Programming of hepatic gene expression by maternal folic acid and vitamin B12 imbalance

Folate is a B-vitamin required for cell growth and division, and its metabolism is linked to vitamin B12 (B12). Food fortification with folic acid (FA) has improved folate status but approximately 5% of Canadian adults, including pregnant women, are B12 deficient. This is concerning because an association between gestational exposure to high maternal folate and low B12 status and greater adiposity and insulin resistance in children has been reported. My thesis examined the effect of developmental exposure to maternal FA/B12 imbalance on programming of liver gene expression in adult offspring using an animal model. Female C57BL/6 mice were fed a high FA/adequate B12 (HFA+B12), high FA/no B12 (HFA-B12), or control diet 6 weeks prior to mating and through pregnancy and lactation. At weaning, offspring mice from each maternal diet group were randomly assigned to receive the control diet or a Western diet (45% fat, 35% carbohydrate) for 20 weeks (n=6 male mice/group) or for 40 weeks (n=6 female mice/group). Serum folate and B12 concentrations were quantified by microbiological assays. Relative mRNA expression of key enzymes in methyl metabolism in liver from adult offspring was quantified by real-time PCR. Male offspring mice from dams fed the HFA-B12 diet had lower Cbs and Mthfr mRNA expression and this was unaffected by post weaning diet. Male offspring mice fed the Western diet had higher Mtr mRNA expression compared to control-fed offspring mice, regardless of maternal diet. Female offspring from dams fed the HFA-B12 diet had lower Mtr mRNA expression and this was not affected by post weaning diet. Moreover, female offspring from dams fed the HFA-B12 diet had higher Mthfr mRNA expression when they were fed the Western diet. No effect of maternal and post weaning diets was observed for serum folate and B12 concentrations. In summary, developmental exposure to maternal FA/B12 imbalance was found to program expression of genes involved in folate and methionine metabolism in the liver of adult offspring mice. The functional consequences of this effect requires further investigation in order to consider B12 screening of pregnant women and to inform the debate on whether B12 fortification should be considered.Land and Food Systems, Faculty ofGraduat