Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/27/2003
Publication Date: 9/1/2003
Citation: Davis, C.D., Uthus, E.O. 2003. Dietary folate and selenium affect dimethylhydrazine-induced aberrant crypt formation, global dna methylation and one-carbon metabolism in rats. Journal of Nutrition. 133:2907-2914.
Interpretive Summary: Selenium and folate, both components of foods, have been shown protective for certain forms of cancer. Animals fed diets low in folate or low in selenium are more prone to cancer. On the other hand, selenium is anticarcinogenic when fed or supplemented at more than the recommended intake. No study before this one has looked at how dietary selenium and folate work with or against each other in the process of preventing cancer. Thus, an animal experiment was conducted to ascertain the effect of dietary selenium and folate on various biomarkers of cancer. Rats were fed diets either deficient or adequate in folate and deficient or supplemented with selenium. To see if any of the dietary combinations affected cancer susceptibility, rats from each dietary group were injected with a carcinogen. Rats administered the carcinogen eventually develop colon cancer. However, before this occurs some of their colon cells become abnormal. These abnormal cells can be counted and the more abnormal cells found, the higher the likelihood that the rats will develop colon cancer. We found that rats fed the diet that was deficient in folate but supplemented with high selenium had the highest number of these abnormal cells. Conversely, a selenium-deficient diet seemed protective in folate-deficient animals. These results show that when studying folate, selenium status should be monitored and, vice versa, when studying selenium, folate status should be monitored. Also, understanding this interaction between selenium and folate may help determine the mechanism of cancer protection afforded by folate and high dietary or supplemental selenium.
Technical Abstract: Several observations suggest a role for DNA methylation in cancer pathogenesis. Although both selenium and folate deficiency have been shown to cause global DNA hypomethylation and increased cancer susceptibility, the nutrients have different effects on one-carbon metabolism. Thus, the purpose of this study was to investigate the interactive effects of dietary selenium and folate. Weanling, Fischer-344 rats (n=23/diet) were fed diets containing 0 or 2.0 mg selenium (as selenite)/kg and 0 or 2.0 mg folate/kg in a 2 x 2 factorial design. After 3 and 4 wk of a 12 wk experiment, 19 rats/diet were injected with dimethylhydrazine (DMH, 25 mg/kg i/p.) and 4 rats/diet were administered saline. Selenium deficiency decreased (p<0.05) colonic DNA methylation and the activities of liver DNA methyltransferase and betaine homocysteine methyltransferase and increased plasma glutathione concentrations. Folate deficiency significantly (p<0.05) increased the number of aberrant crypts per aberrant crypt foci, the concentration of colonic S-adenosylhomocysteine and the activity of liver cystathionine synthase. Selenium and folate had significant (p<0.0001) interactive effects on one-carbon metabolism and cancer susceptibility such that the number of aberrant crypts and the concentrations of plasma folate and liver S-adenosylmethionine and the activity of liver methionine synthase were the lowest when rats were fed deficient folate and supplemental selenium. These results suggest that selenium deprivation ameliorates some of the effects of folate deficiency, probably by shunting the buildup of homocysteine (as a result of folate deficiency) to glutathione.