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Target tissue DNA damage in inbred mouse strains with different susceptibility to the colon carcinogen
C Bolognesi1, M R Mariani, L C Boffa
1Istituto Nazionale per la Ricerca sul Cancro, IST, Genova, Italy.
Abstract:
We have compared liver, kidney and colon DNA damage, as single strand breaks, in mice with different strain-dependent susceptibility to the colon-specific carcinogen 1,2-dimethylhydrazine (DMH). The mouse strains studied were: AKR/J, DBA2 totally resistant; CD1, C57BL/6N moderately susceptible; SWR/J very susceptible to DMH-induced carcinogenesis. DNA breaks were estimated from the elution rate constant (K) according to the alkaline elution technique. At 4 h after carcinogen administration a substantial and comparable DNA damage was found in liver and kidney in all the strains examined. The DNA fragmentation index, however, reached a maximum value at 2 h after treatment in the liver of the most susceptible strain (SWR/J). About 50% of the liver DNA damage detected in all five strains 4 h after DMH administration persisted at 24 h after treatment and was totally repaired at 72 h. Kidney DNA damage decreased in 48 h toward the range of control values. In colon epithelial cells (the carcinogen target tissue) 2 and 4 h after DMH administration the amount of DNA single strand breaks was correlatable with the strain sensitivity to the carcinogen. In the time interval studied (2-72 h after DMH administration) the decrease of colon DNA damage was linear in the resistant strains. In contrast, in the more susceptible strain (SWR/J), the amount of DNA breaks remained high up to 24 h after treatment and returned to background level at 72 h.
Insights
This study reveals that DNA damage from 1,2-dimethylhydrazine (DMH) varies by mouse strain and organ. Colon DNA damage directly correlates with susceptibility to DMH-induced carcinogenesis, unlike liver and kidney damage.
Area of Science:
- Toxicology
- Genetics
- Carcinogenesis
Background:
- 1,2-dimethylhydrazine (DMH) is a colon-specific carcinogen.
- Mouse strains exhibit varying susceptibility to DMH-induced carcinogenesis.
- Understanding DNA damage mechanisms is crucial for cancer research.
Purpose of the Study:
- To compare DNA damage (single-strand breaks) in the liver, kidney, and colon of mice with different DMH susceptibility.
- To correlate DNA damage levels with strain-dependent susceptibility to DMH.
Main Methods:
- Utilized alkaline elution technique to quantify DNA single-strand breaks.
- Administered DMH to five different mouse strains with varying susceptibility (AKR/J, DBA2, CD1, C57BL/6N, SWR/J).
- Assessed DNA damage at multiple time points (2, 4, 24, 48, 72 hours) post-administration.
Main Results:
- Liver and kidney DNA damage were comparable across all strains at 4 hours, with rapid repair.
- Colon epithelial cell DNA damage levels directly correlated with DMH susceptibility.
- Highly susceptible strains (SWR/J) showed persistent colon DNA damage up to 24 hours, while resistant strains repaired damage linearly.
Conclusions:
- Colon DNA damage is a reliable indicator of strain-specific susceptibility to DMH carcinogenicity.
- Liver and kidney exhibit different DNA damage and repair kinetics compared to the colon.
- Strain-dependent differences in DNA repair mechanisms likely contribute to varying cancer susceptibility.