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Genetic factors controlling inheritance of susceptibility to 1,2-dimethylhydrazine
E E Deschner1, M Hakissian, F C Long
1Laboratory of Digestive Tract Carcinogenesis, Memorial Hospital, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Abstract:
Reciprocal crosses were made between AKR/J, a 1,2-dimethylhydrazine (DMH)-resistant mouse strain, and SWR/J, a sensitive strain. The F1 hybrids were tested with DMH and methylazoxymethanol (MAM), two colon carcinogens. Either DMH (20 mg/kg body weight) or MAM (35 mg/kg body weight), a metabolic derivative of DMH, was injected weekly for 10 weeks. In each group of 35 mice, 10 were injected with tritiated thymidine (25 microCi) 1 week after the sixth injection of DMH and MAM for the evaluation of proliferative characteristics and the number of foci of dysplasia occurring in 325 microns of distal colonic mucosa. At 27 weeks after the first injection of the carcinogen, the colons of remaining mice were opened longitudinally and the number of tumors enumerated. Compared with DMH-treated mice, the number of foci of dysplasia per mouse, the percentage of tumor-bearing mice, the number of tumors per animal, and the number of tumors per tumor-bearing animal induced by MAM were severalfold higher. This would suggest the presence of a gene(s) repressing metabolism of DMH to MAM. Moreover, differences in response to the carcinogens were observed between the sexes. In contrast to males, females treated with both DMH and MAM had significantly greater numbers of tumors per animal, tumors per tumor-bearing mice, and a greater proliferative response with extension of S-phase cells to the upper third and luminal surface of crypts. Among males, those with the XAKR/YSWR heritage appeared more resistant than XSWR/YAKR males, particularly in their response to MAM. A twofold difference in the number of foci of dysplasia per mouse, tumors per animal, and the number of tumors per tumor-bearing animals was seen. Analyses of the response to DMH and MAM by F1 reciprocal hybrids of the AKR and SWR strains have shown a complex inheritance pattern governing susceptibility to DMH. Resistance to the carcinogen is provided by at least two specific repressor genes, one governing metabolism of carcinogen from DMH to MAM, and the other controlled by gender. Genetic factors contributed by the AKR female appear to convey additional resistance to male progeny, suggesting more than one gender-related gene.
Insights
Genetic factors influence susceptibility to colon cancer. AKR/J mice exhibit resistance to 1,2-dimethylhydrazine (DMH) and its metabolite methylazoxymethanol (MAM), while SWR/J mice are sensitive. Resistance is linked to repressor genes and gender-specific factors.
Area of Science:
- Genetics
- Cancer Research
- Toxicology
Background:
- 1,2-dimethylhydrazine (DMH) is a colon carcinogen.
- Mouse strains AKR/J and SWR/J exhibit differential sensitivity to DMH.
- Understanding genetic factors influencing carcinogen metabolism and response is crucial for cancer prevention.
Purpose of the Study:
- To investigate the genetic basis of differential susceptibility to DMH and its metabolite methylazoxymethanol (MAM) in mice.
- To determine the role of gender in modulating the response to these colon carcinogens.
- To identify potential repressor genes involved in carcinogen metabolism and tumor development.
Main Methods:
- Reciprocal crosses between AKR/J (DMH-resistant) and SWR/J (DMH-sensitive) mouse strains.
- Treatment of F1 hybrids with DMH or MAM carcinogens weekly for 10 weeks.
- Evaluation of colonic mucosa proliferation, dysplasia foci, and tumor enumeration at 27 weeks post-initiation.
Main Results:
- Methylazoxymethanol (MAM) induced significantly more dysplasia and tumors than DMH, suggesting a repressor gene controlling DMH metabolism to MAM.
- Females exhibited a higher tumor burden and proliferative response compared to males.
- Male progeny with AKR/J heritage showed increased resistance to MAM, indicating gender-related genetic influences.
Conclusions:
- Colon cancer susceptibility to DMH and MAM is governed by a complex inheritance pattern involving at least two repressor genes.
- One repressor gene regulates the metabolism of DMH to MAM, while another is gender-controlled.
- AKR female genetic factors confer additional resistance to male offspring, suggesting multiple gender-related genes.