Abstract
In the current study, we assessed the global DNA methylation changes in human lymphoblastoid (TK6) cells in vitro in response to 5 direct and 10 indirect-acting genotoxic agents. TK6 cells were exposed to the selected agents for 24 h in the presence and/or absence of S9 metabolic mix. Liquid chromatography-mass spectrometry was used for quantitative profiling of 5-methyl-2′-deoxycytidine. The effect of exposure on 5-methyl-2′-deoxycytidine between control and exposed cultures was assessed by applying the marginal model with correlated residuals on % global DNA methylation data. We reported the induction of global DNA hypomethylation in TK6 cells in response to S9 metabolic mix, under the current experimental settings. Benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene induced global DNA hypomethylation in TK6 cells. Furthermore, we showed that dose did not have an effect on global DNA methylation in TK6 cells. In conclusion we report changes in global DNA methylation as an early event in response to agents traditionally considered as genotoxic.
Highlights
Environmental carcinogens are a known risk factor of human cancer [1]
Global DNA methylation in control and exposed cultures per chemical dose without and with S9 metabolic mix is given in Table 1 and 2 respectively
Assuming global DNA methylation to be normally distributed, and Chemicals exposed to TK6 cells in vitro
Summary
Environmental carcinogens are a known risk factor of human cancer [1]. In its classical model, carcinogenesis initiates and proceeds through changes in the genome (i.e., genetic effects) [2]. Initiation per se in a classical carcinogenesis model is not sufficient for tumor development, which results from broader alterations in the cellular homeostasis, mainly because of the inability of initiated cells to properly control and regulate the gene expression [8]. Evidence suggest that non-genotoxic alterations in cells, e.g., alterations in cellular epigenome, could result in the emergence of epigenetically reprogrammed cells [11]. These epigenetically reprogrammed cells show an epigenetic profile similar to that frequently observed in cancer cells, such as altered histone modification patterns, hypomethylation of DNA repetitive elements and proto-oncogenes and hypermethylation of tumor suppressor genes. Epigenetic alterations rather than specific genetic mutations per se are reported for the clonal expansion of altered hepatic preneoplastic foci and tumor development [13]
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