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

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.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Tryndyak V,Borowa-Mazgaj B,Beland FA,Pogribny IP

doi

10.1007/s00204-019-02569-5

subject

Has Abstract

pub_date

2019-11-01 00:00:00

pages

3335-3344

issue

11

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-019-02569-5

journal_volume

93

pub_type

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