Maternal-fetal distribution of synthetic phenolic antioxidants and their associations with gestational diabetes mellitus: A cross-sectional analysis nested within the Chongqing PREBIC cohort.

Synthetic phenolic antioxidants (SPAs) and their transformation products (TPs) are widespread environmental contaminants with endocrine-disrupting potential, yet their distribution across the maternal-fetal interface and relevance to maternal metabolic health remain unclear. Leveraging 222 paired maternal and umbilical cord plasma samples (51 cases of gestational diabetes mellitus [GDM] and 171 normoglycemic controls) from the Chongqing Preconception Reproductive Health and Birth Outcome Cohort (PREBIC), we quantified eight SPAs (AO246, DTBSBP, DtAP, AO2246, 4-tOP, BHA, 2,4-DtBP, and BHT) and five BHT-derived TPs (BHT-OH, BHT-CHO, BHT-COOH, BHT-quinol, and BHT-Q) using UPLC-MS/MS and performed targeted metabolomic profiling of 446 maternal plasma metabolites. In maternal plasma, 2,4-DtBP and BHT were the predominant compounds, whereas BHT-derived TPs, particularly BHT-Q and BHT-quinol, predominated in umbilical cord plasma. The transplacental transfer efficiency of BHT-quinol was significantly lower in GDM pregnancies. Maternal plasma concentrations of BHT-quinol and total TPs were higher in women with GDM. Each one-unit increase in ln-transformed BHT-quinol and total TP concentrations was associated with higher odds of GDM (adjusted odds ratio [OR], 1.83; 95% CI: 1.34-2.59; adjusted OR, 1.49; 95% CI: 1.08-2.11, respectively). Bayesian kernel machine regression identified BHT-quinol as the dominant contributor to the observed positive mixture-GDM association. Integrative metabolomic analyses identified 88 overlapping lipid metabolites showing consistent inverse associations with both maternal BHT-quinol concentrations and GDM status, with enrichment in pathways related to AGE-RAGE signaling in diabetic complications, sphingolipid signaling, and insulin resistance. These findings characterize the maternal-fetal distribution of BHT and its TPs among pregnant women in Southwest China and identify associations of maternal BHT-derived TPs with GDM and related metabolic alterations. Prospective studies are warranted to clarify the potential causal relationships between SPA exposure and maternal metabolic health.