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OVERVIEW OF AN INTERLABORATORY COLLABORATION ON EVALUATING THE EFFECTS OF MODEL HEPATOTOXICANTS ON HEPATIC GENE EXPRESSION
Citation:
Ulrich, R. G., J C. Rockett, G. G. Gibson, AND S. Pettit. OVERVIEW OF AN INTERLABORATORY COLLABORATION ON EVALUATING THE EFFECTS OF MODEL HEPATOTOXICANTS ON HEPATIC GENE EXPRESSION. ENVIRONMENTAL HEALTH PERSPECTIVES 112(4):423-427, (2004).
Description:
Evaluating the Effects of Methapyrilene and Clofibrate on Hepatic Gene Expression: A Collaboration Between Laboratories and a Comparison of Platform and Analytical Approaches
Roger G. Ulrich1, John C. Rockett2, G. Gordon Gibson3 and Syril Pettit4
1 Rosetta Inpharmatics, Merck Research Laboratories, 12040 115th Ave NE, Kirkland, WA 98034, USA.2Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.3 Molecular Toxicology Group, School of BioMedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK.
4ILSI HESI, One Thomas Circle, 9th Floor, NW, Washington, DC 20005.
Abstract
DNA microarrays and related genomic 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 inter-laboratory reproducibility. Towards this goal, the hepatotoxicity working group of the ILSI-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, using a standard experimental protocol. This collaborative effort provided an unprecedented opportunity to evaluate and compare multiple biological, genomic and toxicological parameters across different laboratories and microarray platforms.
Male SD-rats were dosed with clofibrate (25 or 250 mg/kg/day) or methapyrilene (10 or 100 mg/kg/day) by gavage for 1, 3 or 7 days. In-life studies for both compounds were conducted in two laboratories. 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 and gene expression results demonstrated reasonable agreement between laboratories and across platforms. Expression of known specific marker genes for these compounds was observed. Discrepancies in changed expression of some individual genes were largely due to platform differences (in gene representation, annotation and specific sequence differences) and approach to data analysis, rather than biological or inter-laboratory variability. Despite discrepancies for some individual genes, there was overall agreement in the biological pathways affected by these compounds.
Thus, while improvements are needed in annotation and data analysis tools, the current collaborative effort has demonstrated that gene expression profiling of samples generated from different studies and in different laboratories, and analyzed using different microarray platforms, shows relatively consistent identification of affected biological pathways and, to a great extent, identical key individual genes.