title: Zebrafish larva as a reliable model for in vivo assessment of membrane remodeling involvement in the hepatotoxicity of chemical agents.
abstract: The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: UMR Inserm 1085, IRSET, UFR des Sciences Pharmaceutiques et Biologiques, bâtiment 5, 35043, Rennes Cédex, France.|Biosit UMS3480, Université de Rennes 1, 35043, Rennes Cédex, France.
authors.forename: Normand
authors.identifier: 0000-0002-2638-3180
authors.initials: N
authors.lastname: Podechard
authors.affiliation: UMR Inserm 1085, IRSET, UFR des Sciences Pharmaceutiques et Biologiques, bâtiment 5, 35043, Rennes Cédex, France.|Biosit UMS3480, Université de Rennes 1, 35043, Rennes Cédex, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Chevanne
authors.affiliation: UMR Inserm 1085, IRSET, UFR des Sciences Pharmaceutiques et Biologiques, bâtiment 5, 35043, Rennes Cédex, France.|Biosit UMS3480, Université de Rennes 1, 35043, Rennes Cédex, France.
authors.forename: Morgane
authors.initials: M
authors.lastname: Fernier
authors.affiliation: UMR Inserm 1085, IRSET, UFR des Sciences Pharmaceutiques et Biologiques, bâtiment 5, 35043, Rennes Cédex, France.|Biosit UMS3480, Université de Rennes 1, 35043, Rennes Cédex, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Tête
authors.affiliation: UMR Inserm 1085, IRSET, UFR des Sciences Pharmaceutiques et Biologiques, bâtiment 5, 35043, Rennes Cédex, France.|Biosit UMS3480, Université de Rennes 1, 35043, Rennes Cédex, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Collin
authors.affiliation: Inserm, UMR-S 757; Orsay, France; Université Paris-Sud, Orsay, France.
authors.forename: Doris
authors.initials: D
authors.lastname: Cassio
authors.affiliation: Biosit UMS3480, Université de Rennes 1, 35043, Rennes Cédex, France.|UMR Inserm 1085, IRSET, Université de Rennes 1, bâtiment 9, 35000, Rennes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Kah
authors.affiliation: UMR Inserm 1085, IRSET, UFR des Sciences Pharmaceutiques et Biologiques, bâtiment 5, 35043, Rennes Cédex, France.|Biosit UMS3480, Université de Rennes 1, 35043, Rennes Cédex, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagadic-Gossmann
authors.affiliation: UMR Inserm 1085, IRSET, UFR des Sciences Pharmaceutiques et Biologiques, bâtiment 5, 35043, Rennes Cédex, France.|Biosit UMS3480, Université de Rennes 1, 35043, Rennes Cédex, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Sergent
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D000431:Ethanol / Q000633:toxicity; D006801:Humans; D006822:Hybrid Cells; D007814:Larva / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008560:Membrane Fluidity / Q000187:drug effects*; D021962:Membrane Microdomains / Q000187:drug effects* / Q000473:pathology; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology; D051381:Rats; D014580:Ursodeoxycholic Acid / Q000494:pharmacology; D015027:Zebrafish
chemical_list: D000431:Ethanol; D014580:Ursodeoxycholic Acid; D017035:Pravastatin
keywords: chemical agents; hepatotoxicity; in vivo model; membrane remodeling; zebrafish larva