Cadmium is a human
carcinogen that likely acts via epigenetic mechanisms. Since DNA methylation alterations represent an important epigenetic event linked to
cancer, the effect of
cadmium on
DNA methyltransferase (MeTase) activity was examined using in vitro (TRL1215 rat liver cells) and ex vivo (
M.SssI DNA MeTase) systems.
Cadmium effectively inhibited
DNA MeTases in a manner that was noncompetitive with respect to substrate (
DNA), indicating an interaction with the
DNA binding domain rather than the active site. Based on these results, the effects of prolonged
cadmium exposure on
DNA MeTase and genomic DNA methylation in TRL1215 cells were studied. After 1 week of exposure to 0-2.5 microM
cadmium,
DNA MeTase activity was reduced (up to 40%) in a concentration-dependent fashion, while genomic DNA methylation showed slight but significant reductions at the two highest concentrations. After 10 weeks of exposure, the cells exhibited indications of transformation, including hyperproliferation, increased invasiveness, and decreased serum dependence. Unexpectedly, these
cadmium-transformed cells exhibited significant increases in DNA methylation and
DNA MeTase activity. These results indicate that, while
cadmium is an effective inhibitor of
DNA MeTase and initially induces
DNA hypomethylation, prolonged exposure results in
DNA hypermethylation and enhanced
DNA MeTase activity.