Associations of Early Pregnancy Contaminant Exposure with Gestational Diabetes Mellitus and Mediation by Metabolic Pathway Perturbations.

Early pregnancy exposure to environmental contaminants is a known risk factor for gestational diabetes mellitus (GDM), yet the metabolic pathways linking specific chemical categories to disease pathogenesis remain largely unknown. To address this gap, we conducted a meet-in-the-middle mediation analysis within a prospective birth cohort, leveraging a nested case-control study (116 GDM cases, 232 controls) with 182 contaminants across 11 chemical categories and 702 metabolites measured in early pregnancy serum samples. Seven individual contaminants showed significant associations with GDM risk, with BHT-COOH exhibiting the strongest effect (OR = 2.34, 95% CI: 1.59-3.45). Weighted quantile sum (WQS) regression indicated a positive mixture association with GDM, with Bayesian kernel machine regression (BKMR) providing a complementary assessment of mixture effects. Notably, we identified 506 exposure-metabolite pairs with significant mediation and consistent directionality, providing a comprehensive profile of candidate metabolic intermediates in the associations between contaminant exposure and GDM. Pathway-level analysis identified six candidate metabolic pathways with significant mediation effects, among which the phenylalanine, tyrosine and tryptophan biosynthesis pathway showed the largest mediation estimate, accounting for 75.5% of the DEHP/DNOP-GDM association. Similar pathway-level mediation effects were observed for both individual contaminants and the mixture exposure index. Collectively, these findings identify potential metabolic intermediates linking early pregnancy contaminant exposure to GDM and provide hypotheses for further epidemiological and experimental validation.