Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation,p16promoter methylation and the expression ofp16in the mouse colon

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Abstract
Older age, dietary folate and chronic alcohol consumption are important risk factors for the development of colon cancer. The present study examined the effects of ageing, folate and alcohol on genomic andp16-specific DNA methylation, andp16expression in the murine colon. Old (aged 18 months;n70) and young (aged 4 months;n70) male C57BL/6 mice were pair-fed either a Lieber-DeCarli liquid diet with alcohol (18 % of energy), a Lieber-DeCarli diet with alcohol (18 %) and reduced folate (0·25 mg folate/l) or an isoenergetic control diet (0·5 mg folate/l) for 5 or 10 weeks. Genomic DNA methylation,p16promoter methylation andp16gene expression were analysed by liquid chromatography–MS, methylation-specific PCR and real-time RT-PCR, respectively. Genomic DNA methylation was lower in the colon of old mice compared with young mice (P < 0·02) at 10 weeks. Alcohol consumption did not alter genomic DNA methylation in the old mouse colon, whereas it tended to decrease genomic DNA methylation in young mice (P = 0·08).p16Promoter methylation and expression were higher in the old mouse colon compared with the corresponding young groups. There was a positive correlation betweenp16promoter methylation andp16expression in the old mouse colon (P < 0·02). In young mice the combination of alcohol and reduced dietary folate led to significantly decreasedp16expression compared with the control group (P < 0·02). In conclusion, ageing and chronic alcohol consumption alter genomic DNA methylation,p16promoter methylation andp16gene expression in the mouse colon, and dietary folate availability can further modify the relationship with alcohol in the young mouse.