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TBBPA, TBBPS and TCBPA disrupt hESCs hepatic differentiation and promote the proliferation of differentiated cells seemingly via up-regulating the FGF10 signaling pathway

ABSTRACT: Halogenated flame retardants (HFRs) Tetrabromobisphenol A (TBBPA), Tetrabromobisphenol S (TBBPS) and Tetrachlorobisphenol (TCBPA) are wildly applied in manufacturing industry to improve the fire safety of the products. Recent reports demonstrated that TBBPA, TBBPS and TCBPA can be detected in pregnant women serum at nanomolar-level. Considering TBBPA have also been detected in the cord serum and the structural similarity of the 3 HFRs, it is necessary to pay attention to their development toxicity. Liver is the important detoxic organ but also target of TBBPA since it has been demonstrated that TBBPA exposure lead to increased liver weight in mouse and rat. So the developmental hepatic toxicity of the 3 HFRs were studied in this current research with the transcriptomic and human embryonic stem cells hepatic differentiation based toxicity evaluation system. A hepatic differentiation specific lineage development map and cell lineage - gene expression annotations were made and used for easily assessing the lineage alternations caused by toxicant treatment. Together with GO and KEGG analysis, this study mainly demonstrated that, the 3 HFRs have many common disruptive effect on hepatic differentiation, while only TCBPA significantly inhibited hepatic differentiation. The up-regulation of genes related to cell cycle and FGF10 signaling pathway at relatively late stage of hepatic differentiation indicates the proliferation of hepatoblasts were promoted by the 3 HFRs, likely via up-regulating the FGF10 signaling pathway. The proliferating promoting effect may partly explain why liver gain weight in rodents exposed to TBBPA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148518 | GEO | 2023/04/03

REPOSITORIES: GEO

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Project description:3,3’,5.5’-Tetrabromobisphenol A (TBBPA) is a widely used brominated flame-retardant utilized in the production of electronic devices and plastic paints. The objective of this study is to use zebrafish as a model and determine the effects of TBBPA exposure on early embryogenesis. We initiated TBBPA exposures (0, 10, 20 and 40μM) at 0.75 h post fertilization (hpf) and monitored early developmental events such as cleavage, blastula and epiboly that encompass maternal-to-zygotic transition (MZT) and zygotic genome activation (ZGA). Our data revealed that TBBPA exposures induced onset of developmental delays by 3 hpf (blastula). By 5.5 hpf (epiboly), TBBPA-exposed (10-20 μM) embryos showed concentration-dependent developmental lag by up to 3 stages or 100% mortality at 40 μM. Interestingly, while continued 0.75- 48 hpf TBBPA exposures (10 μM) led to severely deformed embryos, replacing exposure solution with chemical-free media at 6 hpf mitigated this effect, with 100% normal embryos at 48 hpf. To examine the genetic basis of TBBPA-induced delays, we conducted mRNA-sequencing on embryos exposed to 0 or 40 μM TBBPA from 0.75 hpf to 2, 3.5 or 4.5 hpf. Read count data showed that while TBBPA exposures had no overall impacts on maternal or maternal-zygotic genes, collective read counts for zygotically activated genes were lower in TBBPA treatment at 4.5 hpf compared to time-matched controls, suggesting that TBBPA delays ZGA. Gene ontology assessments for both time- and stage-matched differentially expressed genes revealed TBBPA-induced inhibition of chromatin assembly- a process regulated by histone modifications. Since acetylation is the primary histone modification system operant during early ZGA, we hypothesized that TBBPA inhibits histone acetylation, resulting in lack of open chromatin within promoters of zygotic genes and delaying ZGA. Therefore, we co-exposed embryos to 20 μM TBBPA and 100 μM N-(4-Chloro-3-(trifluoromethyl)phenyl)-2-ethoxybenzamide (CTB) -a histone acetyltransferase activator that promotes histone acetylation- and showed that TBBPA-CTB co-exposures from 0.75- 3 hpf significantly reversed TBBPA-only developmental delays, suggesting that TBBPA-induced phenotypes are indeed driven by repression of histone acetylation. Collectively, our work demonstrates that TBBPA disrupts ZGA and early developmental morphology, potentially by inhibiting histone acetylation. Future studies will focus on mechanisms of TBBPA-induced chromatin modifications.