ToxSci Advance Access originally published online on May 22, 2009
Toxicological Sciences 2009 110(2):341-352; doi:10.1093/toxsci/kfp103
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Characterization and Interlaboratory Comparison of a Gene Expression Signature for Differentiating Genotoxic Mechanisms
* Bayer HealthCare AG, Special Toxicology, 42096 Wuppertal, Germany
Global Health Sector, SRA International, Inc./NIEHS, Research Triangle Park, North Carolina 27709
Safety Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Kisaradu-shi, Chiba, 292-0818 Japan
Novartis Pharma AG, 4002 Basel, Switzerland
¶ Sanofi aventis R&D, Drug Safety Evaluation, 94403 Vitry-Sur-Seine Cedex, France
|| Pfizer Global Research and Development, Groton, Connecticut 06355
||| Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057
|| || Schering-Plough Research Institute, Summit, New Jersey 07901
# F. Hoffmann La Roche AG, 4070 Basel, Switzerland
** Meiji Seika Kaisha, Ltd, Toxicology Laboratory, Pharmaceutical Research Center, Yokohama-shi, Kanagawa 222-8567, Japan
Biologie SERVIER, Toxicology Center, 45520 Gidy, France
a Personalized Medicine Research Lab, Taiho Pharmaceutical Co., Ltd, Hiraishi, Tokushima, Japan
1 To whom correspondence should be addressed at Pfizer Global R&D, Eastern Point Road, Groton, CT 06355. Fax: (860) 715-7884. E-mail: jiri.aubrecht{at}pfizer.com.
Received March 23, 2009; accepted May 7, 2009
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Abstract |
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The genotoxicity testing battery is highly sensitive for detection of chemical carcinogens. However, it features a low specificity and provides only limited mechanistic information required for risk assessment of positive findings. This is especially important in case of positive findings in the in vitro chromosome damage assays, because chromosome damage may be also induced secondarily to cell death. An increasing body of evidence indicates that toxicogenomic analysis of cellular stress responses provides an insight into mechanisms of action of genotoxicants. To evaluate the utility of such a toxicogenomic analysis we evaluated gene expression profiles of TK6 cells treated with four model genotoxic agents using a targeted high density real-time PCR approach in a multilaboratory project coordinated by the Health and Environmental Sciences Institute Committee on the Application of Genomics in Mechanism-based Risk Assessment. We show that this gene profiling technology produced reproducible data across laboratories allowing us to conclude that expression analysis of a relevant gene set is capable of distinguishing compounds that cause DNA adducts or double strand breaks from those that interfere with mitotic spindle function or that cause chromosome damage as a consequence of cytotoxicity. Furthermore, our data suggest that the gene expression profiles at early time points are most likely to provide information relevant to mechanisms of genotoxic damage and that larger gene expression arrays will likely provide richer information for differentiating molecular mechanisms of action of genotoxicants. Although more compounds need to be tested to identify a robust molecular signature, this study confirms the potential of toxicogenomic analysis for investigation of genotoxic mechanisms.
Key Words: gene expression; genetic toxicology; risk assessment.