ASSOCIATION OF ARSENIC-INDUCED MALIGNANT TRANSFORMATION WITH DNA HYPOMETHYLATION AND ABERRANT GENE-EXPRESSION

Inorganic arsenic, a human carcinogen, is enzymatically methylated for detoxication, consuming s-adenosyl-methionine (SAM) in the process, T he fact that DNA methyltransferases (MeTases) require this same methyl donor suggests a role for methylation in arsenic carcinogenesis Here we test the hypothesis that arsenic-induced initiation results from DN A hypomethylation caused by continuous methyl depletion, The hypothesi s was tested by first inducing transformation in a rat liver epithelia l cell line by chronic exposure to low levels of arsenic, as confirmed by the development of highly aggressive, malignant tumors after inocu lation of cells into Nude mice, Global DNA hypomethylation occurred co ncurrently with malignant transformation and in the presence of depres sed levels of S-adenosyl-methionine Arsenic-induced DNA hypomethylatio n was a function of dose and exposure duration, and remained constant even after withdrawal of arsenic, Hyperexpressibility of the MT gene, a gene for which expression is clearly controlled by DNA methylation, was also detected in transformed cells, Acute arsenic or arsenic at no ntransforming levels did not induce global hypomethylation of DNA, Whe reas transcription of DNA MeTase was elevated, the MeTase enzymatic ac tivity was reduced with arsenic transformation. Taken together, these results indicate arsenic can act as a carcinogen by inducing DNA hypom ethylation, which in turn facilitates aberrant gene expression, and th ey constitute a tenable theory of mechanism in arsenic carcinogenesis.