Dietary l-methionine supplementation mitigates gamma-radiation induced global DNA hypomethylation: Enhanced metabolic flux towards S-adenosyl-l-methionine (SAM) biosynthesis increases genomic methylation potential

Abstract

The objective of this study was to examine the effect of 60Co-gamma (γ) radiation on modulation of genomic DNA methylation, if any, of mice maintained (6weeks) on normal control diet (NCD) and l-methionine supplemented diet (MSD). To elucidate the possible underlying mechanism(s), we exposed the animals to γ-radiation (2, 3 and 4Gy) and investigated the profile of downstream metabolites and enzymes involved in S-adenosyl-l-methionine (SAM) generation. Liver samples were also subjected to histopathological examinations. Compared to NCD fed and irradiated animals, hepatic folate, choline and l-methionine levels decreased moderately, while hepatic SAM levels increased in MSD fed and irradiated animals. Under these conditions, a marked modulation of methionine adenosyltransferase (MAT) and l-methionine synthase (MSase) activities was observed. Concomitant with increase in liver SAM pool, increased DNA methyltransferase (dnmt) activity in MSD fed mice indicated enhanced metabolic flux towards DNA methylation. Further results showed that genomic DNA methylation and 5-methyl-2′-deoxy cytidine residues were maintained at normal levels in MSD fed and irradiated mice compared to NCD fed and irradiated animals. In conclusion, our results suggest that increasing supply of preformed methyl groups, via dietary l-methionine supplementation might significantly increase methylation potential of radiation stress compromised DNA methylation cycle.