Toxicogenomic analysis of N-nitrosomorpholine induced changes in rat liver: Comparison of genomic and proteomic responses and anchoring to histopathological parameters

A common animal model of chemical hepatocarcinogenesis was used to examine the utility of transcriptomic and proteomic data to identify early biomarkers related to chemically induced carcinogenesis. N-nitrosomorpholine, a frequently used genotoxic model carcinogen, was applied via drinking water at...

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Bibliographic Details
Published in:Toxicology and applied pharmacology 2009-12, Vol.241 (2), p.230-245
Main Authors: Oberemm, A., Ahr, H.-J., Bannasch, P., Ellinger-Ziegelbauer, H., Glückmann, M., Hellmann, J., Ittrich, C., Kopp-Schneider, A., Kramer, P.-J., Krause, E., Kröger, M., Kiss, E., Richter-Reichhelm, H.-B., Scholz, G., Seemann, K., Weimer, M., Gundert-Remy, U.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
AMINES
ANIMALS
ANTIBODIES
Biological and medical sciences
BIOLOGICAL MARKERS
Biomarkers, Tumor - biosynthesis
BODY
CARCINOGENESIS
Carcinogenesis, carcinogens and anticarcinogens
CARCINOGENS
Chemical agents
DIGESTIVE SYSTEM
DRINKING WATER
DRUGS
ELECTROPHORESIS
ETHERS
FUNCTIONAL ANALYSIS
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
GENES
Genotoxic carcinogens
GLANDS
GLUTATHIONE
Glutathione Transferase - biosynthesis
HETEROCYCLIC COMPOUNDS
Humans
HYDROGEN COMPOUNDS
LIVER
Liver - drug effects
Liver - metabolism
Liver - pathology
Liver Neoplasms, Experimental - chemically induced
Liver Neoplasms, Experimental - metabolism
Liver Neoplasms, Experimental - pathology
Male
MAMMALS
MATHEMATICS
Mechanistic toxicology
Medical sciences
MORPHOLINES
Nitrosamines - toxicity
NITROSO COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PATHOGENESIS
PEPTIDES
POLYPEPTIDES
Precancerous Conditions - chemically induced
Precancerous Conditions - metabolism
Precancerous Conditions - pathology
PROTEINS
Proteomics
RADIOPROTECTIVE SUBSTANCES
Rat liver
RATS
Rats, Wistar
RESPONSE MODIFYING FACTORS
RODENTS
TOXICITY
Toxicogenetics
Toxicogenomics
Toxicology
Transcriptomics
Tumors
VERTEBRATES
WATER
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Summary:A common animal model of chemical hepatocarcinogenesis was used to examine the utility of transcriptomic and proteomic data to identify early biomarkers related to chemically induced carcinogenesis. N-nitrosomorpholine, a frequently used genotoxic model carcinogen, was applied via drinking water at 120 mg/L to male Wistar rats for 7 weeks followed by an exposure-free period of 43 weeks. Seven specimens of each treatment group (untreated control and 120 mg/L N-nitrosomorpholine in drinking water) were sacrificed at nine time points during and after N-nitrosomorpholine treatment. Individual samples from the liver were prepared for histological and toxicogenomic analyses. For histological detection of preneoplastic and neoplastic tissue areas, sections were stained using antibodies against the placental form of glutathione- S-transferase (GST-P). Gene and protein expression profiles of liver tissue homogenates were analyzed using RG-U34A Affymetrix rat gene chips and two-dimensional gel electrophoresis-based proteomics, respectively. In order to compare results obtained by histopathology, transcriptomics and proteomics, GST-P-stained liver sections were evaluated morphometrically, which revealed a parallel time course of the area fraction of preneoplastic lesions and gene plus protein expression patterns. On the transcriptional level, an increase of hepatic GST-P expression was detectable as early as 3 weeks after study onset. Comparing deregulated genes and proteins, eight species were identified which showed a corresponding expression profile on both expression levels. Functional analysis suggests that these genes and corresponding proteins may be useful as biomarkers of early hepatocarcinogenesis.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2009.08.020