Genome-wide expression changes induced by bisphenol A, F and S in human stem cell derived hepatocyte-like cells

B Lucendo-Villarin, P Nell, B Hellwig, P Filis, D Feuerborn, P J O'Shaughnessy, P Godoy, J Rahnenführer, J G Hengstler, A Cherianidou, A Sachinidis, P A Fowler, D C Hay

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The debate about possible adverse effects of bisphenol A (BPA) has been ongoing for decades. Bisphenol F (BPF) and S (BPS) have been suggested as "safer" alternatives. In the present study we used hepatocyte-like cells (HLCs) derived from the human embryonic stem cell lines Man12 and H9 to compare the three bisphenol derivatives. Stem cell-derived progenitors were produced using an established system and were exposed to BPA, BPF and BPS for 8 days during their transition to HLCs. Subsequently, we examined cell viability, inhibition of cytochrome P450 (CYP) activity, and genome-wide RNA profiles. Sub-cytotoxic, inhibitory concentrations (IC50) of CYP3A were 20, 9.5 and 25 µM for BPA, BPF and BPS in Man12 derived HLCs, respectively. The corresponding concentrations for H9-derived HLCs were 19, 29 and 31 µM. These IC50 concentrations were used to study global expression changes in this in vitro study and are higher than unconjugated BPA in serum of the general population. A large overlap of up- as well as downregulated genes induced by the three bisphenol derivatives was seen. This is at least 28-fold higher compared to randomly expected gene expression changes. Moreover, highly significant correlations of expression changes induced by the three bisphenol derivatives were obtained in pairwise comparisons. Dysregulated genes were associated with reduced metabolic function, cellular differentiation, embryonic development, cell survival and apoptosis. In conclusion, no major differences in cytochrome inhibitory activities of BPA, BPF and BPS were observed and gene expression changes showed a high degree of similarity.

Original languageEnglish
Pages (from-to)1459-1476
Number of pages18
JournalEXCLI journal
Early online date4 Nov 2020
Publication statusPublished - Nov 2020

Bibliographical note

BLV and DCH were funded by an award from the Chief Scientist Office (TCS 16/37).
This work has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 681002 (EU-ToxRisk) and from TransQST (no. 116030).


  • bisphenol A
  • bisphenol F
  • bisphenol S
  • pluripotent stem cell
  • liver
  • hepatocyte-like cells


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