Ulrich Roger G, Rockett John C, Gibson G Gordon, Pettit Syril D
Rosetta Inpharmatics, Merck Research Laboratories, Kirkland, Washington, USA.
Environ Health Perspect. 2004 Mar;112(4):423-7. doi: 10.1289/ehp.6675.
DNA microarrays and related tools offer promise for identification of pathways involved in toxic responses to xenobiotics. To be useful for risk assessment, experimental data must be challenged for reliability and interlaboratory reproducibility. Toward this goal, the Hepatotoxicity Working Group of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Technical Committee on Application of Genomics to Mechanism-Based Risk Assessment evaluated and compared biological and gene expression responses in rats exposed to two model hepatotoxins--clofibrate and methapyrilene. This collaborative effort provided an unprecedented opportunity for the working group to evaluate and compare multiple biological, genomic, and toxicological parameters across different laboratories and microarray platforms. Many of the results from this collaboration are presented in accompanying articles in this mini-monograph, whereas others have been published previously. (Italic)In vivo(/Italic) studies for both compounds were conducted in two laboratories using a standard experimental protocol, and RNA samples were distributed to 16 laboratories for analysis on six microarray platforms. Histopathology, clinical chemistry, and organ weight changes were consistent with reported effects. Gene expression results demonstrated reasonable agreement between laboratories and across platforms. Discrepancies in expression profiles of some individual genes were largely due to platform differences and approaches to data analysis rather than to biological or interlaboratory variability. Despite these discrepancies there was overall agreement in the biological pathways affected by these compounds, demonstrating that transcriptional profiling is reproducible between laboratories and can reliably identify affected pathways necessary to provide mechanistic insight. This effort represents an important first step toward the use of transcriptional profiling in risk assessment.
DNA微阵列及相关工具为识别外源性物质毒性反应所涉及的途径带来了希望。要用于风险评估，实验数据必须接受可靠性和实验室间可重复性的检验。为实现这一目标，国际生命科学研究所（ILSI）健康与环境科学研究所（HESI）基于机制的风险评估基因组学应用技术委员会的肝毒性工作组评估并比较了暴露于两种模型肝毒素（氯贝丁酯和甲吡咯）的大鼠的生物学和基因表达反应。这项合作努力为工作组提供了前所未有的机会，以评估和比较不同实验室和微阵列平台上的多个生物学、基因组学和毒理学参数。本专题论文集中的相关文章介绍了此次合作的许多结果，而其他一些结果此前已发表。针对这两种化合物的（斜体）体内（/斜体）研究在两个实验室按照标准实验方案进行，RNA样本被分发给16个实验室，在六个微阵列平台上进行分析。组织病理学、临床化学和器官重量变化与报道的效应一致。基因表达结果表明实验室之间以及不同平台之间具有合理的一致性。一些个别基因表达谱的差异主要是由于平台差异和数据分析方法，而非生物学或实验室间的变异性。尽管存在这些差异，但在受这些化合物影响的生物学途径方面总体上是一致的，这表明转录谱分析在实验室之间具有可重复性，并且能够可靠地识别受影响的途径，从而提供机制性见解。这项工作是在风险评估中使用转录谱分析的重要第一步。
