Hypomethylation of DNA: A nongenotoxic mechanism involved in tumor promotion

There is an abundant amount of information on the mechanisms of action of genotoxic chemicals that act as carcinogens and the role that mutations play in carcinogenesis. However, carcinogenesis is more than mutagenesis and many carcinogens are not mutagens. Thus, there is a need to consider nongenotoxic mechanisms that may be involved in carcinogenesis. In this paper, we review our working hypothesis that hypomethylation of DNA is an epigenetic, nongenotoxic mechanism that plays a role in tumor promotion by facilitating aberrant gene expression. The utility of employing experimental models that focus on relevant comparisons between sensitive and resistant strains of mice is emphasized. Additionally, aspects of DNA methylation in rodents and humans are compared and contrasted. We discuss hypomethylation of DNA as a secondary mechanism, that is expected to be threshold-exhibiting, and conclude by describing how this information may facilitate a rational approach towards risk assessment when dealing with nongenotoxic compounds that are carcinogenic in a bioassay.