Associations of bisphenol mixture exposure with glucose metabolism during mid-pregnancy: A focus on emerging substitutes in a Chinese birth cohort

With the widespread use of bisphenol A (BPA) substitutes such as BPS and BPF, pregnant women are commonly exposed to complex mixtures of these endocrine-disrupting chemicals. However, epidemiological evidence on the combined effects of bisphenol mixtures on gestational glucose metabolism remains limited. This study included 1,258 pregnant women from the Wuhu Birth Cohort in China. Serum concentrations of BPA, BPS, BPF, and BPAF were measured using UHPLC-MS/MS. Glucose metabolism was assessed by 75-g OGTT measuring fasting, 1-hour, and 2-hour plasma glucose. We employed multivariable linear regression for single-chemical analysis and three advanced mixture models—Weighted Quantile Sum (WQS) regression, Quantile-based g-computation (Qgcomp), and Bayesian Kernel Machine Regression (BKMR)—to evaluate the joint effects. All four bisphenols were frequently detected, with BPS showing 100% detection rate. Single-chemical models revealed that BPS and BPF were significantly associated with elevated glucose levels at all time points (e.g., for BPS: β=0.371, 95% CI: 0.218-0.524 for 1-hour glucose). The mixture analysis consistently demonstrated significant joint effects: WQS showed a positive association between the mixture index and all glucose measures (e.g., β=0.129, 95% CI: 0.058-0.200 for 1-hour glucose); Qgcomp indicated that a simultaneous quartile increase in all bisphenols was associated with a 0.343 mmol/L rise in 1-hour glucose (95% CI: 0.179-0.507); BKMR revealed an approximately linear increase in glucose levels with mixture exposure. Across all mixture models, BPS consistently emerged as the primary contributor, with the highest weights in WQS (up to 0.542) and posterior inclusion probabilities approaching 1.0 in BKMR. Our study demonstrates that exposure to bisphenol mixtures significantly impairs mid-pregnancy glucose metabolism, with BPS and BPF serving as the predominant risk contributors. These findings underscore the necessity of mixture-based exposure assessment and support the inclusion of BPA substitutes in future public health regulations.