| Overview of an Interlaboratory Collaboration on Evaluating the Effects of Model Hepatotoxicants on Hepatic Gene Expression Roger G. Ulrich,1 John C. Rockett,2 G. Gordon Gibson,3 and
Syril D. Pettit4 1 Rosetta Inpharmatics, Merck Research Laboratories, Kirkland, Washington,
USA; 2 Reproductive Toxicology Division, National Health and Environmental
Effects Research Laboratory, Office of Research and Development, U.S. Environmental
Protection Agency, Research Triangle Park, North Carolina, USA; 3 Molecular
Toxicology Group, School of Biomedical and Molecular Sciences, University of
Surrey, Guildford, Surrey, United Kingdom; 4ILSI Health and Environmental
Sciences Institute, Washington, DC, USA Abstract
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. In vivo 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. Key words: clofibrate, gene expression profiling, liver, methapyrilene, microarray, qRT-PCR, rat, toxicogenomics. Environ Health Perspect 112:423-427 (2004) . doi:10.1289/txg.6675 available via http://dx.doi.org/ [Online 15 January 2004]
This article is part of the mini-monograph "Application of Genomics to Mechanism-Based Risk Assessment." Address correspondence to S. Pettit, ILSI HESI, One Thomas Circle, 9th Floor NW, Washington, DC 20005 USA. Telephone: 202-659-3306. Fax: 202-659-3617. E-mail: spettit@ilsi.org The information in this document has been funded in part by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. We thank members of the HESI Technical Committee on Application of Genomics to Risk Assessment for critically reviewing this manuscript prior to submission. The authors declare they have no competing financial interests. Received 14 August 2003 ; accepted 8 January 2004.
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