Metabolomic signatures of prenatal per- and polyfluoroalkyl substance exposure and subtypes of gestational diabetes mellitus: A prospective cohort study

Gestational diabetes mellitus (GDM) is a heterogeneous pregnancy complication comprising insulin-resistant and insulin-deficient subtypes with distinct pathophysiology. Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been implicated in gestational glucose disturbances, yet congener-specific effects on subtypes of GDM and underlying metabolic mechanisms remain unknown. In the Shanghai Birth Cohort, 1789 women had plasma concentrations of 9 PFAS congeners and untargeted serum metabolomics measured in early pregnancy, and GDM subtypes were defined at 24-28 weeks’ gestation using a 75 g oral glucose tolerance test with indices of insulin sensitivity and secretion. Associations of individual and mixture PFAS exposures with GDM subtypes were evaluated using multivariable, weighted quantile sum, quantile-based g-computation, and Bayesian kernel machine regression models. Metabolome-wide and meet-in-the-middle analyses identified metabolites jointly related to key PFAS and GDM subtypes, followed by pathway enrichment and mediation analyses. Across modeling approaches, perfluorooctane sulfonate (PFOS) was associated with insulin-deficient GDM, whereas perfluoroheptanoic acid (PFHpA) was associated with insulin-resistant GDM. Metabolomic analyses revealed that metabolites shared by PFOS and insulin-deficient GDM enriched in fatty-acid metabolism and hormone signaling, and those shared by PFHpA and insulin-resistant GDM enriched in transmembrane transport and amino-acid metabolism. Mediation analyses further indicated divergent metabolic signatures, with polyunsaturated fatty acids and glycerophospholipids mediating the association between PFOS and insulin-deficient GDM, and medium- to long-chain acylcarnitines, bile acids, and glucogenic amino acids primarily mediating the association between PFHpA and insulin-resistant GDM. This prospective study provides the first evidence that specific PFAS congeners differentially influence GDM subtypes through distinct metabolic disruptions. • PFAS exposure, metabolites, and GDM subtypes were assessed in 1789 pregnant women. • PFOS associates with insulin-deficient GDM, while PFHpA with insulin-resistant GDM. • Fatty acids and glycerophospholipids link PFOS to insulin-deficient GDM. • Acylcarnitines, bile acids, and amino acids link PFHpA to insulin-resistant GDM. • Distinct metabolic mediators underlie PFAS-specific associations with GDM subtypes.