ToxSci Advance Access originally published online on June 11, 2007
Toxicological Sciences 2007 99(1):326-337; doi:10.1093/toxsci/kfm150
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Multicenter Study of Acetaminophen Hepatotoxicity Reveals the Importance of Biological Endpoints in Genomic Analyses
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,1,1,1
,1,1,2,2,3,2,2
* University of Washington, Seattle, Washington 98195
Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Oregon Health & Science University, Portland, Oregon 97239
University of North Carolina, Chapel Hill, North Carolina 27599
¶ National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
|| Cogenics, a Division of Clinical Data, Inc., Morrisville, North Carolina 27560
||| SAS Institute, Inc., Cary, North Carolina 27513
|||| Duke University Medical Center, Durham, North Carolina 27710
# Fred Hutchinson Cancer Research Center, Seattle, Washington 98109
3 To whom correspondence should be addressed at Department of Environmental Sciences and Engineering, School of Public Health, University of North Carolina at Chapel Hill, CB #7431, Chapel Hill, NC 27599. Fax: (919) 843-2596. E-mail: iir{at}unc.edu.
Received April 19, 2007; accepted June 5, 2007
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Abstract |
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Gene expression profiling is a widely used technique with data from the majority of published microarray studies being publicly available. These data are 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 multilaboratory 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 nonhepatotoxic 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.
1 Equally contributing first author.
2 Equally contributing senior author.
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