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 muta tions play in carcinogenesis. However, carcinogenesis is more than mut agenesis and many carcinogens are not mutagens. Thus, there is a need to consider nongenotoxic mechanisms that may be involved in carcinogen esis. In this paper, we review our working hypothesis that hypomethyla tion of DNA is an epigenetic, nongenotoxic mechanism that plays a role in tumor promotion by facilitating aberrant gene expression. The util ity of employing experimental models that focus on relevant comparison s between sensitive and resistant strains of mice is emphasized. Addit ionally, aspects of DNA methylation in rodents and humans are compared and contrasted. We discuss hypomethylation of DNA as a secondary mech anism, that is expected to be threshold-exhibiting, and conclude by de scribing how this information may facilitate a rational approach towar ds risk assessment when dealing with nongenotoxic compounds that are c arcinogenic in a bioassay.