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Carcinogenesis Advance Access published online on December 23, 2004
Carcinogenesis, doi:10.1093/carcin/bgi005
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Oxford University Press
Received September 17, 2004
Revised December 8, 2004
Accepted December 10, 2004

CARCINOGENESIS

Unique patterns of gene expression changes in liver after treatment of mice for two weeks with different known carcinogens and non-carcinogens

Mari Iida 1, Colleen H. Anna 1, Wanda M. Holliday 1, Jennifer B. Collins 2, Michael L. Cunningham 3, Robert C. Sills 4, and Theodora R. Devereux 1*

1 Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 USA
2 National Center for Toxicogenomics, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 USA
3 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 USA
4 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709 USA

* To whom correspondence should be addressed.
Theodora R. Devereux, E-mail: devereux{at}niehs.nih.gov


  Abstract

Previously, we demonstrated that the mouse liver tumor response to non-genotoxic carcinogens oxazepam or Wyeth-14,643 involved more differences than similarities in early gene expression changes. In this study we used quantitative real-time PCR and oligonucleotide microarray analysis to identify genes that were up- or down-regulated in mouse liver early after treatment with different known-carcinogens, including oxazepam (125 or 2500 ppm), o-nitrotoluene (1250 ppm, 5000 ppm), and methyleugenol (75 mg/kg/day), or non-carcinogens p-nitrotoluene (5000 ppm), eugenol (75 mg/kg/day), and acetaminophen (6000 ppm). Starting at 6 weeks of age, mice were treated with different compounds for 2 weeks in the diet at which time the livers were collected. First, expression of 12 genes found previously to be altered in liver after 2 weeks treatment of oxazepam and/or Wyeth-14,643 was examined in livers from the various chemical treatment groups. These gene expression changes were confirmed for the livers from the oxazepam treated mice in the present study, but were not good early markers for all the carcinogens in this study. In addition, expression of 20,842 genes was assessed by oligonucleotide microarray [Agilent Technologies, Palo Alto, CA, n=4 individual livers/group, two hybridizations per liver (with fluor-reversals)], and the results were analyzed using the Rosetta Resolver System and GeneSpring software. The analyses revealed that several cancer-related genes, including Fhit, Wwox, Tsc-22, and Gadd45b, were induced or repressed in unique patterns for specific carcinogens and not altered by the non-carcinogens. The data indicate that even if the tumor response, including molecular alterations, is similar, such as for oxazepam and methyleugenol, early gene expression changes appear to be carcinogen specific and seem to involve apoptosis and cell cycle related genes.


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