellitus, PPARs, L-FABP, Mediating Effect