PFAS Exposure Perturbs Lipid Metabolism to Promote Gestational Diabetes Mellitus and Alter Growth Trajectories via Distinct Mechanisms in Singletons and Twins

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that cross the placenta, posing a potential threat to maternal and fetal health. However, epidemiological evidence linking PFAS exposure to gestational diabetes mellitus (GDM) remains limited, almost exclusively to singleton pregnancies, with mechanistic understanding notably lacking. In this nested case-control study, we integrated exposomic and metabolomic analyses of serum from 462 singleton and 84 twin pregnancies, quantifying 48 PFAS alongside lipid metabolites. PFAS exposure was positively associated with GDM risk, with distinct congener profiles observed between singletons and twins. In mixture analyses, the association was stronger in twins, and PFOA and PFNA emerged as the primary risk contributors for singletons and twins, respectively. Mechanistically, PFAS perturbed lipid metabolism and increased GDM risk through pregnancy-type-specific pathways. In singletons, lipid mediators were linked to branched-chain amino acid and eicosanoid metabolism pathways, whereas in twins, bile acid metabolism emerged as a potentially predominant pathway. Maternal diet significantly shaped this environmental risk, revealing a key exposure-lifestyle interaction. Importantly, maternal PFAS exposure and GDM status together influenced offspring growth trajectories up to age 4, indicating potential long-term developmental consequences. We provide the first evidence that PFAS exposure induces pregnancy-type-specific metabolic disruptions, establishing a novel mechanistic link to GDM and highlighting its public health implications.