Impact of the Total Western Diet for Rodents on Colon Mucosal Gene Expression in a Multigenerational Murine Model of Colitis-associated Colorectal Cancer (OR04-03-19)

Abstract

ObjectivesA Western type dietary pattern is a major risk factor for colitis-associated colorectal cancer (CAC). Observations from transgenerational studies suggest that epimutations may be inherited, resulting in persistent aberrant gene expression in offspring. Previously, our group reported that ancestral exposure to the total Western diet (TWD) markedly increased colon cancer incidence and disease severity in F3 offspring that were not fed this diet directly. Moreover, exposure to TWD over multiple generations markedly exacerbated the disease in F3 offspring as compared to those fed TWD directly. For the present work, we hypothesized that ancestral or multiple generation exposure to the TWD may result in differential expression of cancer critical genes in such a way that explains the greater tumor abundance and burden observed in these mice. MethodsC57BL/6 J mice were bred for three generations, during which they were fed a standard diet (AIN93G) for all generations or the total Western diet for rodents (TWD) during only the F0 generation (ancestral), the F0 through F3 generations (multi-generation), or only the F3 generation (direct). The azoxymethane and dextran sodium sulfate (AOM/DSS) model of CAC was employed in F3 offspring, from which colon mucosa RNA was isolated and used for Illumina RNAseq with EdgeR for differential expression analysis. ResultsAbout 700 to 4500 differentially expressed genes (DEGs) were identified for colon mucosa from AOM/DSS-initiated offspring compared to their sham controls. For AOM/DSS-initiated mice, >100 DEGs were identified comparing multi-generation TWD-fed mice to their AIN93G-fed counterparts, and 36 genes were different from those direct TWD-fed. Of note, in sham-initiated mice, 101 DEGs were identified comparing direct TWD-fed mice to multi-generation TWD-exposed offspring. Interestingly, these DEGs were associated with defense response, immune response, and response to interferon biological process ontology terms. ConclusionsExposure to the TWD over multiple generations caused significant changes in genes involved in immune response in third generation offspring. Assessment of genome-wide patterns of DNA methylation in these colon tissue samples is ongoing. Funding SourcesUSDA NIFA AFRI Grant No. 2014-67017-21755; Utah Agricultural Experiment Station Project UTA-1178.