title: Transcriptomic responses generated by hepatocarcinogens in a battery of liver-based in vitro models.
abstract: As the conventional approach to assess the potential of a chemical to cause cancer in humans still includes the 2-year rodent carcinogenicity bioassay, development of alternative methodologies is needed. 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 cell lines HepaRG and HepG2 and human embryonic stem cell-derived hepatocyte-like cells, are examined. For full characterization of the systems, several bioinformatics approaches are employed including gene-based, ConsensusPathDB-based and classification analysis. They provide convincingly similar outcomes, namely that upon exposure to carcinogens, the HepaRG generates a gene classifier (a gene classifier is defined as a selected set of characteristic gene signatures capable of distinguishing GTX, NGTX carcinogens and NC) able to discriminate the GTX carcinogens from the NGTX carcinogens and NC. The other in vitro models also yield cancer-relevant characteristic gene groups for the GTX exposure, but some genes are also deregulated by the NGTX carcinogens and NC. Irrespective of the tested in vitro model, the most uniformly expressed pathways following GTX exposure are the p53 and those that are subsequently induced. The NGTX carcinogens triggered no characteristic cancer-relevant gene profiles in all liver-based in vitro systems. In conclusion, liver-based in vitro models coupled with transcriptomics techniques, especially in the case when the HepaRG cell line is used, represent valuable tools for obtaining insight into the mechanism of action and identification of GTX carcinogens.
authors: Department of Toxicology, Center for Pharmaceutical Research, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium.
authors: Tatyana Y
authors: TY
authors: Doktorova
authors: Reha
authors: R
authors: Yildirimman
authors: Mathieu
authors: M
authors: Vinken
authors: Mireia
authors: M
authors: Vilardell
authors: Tamara
authors: T
authors: Vanhaecke
authors: Hans
authors: H
authors: Gmuender
authors: Roque
authors: R
authors: Bort
authors: Gabriella
authors: G
authors: Brolen
authors: Gustav
authors: G
authors: Holmgren
authors: Ruoya
authors: R
authors: Li
authors: Christophe
authors: C
authors: Chesne
authors: Joost
authors: J
authors: van Delft
authors: Jos
authors: J
authors: Kleinjans
authors: Jose
authors: J
authors: Castell
authors: Petter
authors: P
authors: Bjorquist
authors: Ralf
authors: R
authors: Herwig
authors: Vera
authors: V
authors: Rogiers
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity*; D045744:Cell Line, Tumor; D053595:Embryonic Stem Cells / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008113:Liver Neoplasms; D009153:Mutagens / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
chemical_list: D002273:Carcinogens; D009153:Mutagens; D016159:Tumor Suppressor Protein p53