Abstract

Halogenated bisphenol flame retardants, including tetrabromobisphenol A (TBBPA) and its analogues tetrabromobisphenol S (TBBPS) and tetrachlorobisphenol A (TCBPA), are prevalent in human cord blood; However, their impact on embryonic hepatic development remains poorly understood. Using a human embryonic stem cell (hESC)-based hepatic development model, we demonstrate that these contaminants at 10 nmol/L impair hepatic specification, as evidenced by attenuated ALB expression and protein secretion, while CYP3A4 expression exhibited marginal sensitivity. Stage-specific analysis identified the definitive endoderm-to-hepatoblast transition as the critical window of vulnerability. Multiomics integration revealed that exposure triggers aberrant cell-cycle progression, corroborated by shifted phase distribution and increased EdU incorporation. Notably, untargeted metabolomics identified guanosine monophosphate (GMP) as a candidate convergent metabolic signature (AUC ≥ 0.90) across all exposure groups. Elevated ROS and GMP fluctuations were associated with G-quadruplex-linked transcriptional alterations, and coordinated changes in proliferative and metabolic transcriptional modules. Our findings suggest that GMP is a candidate convergent metabolic signature associated with oxidative stress, metabolic perturbation, and developmental reprogramming during human liver specification.