Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mice liver after treatment for 2 weeks with different known carcinogens and non-carcinogens

ABSTRACT: Previously we demonstrated that the mouse liver tumor response to the non-genotoxic carcinogens oxazepam [CAS:604-75-1;CHEBI:7823] and Wyeth-14,643 [CAS:50892-23-4;CHEBI:32509] involved more differences than similarities in changes in early gene expression. In this study we used quantitative real-time PCR and oligonucleotide microarray analysis to identify genes that were up- or downregulated in mouse liver early after treatment with different known carcinogens, including oxazepam [CAS:604-75-1 CHEBI:7823] (125 and 2500 p.p.m.), o-nitrotoluene [CAS:88-72-2;CHEBI:33098] (1250 and 5000 p.p.m.) and methyleugenol [CAS:93-15-2;CHEBI:4918] (75 mg/kg/day), or the non-carcinogens p-nitrotoluene [CAS:99-99-0;CHEBI:33097] (5000 p.p.m.), eugenol [CAS:97-53-0;CHEBI:4917] (75 mg/kg/day) and acetaminophen [CAS:103-90-2;CHEBI:2386] (6000 p.p.m.). Starting at 6 weeks of age, mice were treated with the 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 with 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 [n ¼ 4 livers/group, 2 hybridizations/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 cyclerelated genes.

ORGANISM(S): Mus musculus

SUBMITTER: Mary Iida

PROVIDER: E-TOXM-18 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description: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 [CAS:62-75-9;CHEBI:21778] (4 mg/kg/day), 2-nitrofluorene [CAS:607-57-8;CHEBI:1224] (44 mg/kg/day), Aflatoxin B1 [CAS:1162-65-8;CHEBI:2504] (0.24 mg/kg/day), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [CAS:64091-91-4;CHEBI:32692] (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.

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Transcription profiling of mice liver after treatment for 2 weeks with different known carcinogens and non-carcinogens

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