Prediction of a carcinogenic potential of rat hepatocarcinogens using toxicogenomics analysis of short-term in vivo studies.
The carcinogenic potential of chemicals is currently evaluated with rodent life-time bioassays, which are time consuming, and expensive with respect to cost, number of animals and amount of compound required. Since the results of these 2-year bioassays are not known until quite late during development of new chemical entities, and since the short-term test battery to test for genotoxicity, a characteristic of genotoxic carcinogens, is hampered by low specificity, the identification of early biomarkers for carcinogenicity would be a big step forward. Using gene expression profiles from the livers of rats treated up to 14 days with genotoxic and non-genotoxic carcinogens we previously identified characteristic gene expression profiles for these two groups of carcinogens. We have now added expression profiles from further hepatocarcinogens and from non-carcinogens the latter serving as control profiles. We used these profiles to extract biomarkers discriminating genotoxic from non-genotoxic carcinogens and to calculate classifiers based on the support vector machine (SVM) algorithm. These classifiers then predicted a set of independent validation compound profiles with up to 88% accuracy, depending on the marker gene set. We would like to present this study as proof of the concept that a classification of carcinogens based on short-term studies may be feasible.
Ellinger-Ziegelbauer
Heidrun
H
Bayer Healthcare AG, Department of Molecular and Special Toxicology, Aprather Weg 18a, 42096, Wuppertal, Germany. heidrun.ellinger-ziegelbauer@bayerhealthcare.com
Gmuender
Hans
H
Bandenburg
Arnd
A
Ahr
Hans Juergen
HJ
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000145:classification; D020869:Gene Expression Profiling; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000145:classification; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D043922:Toxicogenetics
D002273:Carcinogens; D009153:Mutagens