Proliferative characteristics of chronic crypt cells in C57BL/6J and A/J mice as predictors of subsequent tumor formation.

It has been proposed that the number and extent of tumors formed after chronic exposure to dimethylhydrazine (DMH) can be predicted by the indigenous number and distribution of DNA-synthesizing cells in the murine colonic mucosa, and that this sensitivity to DMH is genetically determined. In order to test this hypothesis we studied two genetically distinct inbred strains of mice; the DMH-sensitive A/J (A) mouse, and the relatively DMH-resistant C57BL/6J (B) mouse before and after a single exposure to DMH. The untreated A strain had the longer crypt column [33.2 +/- 0.8 (SD) cells versus 28.8 +/- 0.9 cells], a higher absolute number of labeled cells per crypt column (4.4 +/- 0.6 versus 2.6 +/- 0.9), a greater labeling index (13.4 +/- 1.6% versus 9.1 +/- 2.9%), a wider proliferative compartment, and a greater number and percentage of labeled cells in the middle and upper thirds of the crypt than the untreated B strain. After acute exposure to DMH the A strain lost 14 +/- 3% of their total body weight, while the B strain lost 0.5 +/- 2% total body weight 48 h post-DMH. There was an initial loss of cryptal cells, a drop in the labeling index, and a subsequent increase and overshoot in the number of labeled cells and the labeling index. This pattern of cell loss and recovery over time was parallel in both strains, and thus cannot explain the differences in ultimate tumor formation after chronic exposure to the carcinogen. The data are consistent with the theory that the susceptibility to DMH carcinogenesis can be predicted by the indigenous proliferative characteristics of the murine colonic mucosa. The acute proliferative response to DMH in these strains is similar and parallel; thus ultimate tumor load may depend on long term effects such as the establishment of stable transmissible mutations.