Genomic homeostasis is dysregulated in favour of apoptosis in the colonic epithelium of the azoxymethane treated rat.
BACKGROUND
The 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.


RESULTS
There 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.


CONCLUSIONS
The 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.
CSIRO Preventative Health Flagship, CSIRO, North Ryde, NSW 2113, Australia. Caroline_Kerr@uow.edu.au
Caroline A
CA
Kerr
Barney M
BM
Hines
Janet M
JM
Shaw
Robert
R
Dunne
Lauren M
LM
Bragg
Julie
J
Clarke
Trevor
T
Lockett
Richard
R
Head
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D001397:Azoxymethane / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D023281:Genomics / Q000379:methods; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D016159:Tumor Suppressor Protein p53; D001397:Azoxymethane