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Archives of Toxicology

, Volume 93, Issue 11, pp 3335–3344 | Cite as

Gene expression and cytosine DNA methylation alterations in induced pluripotent stem-cell-derived human hepatocytes treated with low doses of chemical carcinogens

  • Volodymyr Tryndyak
  • Barbara Borowa-Mazgaj
  • Frederick A. Beland
  • Igor P. PogribnyEmail author
Genotoxicity and Carcinogenicity

Abstract

The increasing number of man-made chemicals in the environment that may pose a carcinogenic risk emphasizes the need to develop reliable time- and cost-effective approaches for carcinogen detection. To address this issue, we have investigated the utility of human hepatocytes for the in vitro identification of genotoxic and non-genotoxic carcinogens. Induced pluripotent stem-cell (iPSC)-derived human hepatocytes were treated with the genotoxic carcinogens aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P), the non-genotoxic liver carcinogen methapyrilene, and the non-carcinogens aflatoxin B2 (AFB2) and benzo[e]pyrene (B[e]P) at non-cytotoxic concentrations for 7 days, and transcriptomic and DNA methylation profiles were examined. 1569, 1693, and 2061 differentially expressed genes (DEGs) were detected in cells treated with AFB1, B[a]P, and methapyrilene, respectively, whereas no DEGs were found in cells treated with AFB2 or B[e]P. In contrast to the profound cellular transcriptomic responses, exposure of iPSC-derived hepatocytes to the test chemicals resulted in minor random alterations in global DNA methylome, most of which were not associated with changes in gene expression. Overall, our results demonstrate that the major non-genotoxic effect of exposure to carcinogens, regardless of their mode of action, is a profound global transcriptomic response rather than global DNA methylome alterations, indicating the significance of transcriptomic alterations as an informative endpoint in short-term in vitro carcinogen testing.

Keywords

Chemical carcinogens In vitro iPSC-derived human hepatocytes Gene expression DNA methylation 

Notes

Acknowledgements

This work was partly supported by appointment (BBM) to the Postgraduate Research Program at the NCTR administered by the Oak Ridge Institute for Science and Education (ORISE).

Compliance with ethical standards

Conflict of interest

The authors have declared no potential conflict of interest.

Supplementary material

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Supplementary material 3 (DOCX 15 kb)
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Supplementary material 4 (TIFF 471 kb)

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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2019

Authors and Affiliations

  1. 1.Division of Biochemical ToxicologyFDA-National Center for Toxicological ResearchJeffersonUSA

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