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ToxSci Advance Access published online on June 11, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm150
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Multi-Center Study of Acetaminophen Hepatotoxicity Reveals the Importance of Biological Endpoints in Genomic Analyses

Richard P. Beyer§,*, Rebecca C. Fry&,*, Michael R. Lasarev$,*, Lisa A. McConnachie§,*, Lisiane B. Meira&,*, Valerie S. Palmer$,*, Christine L. Powell£,*, Pamela K. Ross£,*, Theo K. Bammler§, Blair U. Bradford£, Alex B. Cranson$, Michael L. Cunningham, Rickie D. Fannin, Gregory M. Higgins$, Patrick Hurban, Robert J. Kayton$, Kathleen F. Kerr§, Oksana Kosyk£, Edward K. Lobenhofer, Stella O. Sieber, Portia A. Vliet§, Brenda K. Weis, Russel Wolfinger#, Courtney G. Woods£, Jonathan H. Freedman{dagger},^, Elwood Linney{dagger},^, William K. Kaufmann£,^, Terrance J. Kavanagh§,^, Richard S. Paules,^, Ivan Rusyn£,^,%, Leona D. Samson&,^, Peter S. Spencer$,^, William Suk,^, Raymond J. Tennant,^, Helmut Zarbl{ddagger},^ and Members of the Toxicogenomics Research Consortium

National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 § University of Washington, Seattle, WA 98195 & Massachusetts Institute of Technology, Cambridge, MA 02139 $ Oregon Health & Science University, Portland, OR 97239 £ University of North Carolina, Chapel Hill, NC 27599 Cogenics, a Division of Clinical Data, Inc., Morrisville, NC 27560 # SAS Institute, Inc., Cary, NC 27513 {dagger} Duke University Medical Center, Durham, NC 27710 {ddagger} Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Corresponding Author: Ivan Rusyn, M.D., Ph.D., Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, NC 27599; Phone/Fax: 919-843-2596, Email: iir{at}unc.edu

Received April 19, 2007; revision received June 4, 2007; accepted June 5, 2007


  Abstract

Gene expression profiling is a widely-used technique with data from the majority of published microarray studies being publicly available. This data is being used for meta-analyses and in silico discovery; however, the comparability of toxicogenomic data generated in multiple laboratories has not been critically evaluated. Using the power of prospective multi-laboratory investigations, seven centers individually conducted a common toxicogenomics experiment designed to advance understanding of molecular pathways perturbed in liver by an acute toxic dose of N-acetyl-p-aminophenol (APAP) and to uncover reproducible genomic signatures of APAP-induced toxicity. The non-hepatotoxic APAP isomer N-acetyl-m-aminophenol was used to identify gene expression changes unique to APAP. Our data show that c-Myc is induced by APAP and that c-Myc-centered interactomes are the most significant networks of proteins associated with liver injury. Furthermore, sources of error and data variability among Centers and methods to accommodate this variability were identified by coupling gene expression with extensive toxicological evaluation of the toxic responses. We show that phenotypic anchoring of gene expression data is required for biologically meaningful analysis of toxicogenomic experiments.

Key Words: liver injury; toxicogenomics; phenotypic anchoring.

* Equally contributing first author

^ Equally contributing senior author

% Corresponding author


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