EFFECTS OF EPIDERMAL GROWTH-FACTOR AND DIMETHYLHYDRAZINE ON CRYPT SIZE, CELL-PROLIFERATION, AND CRYPT FISSION IN THE RAT COLON - CELL-PROLIFERATION AND CRYPT FISSION ARE CONTROLLED INDEPENDENTLY

Crypt fission is now established as an important mechanism of intestin al growth and regeneration, It has been proposed that increased crypt size is the stimulus for crypt fission, because crypts preparing for f ission are generally larger, Consequently, me investigated the effects of epidermal growth factor (EGF) and dimethylhydrazine, which are bot h known to stimulate crypt cell proliferation, on crypt fission in the rat intestine, We also examined whether the effects of EGF on both pr oliferation and crypt fission are modified by the pretreatment with di methylhydrazine, Rats were given subcutaneous dimethylhydrazine for 16 weeks, dimethylhydrazine was then discontinued for 8 weeks, followed by intravenous infusion of EGF for 1 week, There were four groups: veh icle alone, EGF alone, dimethylhydrazine alone, and dimethylhydrazine followed by EGF infusion, The rats were killed at 25 weeks and rates o f intestinal crypt cell production, crypt size, and crypt fission were determined. Intravenously infused EGF significantly increased crypt c ell production rate, but the magnitude of the effect decreased from th e proximal to the distal colon, EGF caused an increase in crypt area, possibly reflecting an increase in crypt size, Importantly dimethylhyd razine had no significant effect on crypt cell production rate nor on crypt area in the distal colon, but it did cause an increase in crypt area in the mid-colon, The crypt fission index was significantly decre ased by EGF and increased by dimethylhydrazine. There was no qualitati ve interaction between EGF and dimethylhydrazine, These results demons trate the marked proliferative effect of intravenously infused EGF in the colon of orally fed rats, with significant site effects (P = 0.000 7); the effect was greatest in the proximal colon and disappeared in t he distal colon, The observation that EGF reduced crypt fission indica tes that increased cell proliferation, per se, is not a stimulus for c rypt fission, This is further supported by the observation that dimeth ylhydrazine increases crypt fission in crypts of normal size in the di stal colon without significantly increasing cell proliferation, These results suggest that increasing crypt cellularity by proliferation is not sufficient to induce crypt fission, and factors other than increas ed crypt size by proliferation can control crypt fission, It is also p robable that cell proliferation and crypt fission are independently re gulated. Crypt fission appears to play a considerable role in the inte stinal response to carcinogens.