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United States Department of Agriculture

Agricultural Research Service

Title: Dietary Selenium and Azadeoxycytidine Treatment Affect Dimethylhydrazine Induced Aberrant Crypt Formation in Rat Colon and DNA Methylation in Ht-29 Cells

Authors
item Davis, Cindy
item Uthus, Eric

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 6, 2001
Publication Date: February 1, 2002
Citation: Davis, C.D., Uthus, E.O. 2002. Dietary selenium and azadeoxycytidine treatment affect dimethylhydrazine-induced aberrant crypt formation in rat colon and DNA methylation in HT-29 cells. Journal of Nutrition. 132:292-297.

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. Several observations implicate a role for altered methylation of DNA, the molecule that forms genes, in cancer pathogenesis: the total amount of DNA that is methylated is generally lower and the activity of the enzyme, DNA methyltransferase, that methylates DNA is usually higher in tumor cells than in normal cells. Studies were conducted to determine whether a DNA methyltransferase inhibitor would alter the effect of dietary selenium on the formation of aberrant crypts, a preneoplastic lesion for colon cancer. Animals fed a selenium-deficient diet had a significantly higher number of aberrant crypts than animals fed adequate dietary selenium; however, when animals were injected with a DNA methyltransferase inhibitor, there was a significant reduction in aberrant crypt formation and dietary selenium did not affect aberrant crypt formation. These results suggest that decreased DNA methyltransferase activity may protect selenium deficient animals against colon cancer susceptibility.

Technical Abstract: Several observations implicate a role for altered DNA methylation in cancer pathogenesis. The global level of DNA methylation is generally lower; however, DNA methyltrasferase activity is usually higher in tumor cells than in normal cells. This study investigated whether the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (aza-dC) would alter the effect of dietary selenium (Se) on the formation of aberrant crypts. Sixty weanling rats were fed three concentrations of Se (deficient, 0.1 and 2.0 mg/kg diet) in a Torula yeast based diet. Half of the animals were injected weekly with aza-dC (1 ug/g, sc) and half were injected with the vehicle control. After 3.5 weeks on the experimental diets, the animals were given 2 injections of dimethylhydrazine, 25 mg/kg i.p.. Animals fed the Se deficient diet and injected with PBS had a significantly (p<0.006) higher number of aberrant crypts than animals fed 0.1 or 2.0 mg Se/kg diet In contrast, when animals were injected with aza-dC, there was a significant (p<0.0001) reduction in aberrant crypt formation and dietary Se did not affect aberrant crypt formation HT-29 cells cultured in the absence of Se had significantly hypomethylated DNA but significantly more Dnmt1 protein expression than cells cultured in the presence of 1 or 2 umol/L Se. Results suggest that decreased DNA methyltransferase activity may protect Se deficient animals against carcinogen-induced aberrant crypt formation.

Last Modified: 9/10/2014
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