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Effects of Black Raspberry diet on N-Nitrosomethylbenzylamine-altered gene expression in Rat Esophagus

ABSTRACT: Our recent study (Reen et al., Cancer Res 2007;67:6484-92) identified 2261 dysregulated genes in the esophagi of rats that received a one week exposure to the carcinogen, N-Nitrosomethylbenzylamine (NMBA). We further reported that 1323 of these genes were positively modulated in the esophagus of NMBA-treated animals that also consumed dietary phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables. Herein, we report our companion study wherein litter mate rats either received regular chow or chow with 5% freeze-dried black raspberries (BRB) for three weeks. During the third week one-half of these animals received three subcutaneous injections of NMBA (0.5 mg/kg body weight). All animals were sacrificed 24h after the last dose of NMBA, and their esophagi excised and processed for histological grading and RNA microarray profiling. Two hundred and fifty nine of the 2261 genes that were dysregulated by NMBA-alone were expressed at control levels in the esophagus of BRB-fed rats. Overall, the data indicate that a BRB diet has a genome-wide modulating effect on NMBA-caused dysregulation of gene expression in rat esophagus, including genes involved in phase I and phase II metabolism, oxidative damage, inflammation, differentiation, chromosome partitioning, cell adhesion, motility and cytoskeleton formation, and genes known to act as oncogenes and tumor suppressor genes regulating apoptosis, cell-cycling and proliferation, and angiogenesis. Keywords: Toxicogenomics, reference design.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE10623 | GEO | 2009/02/23

SECONDARY ACCESSION(S): PRJNA107685

REPOSITORIES: GEO

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Project description:To date, there is little information on early molecular events in the development of N-nitrosomethylbenzylamine (NMBA) induced esophageal tumorigenesis and of the effects of chemopreventive agents on these events. In this study, we identified genes in rat esophagus that were differentially expressed in response to shortâ??term NMBA-treatment and modulated by co-treatment with phenethylisothiocyanate (PEITC). Rats were fed AIN-76A diet or AIN-76A diet containing PEITC for three weeks. During the third week of dietary treatment, they were administered three s.c. doses of NMBA (0.5 mg/kg b.w.). Rats were sacrificed 24 h after the last treatment, esophagi excised and processed for histological grading, microarray and real-time PCR analysis. Our histopathological data showed that treatment of rats with PEITC had protective effect on NMBA-induced preneoplastic lesions in the rat esophagus. We identified 2261 genes that were differentially expressed in the NMBA-treated vs. control esophagi and 1936 genes in the NMBA+PEITC- vs. NMBA-treated esophagi. The intersection of these two sets resulted in the identification of 1323 genes in NMBA-treated esophagus that were modulated by PEITC to near-normal levels of expression. The measured changes in the expression levels of 10 selected genes were validated using real-time PCR. Principle components analysis (PCA) was applied to all twelve microarrays in the study, which suggested that in terms of global gene expression, PEITC treatment had a genome-wide modulating effect on NMBA-induced gene expression. Samples obtained from animals treated with PEITC alone or co-treated with NMBA were more similar to controls than they were to NMBA treatment alone. Experiment Overall Design: For each treatment we used a pooling strategy to enable the inclusion of samples from numerous animals. Three replicate microarrays were completed for each of the four treatments (control, PEITC, NMBA and NMBA+PEITC) for a total of twelve microarrays. Each microarray was hybridized using a pooled RNA sample, and each pool was created from equal amounts of total RNA from two or three independent RNA samples, representing individual animals. Each of these samples was obtained from a different animal, and no sample was included in more than one pool. In total, samples from nine animals per group were pooled for control, NMBA, PEITC and NMBA+PEITC microarrays. To facilitate comparisons of gene expression across all treatments, we utilized a reference design in which each microarray was co-hybridized with a common reference sample labeled with Cy3, and RNA from the treatment pool was labeled with Cy5. Stratageneâ??s Universal Rat reference RNA (Stratagene, La Jolla, CA) was used as the common reference in all microarrays.

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Effects of Black Raspberry diet on N-Nitrosomethylbenzylamine-altered gene expression in Rat Esophagus

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