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

Abstract

Different species and different strains of animals commonly show very different sensitivities to carcinogenic regimes, which are often unexplained. A major possible contributory factor is variation in susceptibility to mutation, but this has not been directly demonstrated. This study therefore quantified the colonic stem cell mutation frequency in three strains of mice using two carcinogens. Stem cell mutations were identified using loss of function of glucose 6-phosphate dehydrogenase (G6PD) in individual crypts, a technique validated by several previous studies. The carcinogens dimethylhydrazine (DMH) and ethyl nitrosurea (ENU) were given to Balb/C, C57BL/6J, and C3H mice. In response to DMH, Balb/C mice were most susceptible, with approximately 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+/-0.8x10(-4)). In response to ENU, Balb/C mice and C3H mice were equally susceptible, showing a stem cell mutation frequency approximately twice that of C57BL/6J (3.1+/-0.4 vs. 3.1+/-0.65 vs. 1.63+/-0.28x10(-4)). The observed differences among the strains with respect to somatic mutation following DMH treatment are likely to be due to the previously documented differences in metabolic conversion to the active metabolite. However, as ENU is a directly acting, rapidly inactivated mutagen, strain differences in response to ENU are unlikely to be due to strain-dependent metabolism of the mutagen and are likely to reflect differences in DNA repair efficiency, or possibly in stem cell kinetics among the strains studied. Susceptibility to the induction of colonic stem cell mutation is an important factor in susceptibility to carcinogens, whether due to differences in DNA repair or to other factors. Direct quantification of stem cell mutation frequency allows the separate identification of this component of the carcinogenic cascade and shows that it can make a major contribution to the differing susceptibility of different mouse strains.

The cables gene on chromosome 18Q regulates colon cancer progression in vivo

“…The C57BL/6J mice used in our study have an intermediate susceptibility to develop colon tumors and do not typically develop other treatment related malignancies. 20,21 In one study, 48% of the C57BL/6J mice treated with DMH developed colorectal tumors. This is similar to our study in which 60% of Cables +/+ mice treated with DMH developed colorectal tumors.…”

Investigation of doublecortin and calcium/calmodulin‐dependent protein kinase‐like‐1‐expressing cells in the mouse stomach

“…Turnover of the epithelial cells in the gastrointestinal tract is a constant process and increases after injury. Studies have shown that all gastrointestinal epithelial cell lineages come from one single stem cell 17,18 . Through asymmetric division, these cells can produce an identical daughter cell.…”

Investigation of Musashi-1 Expressing Cells in the Murine Model of Dextran Sodium Sulfate-Induced Colitis

“…Furthermore, by observing crypts deficient in glucose-6-phosphate dehydrogenase because of gene mutation, Griffith et al have found that all the cells of a crypt derive from a single stem cell through monoclonal cell proliferation (43,44). Since all the cells in the gastrointestinal epithelium, particularly in the small intestine, are renewed in a very short time, 3-5 days, it is thought that precursor cells, not stem cells, in the proliferative zone produce a large number of mature cells in a short time.…”