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IMBALANCE OF DNA METHYLATION, BOTH HYPERMETHYLATION AND HYPOMETHYLATION, OCCUR AFTER EXPOSURE OF HUMAN CELLS TO NANOMOLAR CONCENTRATIONS OF ARSENITE IN CULTURE.
Mass, M J. AND C. X. Zhong. IMBALANCE OF DNA METHYLATION, BOTH HYPERMETHYLATION AND HYPOMETHYLATION, OCCUR AFTER EXPOSURE OF HUMAN CELLS TO NANOMOLAR CONCENTRATIONS OF ARSENITE IN CULTURE. Presented at 4th Int'l Conf. on Arsenic & Health Effects, San Diego, CA, June 18-22, 2000.
Imbalance of DNA methylation, BOTH hypermethylation and hypomethylation, occur after exposure of human cells to nanomolar concentrations of arsenite in culture.
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 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. 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, support the existence of a state of general DNA methylation imbalance induced by arsenicals that could conceivably disrupt appropriate gene expression in arsenic exposed cells. These alterations occur at very low concentration (in the nanomolar range, comparable to many US drinking water sources) and likely do not involve methyl pool alterations. Arsenicals would appear to be affecting some process other than methyl pool sizes that regulate DNA methylation at very low, relevant arsenic concentrations.
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Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL CARCINOGENESIS DIVISION
BIOCHEMISTRY AND PATHOBIOLOGY BRANCH