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Selective induction of micronuclei in the rat/mouse colon and liver by 1,2-dimethylhydrazine: a seven-tissue
V S Zhurkov1, L P Sycheva, O Salamatova
1A.N. Sysin Institute of Human Ecology and Environmental Hygiene, Russian Academy of Medical Sciences, Moscow, Russia.
Abstract:
1,2-Dimethylhydrazine (DMH) was administered to both genders of mice and rats by oral gavage for 3 days. Twenty-four hours later, an assessment of the incidence of micronucleated cells was made in the bone marrow and sections of the gastrointestinal tract. An increase in micronucleated cells was observed in the colon of both genders of both species of rodent. Negative responses were observed in the forestomach, stomach, duodenum, intestine of both species. The bone marrow micronucleus assays were essentially negative, but the absence of a precise definition of the MTD precludes a definitive conclusion from being drawn. These results are consistent with the selective carcinogenicity of DMH to the colon of the rodent GI-tract. DMH is also known to be carcinogenic to rat and mouse liver and, although it is known to induce micronuclei in the hepatocytes of rats, no such data exist for the mouse. Consequently, mice were administered DMH on 13 successive days, followed by 2/3 partial hepatectomy and assessment of micronucleated hepatocytes. A strong positive liver micronucleus assay response was observed. Thus, DMH selectively induces micronuclei in the colon and liver of rats and mice, consistent with its carcinogenicity to these two tissues. No qualitative differences between the genders was observed in any of the assays. These results indicate that the assessment of genetic toxicity in rodents should not rely solely on assays made in bone marrow.
Insights
1,2-Dimethylhydrazine (DMH) selectively induces genetic damage in the colon and liver of rodents, highlighting the need for diverse tissue testing in toxicity assessments. Bone marrow assays alone are insufficient for evaluating DMH
Area of Science:
- Toxicology
- Genetics
- Carcinogenesis
Background:
- 1,2-Dimethylhydrazine (DMH) is a known carcinogen in rodents, primarily targeting the colon.
- Previous studies indicated DMH induces micronuclei in rat hepatocytes, but data for mice were lacking.
- The maximum tolerated dose (MTD) for DMH was not precisely defined in initial bone marrow assays.
Purpose of the Study:
- To investigate the genotoxicity of 1,2-Dimethylhydrazine (DMH) in various rodent tissues.
- To assess the tissue-specific induction of micronuclei by DMH in mice and rats.
- To evaluate the utility of bone marrow versus other tissues for DMH genotoxicity testing.
Main Methods:
- Rodents (mice and rats) of both genders received oral DMH for 3 or 13 days.
- Micronucleated cell incidence was assessed in bone marrow and gastrointestinal tract sections (colon, forestomach, stomach, duodenum, intestine).
- Hepatocyte micronucleus assays were performed in mice after prolonged DMH exposure and partial hepatectomy.
Main Results:
- DMH significantly increased micronucleated cells in the colon of both species and genders.
- Negative results were observed in the forestomach, stomach, duodenum, and intestine.
- Bone marrow assays were largely negative, while liver micronucleus assays in mice showed a strong positive response.
- No gender-specific differences in DMH genotoxicity were observed.
Conclusions:
- DMH selectively induces genotoxicity in the colon and liver of rodents, aligning with its known carcinogenic effects.
- Genotoxicity assessment in rodents should include multiple tissues beyond bone marrow for comprehensive evaluation.
- The findings underscore the importance of tissue-specific testing in toxicological studies of chemical carcinogens.
