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Tissue-specific induction of mutations by streptozotocin in vivo
P Schmezer1, C Eckert, U M Liegibel
1Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg.
Abstract:
Streptozotocin has been reported to induce DNA damage in mouse liver although malignant tumors were not induced in this organ. DNA damage had not yet been monitored in the mouse kidney which was the tumor target organ in two mouse studies. In order to elucidate target organ specificity of genotoxicity and of tumorigenesis, we investigated the induction of DNA damage (microgel electrophoresis assay) and mutations (LacI transgenic mouse mutation assay) in the liver and kidney of male C57BL/6 mice. Our results show that the microgel electrophoresis assay was more sensitive and revealed the genotoxic potential of streptozotocin at lower doses than the mutation assay. It was, however, less specific in that DNA damage was induced both in target and non-target tissues of carcinogenesis at a similar potency. In contrast, the mutation analysis revealed the kidney to be more sensitive when the induced mutation frequencies are expressed as a multiple of the respective spontaneous rates. We conclude, therefore, that the carcinogenic organotropy of streptozotocin correlates better with its tissue-specific mutagenicity than with its pattern of inducing DNA damage when the two in vivo genotoxicity assays mentioned above are used. A combined use of the microgel electrophoresis assay and the transgenic mouse mutation assay is proposed for investigations of tissue-specific genotoxicity.
Insights
Streptozotocin causes DNA damage in mouse liver and kidney. Kidney mutagenicity better predicts cancer risk than DNA damage, suggesting combined genotoxicity assays for accurate risk assessment.
Area of Science:
- Toxicology
- Genetics
- Carcinogenesis
Background:
- Streptozotocin induces DNA damage in mouse liver but not tumors.
- Kidney is a target organ for streptozotocin-induced tumors, but genotoxicity remains unmonitored.
- Understanding tissue-specific genotoxicity is crucial for elucidating carcinogenicity.
Purpose of the Study:
- To investigate the target organ specificity of streptozotocin-induced genotoxicity and tumorigenesis.
- To compare DNA damage and mutation induction in mouse liver and kidney.
- To correlate genotoxicity findings with carcinogenic organotropism.
Main Methods:
- Utilized the microgel electrophoresis assay to detect DNA damage.
- Employed the LacI transgenic mouse mutation assay to detect mutations.
- Assessed genotoxicity in liver and kidney of male C57BL/6 mice exposed to streptozotocin.
Main Results:
- Microgel electrophoresis detected genotoxicity at lower streptozotocin doses but lacked tissue specificity.
- Mutation analysis indicated higher sensitivity in the kidney when mutation frequencies were normalized to spontaneous rates.
- DNA damage occurred similarly in target and non-target tissues, unlike mutation induction.
Conclusions:
- Carcinogenic organotropism of streptozotocin correlates better with tissue-specific mutagenicity than DNA damage patterns.
- The microgel electrophoresis assay is sensitive but less specific for genotoxicity.
- Combined use of DNA damage and mutation assays is recommended for studying tissue-specific genotoxicity.