Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 31, 2000
Publication Date: December 1, 2000
Citation: Davis, C.D., Uthus, E.O., Finley, J.W. 2000. Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 cells in in vivo rat liver and colon. Journal of Nutrition. 130:2903-2909. Interpretive Summary: Selenium is an essential trace element for human health and has received considerable attention for its role as a nutrient which protects against cancer. It is believed that selenium with a methyl molecule attached to it may be directly involved in the protective effects of selenium against cancer. Selenium is methylated by an enzyme which uses S-adenosyl- methionine as the source of the methyl groups. Arsenic and an enzyme involved in the methylation of DNA, the molecule that forms genes, also use S-adenosyl-methionine as a source of methyl groups. Decreases in the amount of methylation of DNA are associated with increased cancer susceptibility. The purpose of the current studies was to determine whether changes in the amount of selenium would affect the methylation of DNA and whether this effect is modified by arsenic. This was investigated in rats and in a human colon cancer cell line. DNA isolated from animals and cells exposed to deficient selenium had significantly lower DNA methylation than DNA isolated from animals and cells exposed to adequate selenium. These results suggest that alterations in DNA methylation may be a potential mechanism whereby deficient dietary selenium increases cancer susceptibility.
Technical Abstract: Selenium is an essential trace element for human health and has received considerable attention for its possible role as an anticarcinogenic agent. It has been hypothesized that the production of partially methylated forms of selenium may be directly involved in the anticarcinogenic action of selenium. Selenium is enzymatically methylated to mono-, di- and trimethylated metabolites that use S-adenosylmethionine (SAM) as the methyl donor. Arsenic and cytosine DNA methyltransferase compete for methyl donation from SAM. The purpose of these studies was to determine whether changes in the amount and the chemical form of selenium would affect DNA methylation and whether this effect would be modified by arsenic. Caco-2 cells were exposed to 0, 1 or 2 uM selenite and 0, 1 or 2 uM arsenite. DNA isolated from Caco-2 cells not treated with selenite was significantly (p<0.0001) hypomethylated compared to that from cells treated with 1 or 2 uM selenite. In addition, methylation of the p53 promoter region of Caco-2 cells decreased when cells were cultured in the absence of selenite and in the absence of arsenite. Similar to the results with Caco-2 cells, rats fed selenium-deficient diets had significantly (p<0.0001) hypomethylated DNA compared to rats fed 0.1 or 2.0 ug selenium/g diets as either selenite or selenomethionine. However, supplemental dietary arsenic (5 ug/g diet) tended (p=0.08) to decrease DNA methylation. There were no interactive effects of dietary selenium and arsenic on DNA methylation in animals. Thus, alterations in DNA methylation may be a potential mechanism whereby deficient dietary selenium increases tumorigenesis.