The colonic response to genotoxic carcinogens in the rat: regulation by dietary fibre.
The apoptotic response to DNA damage appears to be an innate biological mechanism for protection against tumourigenesis. It is possible that agents that protect against colorectal cancer act by enhancing the apoptotic deletion of cells suffering DNA damage, with consequent removal of those with tumourigenic mutations. We examined the acute apoptotic response to genotoxic carcinogens ("AARGC") in colonic epithelium and the possibility that dietary fibres of different fermentability might regulate AARGC. To fully define the time-course and nature of AARGC in response to the carcinogen azoxymethane (AOM), a single injection of AOM (10 mg/kg) was given to rats and apoptosis monitored in the colon by light microscopy and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling staining over a 72 h period. Having defined the site and time of maximum response, two groups of eight rats were fed diets containing 10% wheat bran fibre (WB; fermentable) or 10% methylcellulose (MC; poorly fermentable) for 4 weeks. Colonic AARGC was compared by light microscopy; lumenal short chain fatty acids (SCFAs) and pH were measured as indicators of the fermentative environment. AOM-induced AARGC was maximal at 8 h and greater in distal compared with proximal colon. Apoptotic cells were situated predominantly in the lower half of the crypt, with the median at position 9 indicating involvement of daughter as well as stem cells. There was no "second wave" of apoptosis within 72 h as follows irradiation in small intestine. Distal colonic AARGC in rats fed WB was twice that in rats fed MC (P < 0.01). Compared with MC, WB significantly lowered lumenal pH and increased all SCFAs including butyrate, while proliferation did not differ between the fibres. Certainly, dietary fibres can regulate AARGC and further studies are warranted to determine if this biological effect is the way in which dietary factors regulate tumourigenesis. Lumenal generation of butyrate may enhance AARGC as butyrate is proapoptotic in vitro.
Hu
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Flinders Centre for Digestive Health and Medical Research Institute, Flinders University of South Australia, Adelaide 5042, Australia.
Martin
J
J
Le Leu
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R
Young
G P
GP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001397:Azoxymethane / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects*; D004043:Dietary Fiber / Q000008:administration & dosage*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D020287:In Situ Nick-End Labeling; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009152:Mutagenicity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D004043:Dietary Fiber; D001397:Azoxymethane