Interlaboratory evaluation of rat hepatic gene expression changes induced by methapyrilene.
Several studies using microarrays have shown that changes in gene expression provide information about the mechanism of toxicity induced by xenobiotic agents. Nevertheless, the issue of whether gene expression profiles are reproducible across different laboratories remains to be determined. To address this question, several members of the Hepatotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute evaluated the liver gene expression profiles of rats treated with methapyrilene (MP). Animals were treated at one facility, and RNA was distributed to five different sites for gene expression analysis. A preliminary evaluation of the number of modulated genes uncovered striking differences between the five different sites. However, additional data analysis demonstrated that these differences had an effect on the absolute gene expression results but not on the outcome of the study. For all users, unsupervised algorithms showed that gene expression allows the distinction of the high dose of MP from controls and low dose. In addition, the use of a supervised analysis method (support vector machines) made it possible to correctly classify samples. In conclusion, the results show that, despite some variability, robust gene expression changes were consistent between sites. In addition, key expression changes related to the mechanism of MP-induced hepatotoxicity were identified. These results provide critical information regarding the consistency of microarray results across different laboratories and shed light on the strengths and limitations of expression profiling in drug safety analysis.
Waring
Jeffrey F
JF
Abbott Laboratories, 100 Abbott Park Road, Department R463, Abbott Park, IL 60064-6123, USA. jeff.waring@abbott.com
Ulrich
Roger G
RG
Flint
Nick
N
Morfitt
David
D
Kalkuhl
Arno
A
Staedtler
Frank
F
Lawton
Michael
M
Beekman
Johanna M
JM
Suter
Laura
L
D000818:Animals; D018926:Anti-Allergic Agents / Q000633:toxicity*; D005786:Gene Expression Regulation; D008099:Liver / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D008701:Methapyrilene / Q000633:toxicity*; D015588:Observer Variation; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results
D018926:Anti-Allergic Agents; D012313:RNA; D008701:Methapyrilene