Large-scale assessment of the zebrafish embryo as a possible predictive model in toxicity testing.
Large-scale assessment of the zebrafish embryo as a possible predictive model in toxicity testing.
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DOI：
10.1371/journal.pone.0021076
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Richardson MK
中科院分区：
文献类型：
--
作者：
Ali S;van Mil HG;Richardson MK
在药物发现的管道中，安全药理学是一个主要问题。斑马鱼被提议作为一种模型，可以弥合细胞分析(成本效益高，但数据含量低)和啮齿动物分析(数据含量高，但成本效益较低)之间的差距。然而，斑马鱼的化验只有在被证明具有很高的预测能力的情况下才可能有用。我们通过分析代表一系列化学类别和毒理学机制的60种水溶性化合物来研究这个问题。超过20,000个野生斑马鱼胚胎(包括对照)被单独培养在96孔板中的特定缓冲液中。从受精后24小时开始，对胚胎进行96小时的暴露。使用对数浓度序列进行测距，然后使用较窄的几何序列来确定LC_(50)。斑马鱼胚胎LC_(50)与已发表的啮齿动物LD_(50)数据(对数mmol/kg)之间存在很强的相关性(使用Kendall的等级相关和Pearson的积矩相关)。全套化合物的回归直线斜率为0.73403。然而，我们发现坡度受复合级的影响很大。因此，虽然大多数化合物在这两个物种中的毒性水平相似，但有些化合物对斑马鱼的毒性明显高于对啮齿动物的毒性，反之亦然。对于这里研究的物质，总的来说，斑马鱼胚胎模型对啮齿动物的毒性有很好的预测性。然而，斑马鱼和啮齿动物毒性之间的相关性在单个化合物和化合物类别之间存在很大差异。根据这些发现，我们讨论了斑马鱼模型的优点和局限性。
In the drug discovery pipeline, safety pharmacology is a major issue. The zebrafish has been proposed as a model that can bridge the gap in this field between cell assays (which are cost-effective, but low in data content) and rodent assays (which are high in data content, but less cost-efficient). However, zebrafish assays are only likely to be useful if they can be shown to have high predictive power. We examined this issue by assaying 60 water-soluble compounds representing a range of chemical classes and toxicological mechanisms. Over 20,000 wild-type zebrafish embryos (including controls) were cultured individually in defined buffer in 96-well plates. Embryos were exposed for a 96 hour period starting at 24 hours post fertilization. A logarithmic concentration series was used for range-finding, followed by a narrower geometric series for LC50 determination. Zebrafish embryo LC50 (log mmol/L), and published data on rodent LD50 (log mmol/kg), were found to be strongly correlated (using Kendall's rank correlation tau and Pearson's product-moment correlation). The slope of the regression line for the full set of compounds was 0.73403. However, we found that the slope was strongly influenced by compound class. Thus, while most compounds had a similar toxicity level in both species, some compounds were markedly more toxic in zebrafish than in rodents, or vice versa. For the substances examined here, in aggregate, the zebrafish embryo model has good predictivity for toxicity in rodents. However, the correlation between zebrafish and rodent toxicity varies considerably between individual compounds and compound class. We discuss the strengths and limitations of the zebrafish model in light of these findings.
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