Markers of nitrosamine carcinogenesis?

BrooklynDodger(s) comment: These novel assay experiments should be related to exposure levels in which toxicity or carcinogenicity is expressed in an intact animal.


Toxicology and Applied Pharmacology
Volume 241, Issue 2, 1 December 2009, Pages 230-245

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

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A. Oberemm^{a, ,} , H.-J. Ahr^b, P. Bannasch^c, H. Ellinger-Ziegelbauer^b, M. Glückmann^e, J. Hellmann^d, C. Ittrich^{c, 1}, A. Kopp-Schneider^c, P.-J. Kramer^d, E. Krause^f, M. Kröger^d, E. Kiss^c, H.-B. Richter-Reichhelm^a, G. Scholz^{b, 2}, K. Seemann^d, M. Weimer^c and U. Gundert-Remy^a

^aFederal Institute for Risk Assessment (BfR), 14195 Berlin, Germany

^bBayer Schering Pharma AG, Special Toxicology, 42096 Wuppertal, Germany

^cGerman Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

^dMerck KGaA, Institute for Toxicology, 64293 Darmstadt, Germany

^eApplied Biosystems Deutschland GmbH, 64293 Darmstadt, Germany

^fLeibniz Institute for Molecular Pharmacology (FMP), 13125 Berlin, Germany

Received 29 July 2009;

accepted 18 August 2009.

Available online 28 August 2009.

Abstract

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.