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Valerie A. Baker,¹ Helen M. Harries,¹ Jeff F. Waring,² Colette M. Duggan,¹ Hong A. Ni,³ Robert A. Jolly,² Lawrence W. Yoon,³ Angus T. De Souza,⁴ Judith E. Schmid,⁵ Roger H. Brown,³ Roger G. Ulrich,⁶ and John C. Rockett⁵

¹Safety and Environmental Assurance Centre, Unilever Research Colworth, Sharnbrook, Bedfordshire, United Kingdom; ²Abbott Laboratories, Abbott Park, Illinois, USA; ³GlaxoSmithKline, Research Triangle Park, North Carolina, USA; ⁴GlaxoSmithKline, Ware, Hertfordshire, United Kingdom; ⁵Reproductive 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; ⁶Rosetta Inpharmatics, Merck Research Laboratories, Kirkland, Washington, USA

Abstract
Microarrays have the potential to significantly impact our ability to identify toxic hazards by the identification of mechanistically relevant markers of toxicity. To be useful for risk assessment, however, microarray data must be challenged to determine reliability and interlaboratory reproducibility. As part of a series of studies conducted by the International Life Sciences Institute Health and Environmental Science Institute Technical Committee on the Application of Genomics to Mechanism-Based Risk Assessment, the biological response in rats to the hepatotoxin clofibrate was investigated. Animals were treated with high (250 mg/kg/day) or low (25 mg/kg/day) doses for 1, 3, or 7 days in two laboratories. Clinical chemistry parameters were measured, livers removed for histopathological assessment, and gene expression analysis was conducted using cDNA arrays. Expression changes in genes involved in fatty acid metabolism (e.g., acyl-CoA oxidase) , cell proliferation (e.g., topoisomerase II-) , and fatty acid oxidation (e.g., cytochrome P450 4A1) , consistent with the mechanism of clofibrate hepatotoxicity, were detected. Observed differences in gene expression levels correlated with the level of biological response induced in the two in vivo studies. Generally, there was a high level of concordance between the gene expression profiles generated from pooled and individual RNA samples. Quantitative real-time polymerase chain reaction was used to confirm modulations for a number of peroxisome proliferator marker genes. Though the results indicate some variability in the quantitative nature of the microarray data, this appears due largely to differences in experimental and data analysis procedures used within each laboratory. In summary, this study demonstrates the potential for gene expression profiling to identify toxic hazards by the identification of mechanistically relevant markers of toxicity. Key words: cDNA array, clofibrate, cross-laboratory studies, gene expression profiling, liver, membrane array, microarray, peroxisome proliferator, rat. Environ Health Perspect 112:428-438 (2004) . doi:10.1289/txg.6677 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 V.A. Baker, Sanofi-Synthélabo, Alnwick Research Centre, Willowburn Ave., Alnwick, Northumberland, NE66 2JH, UK. Telephone: 44 01665 608592. Fax: 44 01665 608503. E-mail: val.baker@sanofi-synthelabo.com

We thank G. Gibson (University of Surrey, England) and members of the HESI Technical Committee on Application of Genomics to Mechanism-Based Risk Assessment for critically reviewing this manuscript prior to submission.

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.

The authors declare they have no competing financial interests.

Received 15 August 2003 ; accepted 12 January 2004.

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