Acrylonitrile-induced morphological transformation in Syrian hamster embryo cells

Acrylonitrile (ACN) is a monomer used in the synthesis of of ACN have been suggested as mechanisms for the observed rubber, fibers and plastics. Previous studies demonstrated acute toxic effects of ACN (6,17–20). The mechanism(s) of that ACN induces brain neoplasms (predominately astrocy- ACN-induced carcinogenicity remains unresolved. However, tomas) in rats following chronic treatment. While the previous studies by our group (21,22) and others (23) have mechanisms of ACN-induced glial cell carcinogenicity have shown that ACN exposure is associated with the induction of not been completely elucidated, investigations by our group oxidative stress, indicated by oxidative damage to DNA, and and others have suggested a role for the induction of a decrease in antioxidant enzyme activity, selectively in rat oxidative stress and the resultant oxidative damage in this brain following in vivo exposure and in rat glial cells in vitro. process. In vitro cell transformation models are useful Oxidative stress results when the cellular concentration of for detecting and studying the mechanisms of chemical reactive oxygen species (ROS) exceeds the antioxidant (both carcinogenesis. Cell transformation by chemical carcino- enzymatic and non-enzymatic) capability of the cell (24). ROS gens in Syrian hamster embryo (SHE) cells exhibits a are produced continuously as a result of both endogenous and multistage process similar to that observed in vivo, for both exogenous functions. Damage resulting from excess oxygen non-genotoxic and genotoxic carcinogens. In the present radicals has been implicated in the pathogenesis of aging and study, the ability of ACN to induce morphological trans- several associated chronic diseases, including cardiovascular formation and oxidative damage was examined in SHE and neurodegenerative diseases (25,26), rheumatoid arthritis cells. ACN induced an increase in morphological trans- (27) and cancer (28–30). With respect to carcinogenesis, ROS formation at doses of 50, 62.5 and 75 µg/ml (maximum formation and the resulting oxidative damage have been sub-toxic dose tested) following 7 days of continuous treat- associated with several steps in the multistage cancer process ment. SHE cells exposed to ACN for 24 h failed to increase (28,29). Once generated, ROS can interact with and modify morphological transformation. Morphological transforma- both structural and functional cellular macromolecules. The tion by ACN was inhibited by co-treatment with the result ultimately is modification of cell function and/or cell antioxidants α-tocopherol and (‐)-epigallocathechin-3 gall- death through oxidative damage to lipids (lipid peroxidation), ate (EGCG) for 7 days. Treatment of SHE cells with 75 DNA and/or proteins. Formation of DNA hydroxyl adducts µg/ml ACN produced a significant increase in 8-hydroxy- can interfere with normal cell growth by causing genetic 2-deoxyguanosine that was also inhibited by co-treatment mutations and/or altering normal gene transcription. Oxidative with α-tocopherol or EGCG. These results support the DNA damage can lead to the formation of mutations through proposal that oxidative stress and the resulting oxidative nucleotide modification, alterations in hydrogen bonds and damage is involved in ACN-induced carcinogenicity. conformational changes in the DNA templates (31). Of the oxidative DNA modifications, 8-hydroxy-2-deoxyguanosine (OH8dG) is the most abundant oxidative DNA damage formed