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Vol. 20, Art. 21 (pp. 242-253)    |    2019       

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The study of mechanisms of genotoxic and cytotoxic action of low doses of nitrosodimethylamine in chronic administration

Tomilin N. V., Filko O. A., Gaikova O. N., Khrabrova A. V., Solovyeva N. E., Krasnov К. А., Utsal V. A.

Institute of Toxicology of Federal Medico-Biological Agency
St. -Petersburg, Russia

Brief summary

The objects of this study were leukocytes and hepatocytes of white rats. The purpose of this study is to explore the mechanisms of the genotoxic and cytotoxic effects of nitrosodimethylamine (NDMA) in doses of 0,01, 0,1 and 1 mg/kg for 7, 14 and 21 days. It is shown by Comet assay that the genotoxic effect of NDMA on leukocytes appears when administered at a dose of 1 mg/kg for 7, 14, and 21 days. The number of ?hedgehogs? did not change. An increase of nuclear DNA damage of hepatocytes was first obtained with the administration of NDMA at a dose of 1 mg/kg for 7 days. After 14 and 21 days, a dose-dependent increase of DNA damage was found after administration at doses of 0,1 and 1 mg/kg. The number of ?hedgehogs? increased dramatically (12 times) after 21 days of administration at a dose of 1 mg/kg. The oxidative effect on the nuclear DNA of leukocytes determined by Comet assay with formamidopyrimidine-DNA glycosylase (Fpg) was revealed after administration of NDMA after 14 and 21 days at a dose of 1 mg/kg. A dose-dependent increase of the oxidizing DNA damage in hepatocyte was obtained after 7 days of NDMA administration, but the difference was significant only after administration at a dose of 1 mg/kg. After 14 and 21 days of administration of NDMA at a dose of 1 mg/kg, the degree of oxidative DNA damage returned to the control value, while maintaining a tendency to increase in doses of 0,01 and 0,1 mg/kg. The decrease in oxidative damage to hepatocyte nuclear DNA after 14 and 21 days of administration at a dose of 1 mg/kg can probably be explained by the death of some hepatocytes with a high degree of DNA damage. This is confirmed by morphological studies that revealed the appearance of a single foci of necrosis after 14 days of administration of NDMA at a dose of 1 mg/kg, and a multiple foci of necrosis after 21 days.


Key words

genotoxicity, cytotoxicity, leukocytes, hepatocytes, Comet assay, formamidopyrimidine DNA glycosylase

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