[DNA methylation--alternative mechanism of chemical carcinogenesis]

Abstract

It is increasingly accepted that the initiation of chemical carcinogenesis should be considered as a transformation process of a normal cell caused by genetic changes, i.e. mutational DNA damage and/or epigenetic changes, which render normal gene expression impossible with the preservation of the DNA sequence intact. Epigenetic DNA methylation changes have been among the most extensively investigated processes in the recent years. Many types of cancer cells have been found to exhibit an increased or reduced level of CpG sequence methylation in promoter regions of genes, especially the genes whose protein products take part in the control of cell cycle regulation. In view of the fact that DNA methylation is thought to play a role in gene expression, its abnormal level in the genes that encode proteins participating in the control of the cell cycle and apoptosis regulation may disturb cell homeostasis resulting in pathologies that may, in turn, lead to neoplastic transformation. Although changes in the mechanisms of transcriptional activity caused by methylation of cytosine in CpG sequences have not been completely elucidated, it has been determined that this relationship is associated with a decreased level of histone acetylation, which induced a more densely-packaged chromatin structures in the methylated regions of chromosomal DNA. A large proportion of chemical carcinogens consists of chemicals whose carcinogenic activity is not related to direct damage of the genetic material. The changes in DNA methylation are being considered as one mechanism of action for non-genotoxic carcinogens (NGCs). The significance of non-genotoxic agents in the development of the carcinogenesis process indicate that their mechanisms of the action should be investigated in terms of health hazards they pose to humans exposed to this type of environmental pollutants.