Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression data from CD-1 mouse liver samples obtained from in-vivo treatment with genotoxic carcinogens, non-genotoxic carcinogens or non-hepatocarcinogens.

ABSTRACT: Assessing the carcinogenic potential of drug candidates is a costly procedure which requires the life-long treatment of rodents at different dose levels. A promising approach, which may to a certain degree reduce the need for animal studies in the future is toxicogenomics. The idea is to employ microarray platforms for the genome-wide expression profiling of compounds, which may facilitate the discovery of biomarker genes and provide insights in molecular mechanisms. We profiled global mRNA expression in the liver of male and female CD-1 mice treated with genotoxic, nongenotoxic, and non-hepatocarcinogenic compounds up to two weeks. Diverse compounds were administrated to male and female mice CD-1 mice by oral gavage up to 14 days. In order to chose appropriate dose levels for the carcinogenic substances, the dose reported to be carcinogenic in the 2-year mouse bioassay as stated in the CPDB database (http://potency.berkeley.edu/) was used. To ensure clearly visible changes in gene expression in response to treatment with non-hepatocarcinogens, a high dose was used for these compounds. After 3 and 14 days of treatment, respectively, the animals were anesthetized using isoflurane, exsanguinated from the heart and then subjected to necropsy. The median lobe and left lateral liver lobe were cut in cubes with 4-5 mm side length, placed in Wheaton Cryovials, snap frozen in liquid nitrogen and kept at -80Â°C until extraction.

ORGANISM(S): Mus musculus

SUBMITTER: Johannes Eichner

PROVIDER: E-GEOD-44783 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

A toxicogenomic approach for the prediction of murine hepatocarcinogenesis using ensemble feature selection.

Eichner Johannes J Kossler Nadine N Wrzodek Clemens C Kalkuhl Arno A Bach Toft Dorthe D Ostenfeldt Nina N Richard Virgile V Zell Andreas A

PloS one 20130910 9

The current strategy for identifying the carcinogenicity of drugs involves the 2-year bioassay in male and female rats and mice. As this assay is cost-intensive and time-consuming there is a high interest in developing approaches for the screening and prioritization of drug candidates in preclinical safety evaluations. Predictive models based on toxicogenomics investigations after short-term exposure have shown their potential for assessing the carcinogenic risk. In this study, we investigated a ...[more]

PMID: 24040119

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Project description:Liver tumors in rodents are frequently induced by non-genotoxic carcinogens. These hepatocarcinogens generally activate hepatic nuclear receptors (e.g., CAR and PXR), resulting in a cascade of signals causing modifications in the expression of genes responsible for several processes involved in carcinogenesis. Evaluation of the carcinogenic potential of chemicals is a regulatory requirement but is time-consuming and expensive. Consequently, several short-term in vivo and in vitro approaches, using molecular tools, have been proposed as predictive models for non-genotoxic hepatocarcinogens. The objective of our study was to discriminate between chemicals that are either non-genotoxic hepatocarcinogens or merely hepatotoxicants and also between CAR and PXR modulators on the basis of their gene expression profiles. Thus, we treated rats for seven days with the hepatoxicants, diclofenac and diazepam, or with several CAR and PXR modulators, which were mainly hepatocarcinogens. Different hepatic gene expression profiles were obtained not only between the hepatotoxicants and the non-genotoxic hepatocarcinogens but also between the CAR activators phenobarbital, phenytoin and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene which were grouped together, and the two PXR activators pregnenolone 16Î±-carbonitrile and clotrimazole. Diethylstilbestrol had an expression profile that was quite distinct from the other PXR activators, suggesting that this compound is certainly not a classic PXR modulator. Moreover, some differences were observed between phenytoin (not considered as a hepatocarcinogen), and the other two CAR activators. Our data therefore indicate that discrimination is possible between hepatocarcinogens and hepatotoxicants, between CAR and PXR modulators and also between compounds within the same class of modulators using a short-term transcriptomic approach. CAR or PXR inducers were administered in suspension to rats (7 weeks old at start of treatment) by oral gavage at a daily dose for 7 consecutive days. Treatment-related changes in gene expression were determined in the liver using whole genome oligonucleotide microarrays.

Dataset Information

Expression data from CD-1 mouse liver samples obtained from in-vivo treatment with genotoxic carcinogens, non-genotoxic carcinogens or non-hepatocarcinogens.

Publications

A toxicogenomic approach for the prediction of murine hepatocarcinogenesis using ensemble feature selection.

Similar Datasets

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