Abstract

BackgroundThe acute response to genotoxic carcinogens in rats is an important model for researching cancer initiation events. In this report we define the normal rat colonic epithelium by describing transcriptional events along the anterior-posterior axis and then investigate the acute effects of azoxymethane (AOM) on gene expression, with a particular emphasis on pathways associated with the maintenance of genomic integrity in the proximal and distal compartments using whole genome expression microarrays.ResultsThere are large transcriptional changes that occur in epithelial gene expression along the anterior-posterior axis of the normal healthy rat colon. AOM administration superimposes substantial changes on these basal gene expression patterns in both the distal and proximal rat colonic epithelium. In particular, the pathways associated with cell cycle and DNA damage and repair processes appear to be disrupted in favour of apoptosis.ConclusionsThe healthy rats’ colon exhibits extensive gene expression changes between its proximal and distal ends. The most common changes are associated with metabolism, but more subtle expression changes in genes involved in genomic homeostasis are also evident. These latter changes presumably protect and maintain a healthy colonic epithelium against incidental dietary and environmental insults. AOM induces substantial changes in gene expression, resulting in an early switch in the cell cycle process, involving p53 signalling, towards cell cycle arrest leading to the more effective process of apoptosis to counteract this genotoxic insult.

Highlights

  • The acute response to genotoxic carcinogens in rats is an important model for researching cancer initiation events

  • Using this latter acute AOM model, we report here some of the early transcriptional events induced by this carcinogen in mucosal tissue along the length of the colon in rats

  • It has been demonstrated that rat colonic stem cells are located in different positions and behave differently in crypts sampled from different points along the anterior-posterior length of the colon [12]

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Summary

Introduction

The acute response to genotoxic carcinogens in rats is an important model for researching cancer initiation events. The other main version of the AOM model is the ‘cancer initiation’ model, which is used to study the early response to the carcinogen, where tissues are harvested shortly after treatment (around 0–48 hours) [11]. Using this latter acute AOM model, we report here some of the early transcriptional events induced by this carcinogen in mucosal tissue along the length of the colon in rats

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