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Differential DNA adduct formation and disappearance in three mouse tissues after treatment with the mycotoxin
A Pfohl-Leszkowicz1, Y Grosse, A Kane
1Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Strasbourg, France.
Abstract:
Ochratoxin A (OTA) is a mycotoxin which has been implicated in Balkan endemic nephropathy, a disease characterized by a high incidence of urinary tract tumors. It induces DNA single-strand breaks and has been shown to be carcinogenic in two rodent species. For a better understanding of the OTA genotoxic effect, OTA-DNA adduct formation and disappearance has been measured using the 32P-post-labelling method after oral administration of 2.5 mg/kg of OTA to mice. In kidney, liver and spleen, several modified nucleotides were clearly detected in DNA, 24 h after administration of OTA, but their level varied significantly in a tissue and time dependent manner over a 16-day period. Total DNA adducts reached a maximum at 48 h when 103, 42 and 2.2 adducts per 10(9) nucleotides were found respectively in kidney, liver and spleen, indicating that kidney is the main target of the genotoxicity and likely carcinogenicity of OTA. The major adduct differed between kidney and liver. All adducts disappeared in liver and spleen 5 days after compound administration, whereas some adducts persisted for at least 16 days in the kidney. Some adducts were organ specific. The finding that the adducts are not quantitatively and qualitatively the same in the three organs examined is likely due to differences of metabolism in these organs, leading to different ultimate carcinogens and may also result from differences in the efficiency of repair processes.
Insights
Ochratoxin A (OTA) causes DNA damage, with the kidney being the primary target organ. OTA-DNA adducts persist longer in kidneys than in the liver or spleen, suggesting a higher risk for kidney toxicity.
Area of Science:
- Toxicology
- Molecular Biology
- Carcinogenesis
Background:
- Ochratoxin A (OTA) is a mycotoxin linked to Balkan endemic nephropathy and urinary tract tumors.
- OTA is a known carcinogen in rodents, inducing DNA single-strand breaks.
Purpose of the Study:
- To investigate the genotoxic effects of OTA by measuring OTA-DNA adduct formation and disappearance in mice.
- To identify target organs and understand the time- and tissue-dependent kinetics of OTA genotoxicity.
Main Methods:
- Oral administration of 2.5 mg/kg Ochratoxin A to mice.
- Quantification of OTA-DNA adducts using the 32P-post-labelling method.
- Analysis of DNA adducts in kidney, liver, and spleen over a 16-day period.
Main Results:
- Multiple OTA-DNA adducts were detected in kidney, liver, and spleen 24 hours post-administration.
- Kidney DNA adduct levels peaked at 48 hours (103 adducts/10^9 nucleotides), significantly higher than liver (42) and spleen (2.2).
- Adducts persisted for at least 16 days in the kidney, while disappearing within 5 days in the liver and spleen, indicating organ-specific persistence and repair differences.
Conclusions:
- The kidney is the primary target organ for Ochratoxin A genotoxicity and potential carcinogenicity.
- Differences in adduct levels and persistence suggest organ-specific metabolism and DNA repair mechanisms for OTA.
- Persistent DNA adducts in the kidney highlight a potential long-term risk associated with OTA exposure.