Differential susceptibility of inbred mouse strains forecast by acute colonic proliferative response to methylazoxymethanol

Abstract

The proliferative response of colonic epithelial cells to methylazoxymethanol (MAM) was followed in 1,2-dimethylhydrazine (DMH)-sensitive SWR/J, moderately resistant C57BL/6J, and resistant AKR/J strains. Untreated AKR mice had a significantly lower labeling index (L1) a shorter proliferative compartment (PC), and a smaller percentage of DNA synthesizing cells in the middle third of the crypts than did the SWR strain. SWR had the highest Ll, the widest PC, and the largest percentage of DNA synthesizing cells in the middle third of the crypts. C57BL/6 mice had characteristics that lay between the sensitive and resistant strains. Pooled data from 1 week after the fifth and sixth injections and 12 weeks after the first MAM injection revealed that extension of the PC had occurred in all strains, but it was only the DMH-sensitive SWR strain that showed extension of the PC to the upper third of the crypt, the greatest shift of proliferating cells to the middle and upper third of crypts, and the greatest increase in Ll. The AKR strain demonstrated these proliferative alterations least, and the C57BL/6 strain fell between them. This differential response to MAM among the strains mimicked that previously reported by us when DMH was investigated. The similarity in response of the colonic epithelial cells of each strain to either a direct-acting (MAM) or indirect-acting carcinogen (DMH) would support the concept that susceptability to this family of carcinogens is directly related to the genetically controlled indigenous proliferative characteristics of the colon.