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Gene expression and epigenetic alterations in 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 for the development of 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) and with the non-genotoxic liver carcinogen methapyrilene at non-cytotoxic concentrations for 7 days, and transcriptomic profile was examined. 1569 (892 protein-coding and 677 non-coding), 1693 (922 protein-coding and 771 non-coding), and 2061 (1462 protein-coding and 599 non-coding) differentially expressed genes were detected in cells treated with AFB1, B[a]P, and methapyrilene, respectively. Additionally, we examined the toxicogenomics response to AFB1, B[a]P, and methapyrilene exposure in human HepaRG cells and demonstrated that carcinogens had a less prominent effect on the cellular transcriptome as compared to that in human iPSC-derived hepatocytes. Overall, the results demonstrate that the prime non-genotoxic effect of exposure to carcinogens, regardless of their mode of action, in short-term in vitro testing is a profound global transcriptome response, indicating a greater value of toxicogenomics for rapid carcinogen screening in vitro.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127791 | GEO | 2019/03/05

REPOSITORIES: GEO

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Project description:For assessing the cancer-causing potential for humans of a chemical compound, the conventional approach is the use of the 2-year rodent carcinogenicity bioassay, thus alternatives such as in vitro toxicogenomics are highly desired. In the present study, the transcriptomics responses following exposure to genotoxic (GTX) and non-genotoxic (NGTX) hepatocarcinogens and non-carcinogens (NC) in five liver-based in vitro models, namely conventional and epigenetically-stabilized cultures of primary rat hepatocytes, the human hepatoma-derived HepaRG and HepG2 cell lines and the human embryonic stem cell-derived hepatocyte-like cells hES-Heps are examined and compared. The global gene expression profiles of five commonly used liver-based in vitro systems are investigated, namely conventional cultures of primary rat hepatocytes (HepsC), Trichostatin A (TSA)-stabilized cultures of primary rat hepatocytes (HepsT), human embryonic stem cell-derived hepatocyte-like cells (hES-Hep), HepG2 and HepaRG cells. These models are exposed to 15 prototypical compounds which have been carefully chosen and belong to 3 toxic classes i.e. (i) genotoxic (GTX) (aflatoxin B1, AFB1; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK; 2-nitrofluorene, 2NF; benzo(a)pyrene, BaP; cyclophosphamide, CYCLO), (ii) non-genotoxic (NGTX) (methapyrilene hydrochloride, MPH; piperonylbutoxide , PIPB; Wy-14643, WYE; phenobarbital sodium, SPB; 12-O-tetradecanoylphorbol-13-acetate, TPA) carcinogens and (iii) non-carcinogens (NC) (nifedipine, NIF; clonidine, CND; D-mannitol, MAN; tolbutamide, TOL; diclofenac sodium, SDF). For the gene- and pathway- based analysis, the raw microarray data was re-annotated to Ensembl version 61 genome and Gene Chip Robust Multi-array Average (GC-RMA) normalized (Dai et al. 2005). This resulted in 11,187 and 18,919 probe sets for the rat and the human models, respectively. For the classification analysis, the raw microarray data was annotated using the chip description files from Affymetrix and then GC-RMA normalized. In order to eliminate batch effects, data from the different studies were half-z normalized. Half-z-normalization adjusts the logarithmic expression values of transcripts within a group such that each transcript has zero mean.

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Gene expression and epigenetic alterations in human hepatocytes treated with low doses of chemical carcinogens

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