Differences in susceptibility to colonic stem cell somatic mutation in three strains of mice

Different species and different strains of animals commonly show very diffe rent sensitivities to carcinogenic regimes, which are often unexplained, A major possible contributory factor is variation in susceptibility to mutati on, but this has not been directly demonstrated. This study therefore quant ified the colonic stem cell mutation frequency in three strains of mice usi ng two carcinogens. Stem cell mutations were identified using loss of funct ion of glucose 6-phosphate dehydrogenase (G6PD) in individual crypts, a tec hnique validated by several previous studies. The carcinogens dimethylhydra zine (DMH) and ethyl nitrosurea (ENU) were given to Balb/C, C57BL/6J, and C 3H mire, In response to DMH, Balb/C mice were most susceptible, with approx imately double the stem cell mutation frequency found in C3H and more than ten-fold that found in C57BL/6J (3.3 +/- 0.71 vs. 1.5 +/- 0.52 vs. 0.28 +/- 0.8 x 10(-4)), In response to ENU. Balb/C mice and C3H mice were equally s usceptible, showing a stem cell mutation frequency approximately twice that of C57BL/6J (3.1+/-0.4 vs. 3.1+/-0.65 vs. 1.63+/-0.28 x 10(-4)), The obser ved differences among the strains with respect to somatic mutation followin g DMH treatment are likely to be due to the previously documented differenc es in metabolic conversion to the active metabolite. However, as ENU is a d irectly acting, rapidly inactivated mutagen, strain differences in response to ENU are unlikely to be due to strain-dependent metabolism of the mutage n and are likely to reflect differences in DNA repair efficiency, or possib ly in stem cell kinetics among the strains studied. Susceptibility to the i nduction of colonic stem cell mutation is an important factor in susceptibi lity to carcinogens, whether due to differences in DNA repair or to other f actors, Direct quantification of stem cell mutation frequency allows the se parate identification of this component of the carcinogenic cascade and sho ws that it can make a major contribution to the differing susceptibility of different mouse strains. Copyright (C) 2001 John Wiley & Sons, Ltd.