ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh016
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Bayer AG, Dept. of Molecular and Genetic Toxicology, Aprather Weg 18a, 42096 Wuppertal, Germany
* To whom correspondence should be addressed. E-mail: heidrun.ellinger-ziegelbauer.he{at}bayer-ag.de.
When applied in toxicological studies, the recently developed gene expression profiling techniques using microarrays facilitate the interpretation of a toxic compound's mechanism of action, which brought forth the new field of toxicogenomics. In this study, we investigated whether genotoxic carcinogens at doses known to induce liver tumors in the two year rat bioassay deregulate a common set of genes in a short term in vivo study, and whether these deregulated genes represent defined biological pathways. Rats were dosed with the four genotoxic hepatocarcinogens Dimethylnitrosamine (4 mg/kg/d), 2-Nitrofluorene (44 mg/kg/d), Aflatoxin B1 (0.24 mg/kg/d), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) (20 mg/kg/d). After treatment for up to 14 days, the expression profiles of the livers were analyzed on Affymetrix RG_U34A microarrays. Among the significantly upregulated genes were a set of target genes of the tumor suppressor protein p53, indicating a DNA damage response. Such a response was expected and therefore confirmed the validity of our approach. In addition, the gene expression changes suggest a specific detoxification response, the activation of proliferative and survival signaling pathways, and some cell structural changes. These responses were strong throughout the 14 day time course for 2-Nitrofluorene and Aflatoxin B1, but were more weakly yet detectably affected at day 1 and then increased with time in the case of Dimethylnitrosamine and NNK. For Dimethylnitrosamine and Aflatoxin B1, which caused observable inflammation in vivo we found a corresponding upregulation of inflammatory genes at the same time points. Thus by the toxicogenomic analysis of short term in vivo studies we identified genes and pathways commonly deregulated by genotoxic carcinogens which may be indicative for the early events in tumorigenesis and thus predictive of tumor development later on.
© 2003 Society of Toxicology
Carcinogenicity
Characteristic Expression Profiles Induced by Genotoxic Carcinogens in Rat Liver
2 Bayer Crop Science, Dept. of Research Toxicology, Stilwell, KS, USA
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