Podechard Normand, Chevanne Martine, Fernier Morgane, Tête Arnaud, Collin Aurore, Cassio Doris, Kah Olivier, Lagadic-Gossmann Dominique, Sergent Odile
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.
J Appl Toxicol. 2017 Jun;37(6):732-746. doi: 10.1002/jat.3421. Epub 2016 Nov 28.
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.
易于使用的体内模型斑马鱼幼虫正越来越多地用于筛选化学诱导的肝毒性，对各种肝损伤机制具有良好的预测性。然而，对于其在探索称为膜重塑（表现为膜流动性或脂筏特性变化）的机制方面的适用性却一无所知。因此，本研究的目的是证实斑马鱼幼虫在这种情况下是一种合适的体内模型。选择乙醇作为原型毒物，因为在肝细胞培养物和啮齿动物中，乙醇在很大程度上被描述为能够诱导膜重塑，导致肝细胞死亡和肝损伤。斑马鱼幼虫模型被证明是完全相关的，因为即使在暴露1周后，膜重塑仍得以维持，且没有像在啮齿动物和肝细胞培养物中通常报道的那样出现任何适应性变化。还证明它具有高敏感性，因为它能根据膜重塑变化的程度区分不同水平的细胞毒性。在这种情况下，它的敏感性似乎高于适合分析这种肝毒性的WIF-B9肝细胞。最后，膜稳定剂熊去氧胆酸（UDCA）或脂筏破坏剂普伐他汀提供的保护，明确证实斑马鱼幼虫是一种可靠的模型，可快速评估膜重塑在化学诱导的肝毒性中的作用。总之，这个与高通量筛选兼容的模型，可能适用于通过膜重塑寻找肝毒性物质，以及靶向膜特征的药物，从而为化学诱导的肝病提出新的预防或治疗策略。版权所有© 2016约翰威立父子有限公司。
