Gene expression markers in the zebrafish embryo reflect a hepatotoxic response in animal models and humans

被引：28

作者：

Driessen, Marja ^{[1
,2
]}

Kienhuis, Anne S. ^{[1
]}

Vitins, Alexa P. ^{[1
,3
]}

Pennings, Jeroen L. A. ^{[1
]}

Pronk, Tessa E. ^{[1
,3
]}

van den Brandhof, Evert-Jan ^{[4
]}

Roodbergen, Marianne ^{[1
,2
]}

van de Water, Bob ^{[2
]}

van der Ven, Leo T. M. ^{[1
]}

机构：

[1] Natl Inst Publ Hlth & Environm RIVM, Ctr Hlth Protect, NL-3720 BA Bilthoven, Netherlands

[2] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Toxicol, NL-2333 CC Leiden, Netherlands

[3] Maastricht Univ, Dept Toxicogen, NL-6200 MD Maastricht, Netherlands

[4] Natl Inst Publ Hlth & Environm RIVM, Ctr Environm Qual, NL-3720 BA Bilthoven, Netherlands

来源：

TOXICOLOGY LETTERS | 2014年 / 230卷 / 01期

关键词：

OXIDATIVE STRESS; LIVER TOXICITY; OXIDANT STRESS; MECHANISMS; METABOLISM; IDENTIFICATION; DYSFUNCTION; DRUGS;

D O I：

10.1016/j.toxlet.2014.06.844

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 ;

摘要：

The zebrafish embryo (ZFE) is a promising non-rodent model in toxicology, and initial studies suggested its applicability in detecting hepatotoxic responses. Here, we hypothesize that the detailed analysis of underlying mechanisms of hepatotoxicity in ZFE contributes to the improved identification of hepatotoxic properties of new compounds and to the reduction of rodents used for screening. ZFEs were exposed to nine reference hepatotoxicants, targeted at induction of cholestasis, steatosis and necrosis, and two non-hepatotoxic controls. Histopathology revealed various specific morphological changes in the ZFE hepatocytes indicative of cell injury. Gene expression profiles of the individual compounds were generated using microarrays. Regulation of single genes and of pathways could be linked to hepatotoxic responses in general, but phenotype-specific responses could not be distinguished. Hepatotoxicity-associated pathways included xenobiotic metabolism and oxidoreduction related pathways. Overall analysis of gene expression identified a limited set of potential biomarkers specific for a common hepatotoxicity response. This set included several cytochrome P450 genes (cyp2k19, cyp4v7, cyp2aa3), genes related to liver development (pklr) and genes important in oxidoreduction processes (zgc:163022, zgc:158614, zgc:101858 and sqrdl). In conclusion, the ZFE model allows for identification of hepatotoxicants, without discrimination into specific phenotypes. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

引用

页码：48 / 56

页数：9

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