ToxSci Advance Access originally published online on November 4, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Toxicological Sciences 77, 19-34 (2004)
Copyright © 2004 by the Society of Toxicology
CARCINOGENICITY |
Characteristic Expression Profiles Induced by Genotoxic Carcinogens in Rat Liver
* Department of Molecular and Genetic Toxicology, Bayer AG, Wuppertal, Germany, and
Department of Research Toxicology, Bayer Crop Science, Stilwell, Kansas 66085
When applied in toxicological studies, the recently developed gene expression profiling techniques using microarrays, which brought forth the new field of toxicogenomics, facilitate the interpretation of a toxic compound’s mechanism of action. In this study, we investigated whether genotoxic carcinogens at doses known to induce liver tumors in the 2-year rat bioassay deregulate a common set of genes in a short-term in vivo study and, if so, whether these deregulated genes represent defined biological pathways. Rats were dosed with the four genotoxic hepatocarcinogens dimethylnitrosamine (4 mg/kg/day), 2-nitrofluorene (44 mg/kg/day), aflatoxin B1 (0.24 mg/kg/day), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 20 mg/kg/day). 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; in the case of dimethylnitrosamine and NNK, the effects were weakly detectable at day 1 and then increased with time. 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 later tumor development.
Key Words: toxicogenomics; microarray; genotoxic carcinogens; rat liver; characteristic profiles.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Rokushima, K. Omi, K. Imura, A. Araki, N. Furukawa, F. Itoh, M. Miyazaki, J. Yamamoto, M. Rokushima, M. Okada, et al. Toxicogenomics of Drug-Induced Hemolytic Anemia by Analyzing Gene Expression Profiles in the Spleen Toxicol. Sci., November 1, 2007; 100(1): 290 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. W. Ku, J. Aubrecht, R. J. Mauthe, R. H. Schiestl, and A. J. Fornace Jr Genetic Toxicity Assessment: Employing the Best Science for Human Safety Evaluation Part VII: Why Not Start with a Single Test: A Transformational Alternative to Genotoxicity Hazard and Risk Assessment Toxicol. Sci., September 1, 2007; 99(1): 20 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Michel, C. Desdouets, M. Slaoui, K. R. Isaacs, R. A. Roberts, and E. Boitier Diethylnitrosamine Initiation Does Not Alter Clofibric Acid Induced Hepatocarcinogenesis in the Rat Toxicol. Sci., September 1, 2007; 99(1): 58 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. R. Foster, S.-J. Chen, A. He, A. Truong, V. Bhaskaran, D. M. Nelson, D. M. Dambach, L. D. Lehman-McKeeman, and B. D. Car A Retrospective Analysis of Toxicogenomics in the Safety Assessment of Drug Candidates Toxicol Pathol, August 1, 2007; 35(5): 621 - 635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rokushima, K. Omi, A. Araki, Y. Kyokawa, N. Furukawa, F. Itoh, K. Imura, K. Takeuchi, M. Okada, I. Kato, et al. A Toxicogenomic Approach Revealed Hepatic Gene Expression Changes Mechanistically Linked to Drug-Induced Hemolytic Anemia Toxicol. Sci., February 1, 2007; 95(2): 474 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Nelson, V. Bhaskaran, W. R. Foster, and L. D. Lehman-McKeeman p53-Independent Induction of Rat Hepatic Mdm2 following Administration of Phenobarbital and Pregnenolone 16{alpha}-Carbonitrile Toxicol. Sci., December 1, 2006; 94(2): 272 - 280. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Freiberg, N. Brunner, L. Macko, and H. P. Fischer Discovering Antibiotic Efficacy Biomarkers: TOWARD MECHANISM-SPECIFIC HIGH CONTENT COMPOUND SCREENING Mol. Cell. Proteomics, December 1, 2006; 5(12): 2326 - 2335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Seidel, W. T. Stott, H. L. Kan, B. R. Sparrow, and B. B. Gollapudi Gene Expression Dose-Response of Liver with a Genotoxic and Nongenotoxic Carcinogen International Journal of Toxicology, January 1, 2006; 25(1): 57 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M Battershill Toxicogenomics: regulatory perspective on current position Human and Experimental Toxicology, January 1, 2005; 24(1): 35 - 40. [Abstract] [PDF]
|
|
|
|
|
|
M. M. Elrick, J. A. Kramer, C. L. Alden, E. A. G. Blomme, R. T. Bunch, M. A. Cabonce, S. W. Curtiss, L. D. Kier, K. L. Kolaja, C. P. Rodi, et al. Differential Display in Rat Livers Treated for 13 Weeks with Phenobarbital Implicates a Role for Metabolic and Oxidative Stress in Nongenotoxic Carcinogenicity Toxicol Pathol, January 1, 2005; 33(1): 118 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. M. van Delft, E. van Agen, S. G. J. van Breda, M. H. Herwijnen, Y. C. M. Staal, and J. C. S. Kleinjans Discrimination of genotoxic from non-genotoxic carcinogens by gene expression profiling Carcinogenesis, July 1, 2004; 25(7): 1265 - 1276. [Abstract] [Full Text] [PDF]
|
|