Model for the epigenetic mechanism of action of nongenotoxic carcinogens.
On the basis of studies with carcinogenic nickel compounds, we propose a new model of how epigenetic carcinogens might act. This model is based on the fact that nickel compounds induce an increase in chromatin condensation, causing neighboring genes that are actively expressed in euchromatin to be condensed into heterochromatin. Such redistribution in condensation of chromatin would probably only be transient were it not for the DNA cytosine methyl transferase enzyme, which through de novo methylation can cause genes to be inherited in an active state. Actively expressed genes have less cytosine methylation in their promoter whereas hypermethylation of cytosine in promoters is characteristic of inactive genes. Therefore, nickel, through induction of an enhanced condensation state of chromatin that results in the incorporation of critical genes such as the senescence and tumor suppressor genes into heterochromatin (ie, thread on a spool) and the subsequent methylation of this DNA, silences the genetic activity that might be essential for maintenance of a normal cell. This model is consistent with the literature on cytosine methylation and is also consistent with studies of nickel carcinogenesis showing that it increases cytosine methylation. It is also consistent with nickel carcinogenesis being synergistic with many other mutagenic carcinogens (ie, x rays, benzopyrene, or ultraviolet light), which has always suggested that it has a unique component that is not part of the mechanism of these mutagenic carcinogens.
Costa
M
M
Nelson Institute of Environmental Medicine, New York, NY.
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002843:Chromatin / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D008745:Methylation; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000235:genetics*; D009532:Nickel / Q000633:toxicity*; D010587:Phagocytosis / Q000187:drug effects
D002273:Carcinogens; D002843:Chromatin; D009532:Nickel; D004247:DNA