title: Vitamin B-12 deficiency induces anomalies of base substitution and methylation in the DNA of rat colonic epithelium.
abstract: Derangements of one-carbon metabolism can directly affect the integrity of the genome by producing inappropriate uracil insertion into DNA and by altering patterns of DNA methylation. Vitamin B-12, a one-carbon nutrient, serves as a cofactor in the synthesis of precursors of biological methylation and in nucleotide synthesis. We therefore examined whether vitamin B-12 deficiency can induce these molecular anomalies in the colonic mucosa of rats. Weanling male Sprague-Dawley rats (n = 30) were divided into 2 groups and fed either a vitamin B-12-deficient diet or a similar diet containing adequate amounts of the vitamin. Rats from each group were killed at 6 and 10 wk. Uracil misincorporation into DNA was measured by GC/MS and genomic DNA methylation was measured by LC/MS. Plasma vitamin B-12 concentrations in deficient rats were below detectable limits at 6 and 10 wk; in control rats, concentrations were 0.46 +/- 0.07 and 0.42 +/- 0.10 nmol/L at those times. Although the colon total folate concentration did not differ between the groups, the proportion that was methylfolate was marginally greater in the deficient rats at 10 wk (P = 0.05) compared with control, consistent with the "methylfolate trap" that develops during vitamin B-12 deficiency. After 10 wk, the colonic DNA of the deficient rats displayed a 35% decrease in genomic methylation and a 105% increase in uracil incorporation (P < 0.05). This vitamin B-12-deficient diet, which was of insufficient severity to cause anemia or illness, created aberrations in both base substitution and methylation of colonic DNA, which might increase susceptibility to carcinogenesis.
authors.affiliation: Vitamins and Carcinogenesis Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston MA 02111, USA. sang.choi@tufts.edu
authors.forename: Sang-Woon
authors.initials: SW
authors.lastname: Choi
authors.forename: Simonetta
authors.initials: S
authors.lastname: Friso
authors.forename: Haifa
authors.initials: H
authors.lastname: Ghandour
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Bagley
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.forename: Joel B
authors.initials: JB
authors.lastname: Mason
mesh_terms: D000818:Animals; D001835:Body Weight; D003106:Colon / Q000737:chemistry / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics; D004247:DNA / Q000032:analysis / Q000737:chemistry; D019175:DNA Methylation; D004848:Epithelium / Q000378:metabolism; D005492:Folic Acid / Q000032:analysis; D008401:Gas Chromatography-Mass Spectrometry; D007413:Intestinal Mucosa / Q000737:chemistry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014498:Uracil / Q000032:analysis / Q000378:metabolism; D014805:Vitamin B 12 / Q000097:blood; D014806:Vitamin B 12 Deficiency / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014498:Uracil; D004247:DNA; D005492:Folic Acid; D014805:Vitamin B 12