Gestational diabetes mellitus (GDM) is a prevalent metabolic disease during pregnancy which has long-term effects on maternal and child health. Although per- and polyfluoroalkyl substances (PFAS) are related to metabolic diseases, the role of the newly emerged short-chain PFAS in GDM remains unclear. Here, we integrated a population-based investigation, systems toxicology, molecular simulations, and experimental validation to clarify the relationship between certain PFAS and the pathogenesis of GDM. Plasma concentrations of 27 PFAS were measured in 200 pregnant women (99 controls and 101 GDM cases). Perfluoropentanoic acid (PFPeA) and perfluorotridecanoic acid (PFTrDA) were significantly elevated in GDM. PFPeA showed a positive correlation with post-load glucose levels and the total glycemic burden, while PFTrDA was mainly associated with 2-hour glucose levels. Network analyses identified lipid metabolic and nuclear receptor signaling pathways, including PPAR, AMPK, FoxO, and PI3K-Akt pathways, as key regulatory mechanisms. Estrogen receptor 1 (ESR1) and sirtuin 1 (SIRT1) were identified as critical regulatory hubs linking PFAS exposure to metabolic dysfunction. Molecular docking and simulations demonstrated stable interactions between PFAS and these targets. Consistently, gestational PFPeA exposure in mice induced maternal hepatic injury and transcriptomic alterations in metabolic signaling pathways, supporting the computational predictions. Collectively, our findings provide multi-level evidence that environmentally relevant PFAS congeners, particularly short-chain PFPeA, are associated with disrupted hepatic metabolic regulatory networks during pregnancy, suggesting a potential role in GDM pathogenesis. These results advance mechanistic understanding of PFAS-associated gestational metabolic toxicity and underscore the need to reconsider the safety of short-chain PFAS in vulnerable populations.
Liu et al. (2026) studied this question.