TBBPA, TBBPS, and TCBPA disrupt hESC hepatic differentiation and promote the proliferation of differentiated cells partly via up-regulation of the FGF10 signaling pathway

Abstract

Halogenated flame retardants (HFRs), including Tetrabromobisphenol A (TBBPA), Tetrabromobisphenol S (TBBPS), and Tetrachlorobisphenol A (TCBPA), are widely applied in the manufacturing industry to improve fire safety and can be detected in pregnant women’s serum at nanomolar levels. Thus, it is necessary to pay attention to the three HFR potential development toxicity, which has not been conclusively addressed yet. The liver is the main organ that detoxifies our body; TBBPA exposure may lead to increased liver weight in rodents. Therefore, in this study, we assessed the developmental hepatic toxicity of the three HFRs with a human embryonic stem cell hepatic differentiation-based system and transcriptomics analyses. We mostly evaluated lineage fate alterations and demonstrated the three HFRs may have common disruptive effects on hepatic differentiation, with TCBPA being significantly more potent. More specifically, the three HFRs up-regulated genes related to cell cycle and FGF10 signaling, at late stages of the hepatic differentiation. This indicates the three chemicals promoted hepatoblast proliferation likely via up-regulating the FGF10 cascade. At the same time, we also presented a powerful way to combine in vitro differentiation and in silico transcriptomic analyses, to efficiently evaluate hazardous materials’ adverse effects on lineage fate decisions during early development.