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Both Hypomethylation and Hypermethylation of Dna Associated With Arsenite Exposure in Cultures of Human Cells Identified by Methylation-Sensitive Arbitrarily-Primed Pcr

Wang, L.; Zhong, C.; Mass, M.

Differentially Methylated DNA Sequences Associated with Exposure to Arsenite in Cultures of Human Cells Identified by Methylation-Sensitive-Primed PCR Arsenic, a known human carcinogen, is converted to methylated derivatives by a methyltransferase (Mtase) and its biotransformation consumes S-adenosylmethionine (SAM) as the methyl donor. We and others have hypothesized that a mechanism of arsenic carcinogenesis could involve alteration of DNA methylation since this process utilizes a methyltransferase and SAM. In order to gain more insight into the characteristics of DNA methylation changes induced by arsenic, we analyzed differentially methylated regions of genomic DNA from human lung A549 cells and three human kidney cell lines after arsenite treatment using methylation-sensitive arbitrarily-primed (AP) PCR. A total of 8 differentially methylated DNA sequences were identified from these cell lines. Six of the fragments were hypermethylated and 2 were hypomethylated relative to untreated controls. DNA sequence analysis revealed that 2 DNA fragments contained repeat sequences of mammalian apparent LTR retrotransposons (MaLRs), and 5 contained promoter-like sequences. The mRNA level and enzymatic activity of DNA Mtase were increased after arsenite exposure in A549 cells. Our results are consistent with a potential role for both hypermethylation and hypomethylation of DNA that coexist even though only increased DNA Mtase activity was demonstrated during exposure to arsenite. The results, in total, would support the existence of a state of methylation imbalance that could conceivably disrupt appropriate gene expression in arsenic exposed cells. This abstract does not necessarily reflect the US EPA policy.

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