title: A transcriptomics-based hepatotoxicity comparison between the zebrafish embryo and established human and rodent in vitro and in vivo models using cyclosporine A, amiodarone and acetaminophen.
abstract: The zebrafish embryo (ZFE) is a promising alternative, non-rodent model in toxicology, which has an advantage over the traditionally used models as it contains complete biological complexity and provides a medium to high-throughput setting. Here, we assess how the ZFE compares to the traditionally used models for liver toxicity testing, i.e., in vivo mouse and rat liver, in vitro mouse and rat hepatocytes, and primary human hepatocytes. For this comparison, we analyzed gene expression changes induced by three model compounds for cholestasis, steatosis, and necrosis. The three compounds, cyclosporine A, amiodarone, and acetaminophen, were chosen because of their relevance to human toxicity and these compounds displayed hepatotoxic-specific changes in the mouse in vivo data. Compound induced expression changes in the ZFE model shared similarity with both in vivo and in vitro. Comparison on single gene level revealed the presence of model specific changes and no clear concordance across models. However, concordance was identified on the pathway level. Specifically, the pathway "regulation of metabolism - bile acids regulation of glucose and lipid metabolism via FXR" was affected across all models and compounds. In conclusion, our study with three hepatotoxic model compounds shows that the ZFE model is at least as comparable to traditional models in identifying hepatotoxic activity and has the potential for use as a pre-screen to determine the hepatotoxic potential of compounds.
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Division of Toxicology, Leiden/Amsterdam Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. Electronic address: marja.driessen@embl.de.
authors.forename: Marja
authors.initials: M
authors.lastname: Driessen
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Department of Toxicogenomics, Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Alexa P
authors.initials: AP
authors.lastname: Vitins
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: Jeroen L A
authors.initials: JL
authors.lastname: Pennings
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Kienhuis
authors.affiliation: Division of Toxicology, Leiden/Amsterdam Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Bob van de
authors.initials: Bv
authors.lastname: Water
authors.affiliation: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: Leo T M
authors.initials: LT
authors.lastname: van der Ven
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000638:Amiodarone / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D016572:Cyclosporine / Q000633:toxicity*; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D059467:Transcriptome / Q000187:drug effects*; D015027:Zebrafish / Q000502:physiology*
chemical_list: D018712:Analgesics, Non-Narcotic; D000889:Anti-Arrhythmia Agents; D007166:Immunosuppressive Agents; D000082:Acetaminophen; D016572:Cyclosporine; D000638:Amiodarone
keywords: Gene expression; Hepatotoxicity; Human in vitro; Mouse in vitro; Mouse in vivo; Rat in vitro; Rat in vivo; Zebrafish embryo