The role of pro- and antioxidant processes in DNA damage originating from combined effects of environmental factors and tumor growth

Muzalov I.I., Ganzha O.B., Mikhailenko V.

I. Muzalov, O. Ganzha, V. Mikhailenko

R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine

Introduction: Influence of environmental factors plays a crucial role in the formation and development of cancer. The peculiarity of combined action of adverse factors on the human organism is the ability of each factor to modify the overall pathogenic effect. Nitrogen oxides (NOx) and low doses of ionizing radiation (LDIR) are genotoxic factors. Their interaction can lead to increased levels of DNA damage, changes in cell response to stressors, alterations in microenvironment of cells in tissues, the development of nitrosative and oxidative stress, resulting in increase of carcinogenic risk. At present, genotoxic effect of combined influence of environmental factors on organism upon tumor growth is studied insufficiently. In this regard, investigation of the antioxidant system status and the development of genetic instability upon the tumor growth and combined action of exogenous NOx and LDIR is important. Aim: To investigate changes in DNA damage and dynamics of the activity of superoxide dismutase (SOD) and catalase (CAT) in the process of tumor growth in the conditions of the individual and combined effect of exogenous NO and LDIRMethods: The formation of DNA strand breaks was determined using horizontal gel electrophoresis of isolated rat’s peripheral blood lymphocytes (PBL). The object of study were PBL of rats exposed to NO inhalation (150 mg/m3 of air) for 30 days and LDIR (10-fold by 0.1 Gy) in the conditions of individual and combined treatment. Changes in CAT and SOD activity in rat peripheral blood were investigated in parallel. Guerin carcinoma (GC) was used as a tumor model. Study was approved by Ethical Committee permission of IEPOR NASU (Kyiv, Ukraine). Results: GC growth was accompanied by decrease of CAT activity in the blood of rats after 12 days of tumor growth. CAT activity increased both upon single LDIR and joint influence of NO+LDIR and reached its maximum upon combined action. The activity of SOD in blood increased in the conditions of the action of LDIR and NO+LDIR, and also upon the GC development. GC inoculation after treatment with NO+LDIR significantly increased the SOD activity on the 12 day followed by normalization on the 18 day of tumor growth. However, the increased activity of antioxidant enzymes was insufficient in the conditions of oxidative and nitrosative stress. Individual action of NO and LDIR resulted in DNA damage gradual increase during tumor growth. Maximal genotoxic effect was observed in the case of NO and LDIR combination (4-fold excess of the control value). Conclusions: Preliminary impact of NO and/or LDIR resulted in persistant additive genotoxic effect accompanied by the increase of genetic damage on background of GC growth after the direct action of these factors. Tumor development and combined effect of environmental factors of different nature were accompanied by complex interactions between the main enzymes of antioxidant protection — CAT and SOD. An imbalance of free radical processes under oxidative and nitrosative stresses lead to the development of genetic instability, which in turn is a factor of increased carcinogenic risk and implemented as accelerated tumor growth

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