Overview on the Application of Transcription Profiling using Selected Nephrotoxicants for Toxicology Assessment Jeffrey A. Kramer,1 Syril D. Pettit,3 Rupesh P. Amin,4 Timothy
A. Bertram,2 Bruce Car,5 Michael Cunningham,4 Sandra
W. Curtiss,1 John W. Davis,6 Clive Kind,7 Michael
Lawton,2 Jorge M. Naciff,8 Victor Oreffo,7Richard J. Roman,9 Frank D. Sistare,10 James Stevens,11 Karol
Thompson,10 Alison E. Vickers,12 Stacey Wild,1,3 and
Cynthia A. Afshari4,13 1Pfizer Inc, St. Louis, Missouri, USA, and 2Groton,
Connecticut, USA; 3ILSI Health and Environmental Sciences Institute,
Washington, DC, USA; 4National Institute of Environmental Health
Sciences, National Institutes of Health, Department of Health and Human Services,
Research Triangle Park, North Carolina, USA; 5Bristol-Myers Squibb,
Wilmington, Delaware, USA; 6Schering-Plough Research Institute,
Lafayette, New Jersey, USA; 7AstraZeneca, Charnwood, Leicestershire,
United Kingdom; 8The Procter & Gamble Company, Miami Valley
Laboratories, Cincinnati, Ohio, USA; 9Medical College of Wisconsin,
Milwaukee, Wisconsin, USA; 10Center for Drug Evaluation and Research,
U.S. Food and Drug Administration, Laurel, Maryland, USA; 11Eli
Lilly, Greenfield, Indiana, USA; 12Novartis Pharmaceuticals Corporation,
East Hanover, New Jersey, USA; 13Amgen Inc., Thousand Oaks, California,
USA Abstract Microarrays allow for the simultaneous measurement of changes in the levels of thousands of messenger RNAs within a single experiment. As such, the potential for the application of transcription profiling to preclinical safety assessment and mechanism-based risk assessment is profound. However, several practical and technical challenges remain. Among these are nomenclature issues, platform-specific data formats, and the lack of uniform analysis methods and tools. Experiments were designed to address biological, technical, and methodological variability, to evaluate different approaches to data analysis, and to understand the application of the technology to other profiling methodologies and to mechanism-based risk assessment. These goals were addressed using experimental information derived from analysis of the biological response to three mechanistically distinct nephrotoxins: cisplatin, gentamicin, and puromycin aminonucleoside. In spite of the technical challenges, the transcription profiling data yielded mechanistically and topographically valuable information. The analyses detailed in the articles from the Nephrotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute suggest at least equal sensitivity of microarray technology compared to traditional end points. Additionally, microarray analysis of these prototypical nephrotoxicants provided an opportunity for the development of candidate bridging biomarkers of nephrotoxicity. The potential future extension of these applications for risk assessment is also discussed. Key words: cisplatin, gentamicin, nephrotoxicity, puromycin, risk assessment. Environ Health Perspect 112:460-464 (2004) . doi:10.1289/txg.6673 available via http://dx.doi.org/ [Online 15 January 2004] This article is part of the mini-monograph "Application of Genomics to Mechanism-Based Risk Assessment." Address correspondence to S. Pettit, ILSI Health and Environmental Sciences Institute, One Thomas Circle NW, 9th Floor, Washington, DC 20005 USA. Telephone: (202) 659-3306, Fax: (202) 659-3617. E-mail: spettit@ilsi.org The authors thank members of the HESI Steering Committee for their critical review of the manuscript and the experimental designs carried out by the nephrotoxicity working group. The authors declare they have no competing financial interests. Received 14 August 2003 ; accepted 8 January 2004. The full version of this article is available for free in HTML or PDF formats. |