DNA Strand Break Accumulation, Thymidylate Synthesis and NAD Levels in Lymphocytes from Methyl Donor-Deficient Rats

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Abstract
Although tumor development with methyl donor-deficient diets has been well established, the biochemical and molecular mechanisms which predispose to tumor development are not yet understood. In the present study, DNA damage and nucleotide metabolism associated with DNA synthesis and repair were evaluated in splenic lymphocytes from rats fed a basal diet low in methionine and lacking in choline and folate or a supplemented control diet for a period of 3 wk. The accumulation of DNA strand breaks, as assessed by DNA unwinding in alkali, was found to be significantly elevated in lymphocytes from rats fed the methyl donor-deficient diet and was associated with an increase in mitogen-stimulated incorporation of [3H]-thymidine via the salvage pathway for thymidylate synthesis. In addition, a significant decrease in the DNA repair-associated pyridine nucleotide, NAD, was observed in lymphocytes from the deficient group and was associated with a decrease in total spleen cell numbers. These results suggest that alterations in nucleotide metabolism and DNA damage are induced when methyl donor pools are stressed by dietary deficiency.