Waring Jeffrey F, Ulrich Roger G, Flint Nick, Morfitt David, Kalkuhl Arno, Staedtler Frank, Lawton Michael, Beekman Johanna M, Suter Laura
Abbott Laboratories, 100 Abbott Park Road, Department R463, Abbott Park, IL 60064-6123, USA.
Environ Health Perspect. 2004 Mar;112(4):439-48. doi: 10.1289/ehp.6643.
Several studies using microarrays have shown that changes in gene expression provide information about the mechanism of toxicity induced by xenobiotic agents. Nevertheless, the issue of whether gene expression profiles are reproducible across different laboratories remains to be determined. To address this question, several members of the Hepatotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute evaluated the liver gene expression profiles of rats treated with methapyrilene (MP). Animals were treated at one facility, and RNA was distributed to five different sites for gene expression analysis. A preliminary evaluation of the number of modulated genes uncovered striking differences between the five different sites. However, additional data analysis demonstrated that these differences had an effect on the absolute gene expression results but not on the outcome of the study. For all users, unsupervised algorithms showed that gene expression allows the distinction of the high dose of MP from controls and low dose. In addition, the use of a supervised analysis method (support vector machines) made it possible to correctly classify samples. In conclusion, the results show that, despite some variability, robust gene expression changes were consistent between sites. In addition, key expression changes related to the mechanism of MP-induced hepatotoxicity were identified. These results provide critical information regarding the consistency of microarray results across different laboratories and shed light on the strengths and limitations of expression profiling in drug safety analysis.
多项使用微阵列的研究表明，基因表达的变化为外源性物质诱导的毒性机制提供了信息。然而，基因表达谱在不同实验室之间是否可重复的问题仍有待确定。为解决这个问题，国际生命科学研究所健康与环境科学研究所肝毒性工作组的几名成员评估了用美吡拉敏（MP）处理的大鼠的肝脏基因表达谱。动物在一个机构接受处理，RNA被分发到五个不同地点进行基因表达分析。对调节基因数量的初步评估发现五个不同地点之间存在显著差异。然而，进一步的数据分析表明，这些差异对绝对基因表达结果有影响，但对研究结果没有影响。对于所有用户来说，无监督算法表明基因表达能够区分高剂量MP与对照组和低剂量组。此外，使用监督分析方法（支持向量机）使得能够正确地对样本进行分类。总之，结果表明，尽管存在一些变异性，但不同地点之间强大的基因表达变化是一致的。此外，还确定了与MP诱导的肝毒性机制相关的关键表达变化。这些结果提供了关于不同实验室微阵列结果一致性的关键信息，并揭示了药物安全性分析中表达谱分析的优势和局限性。
