Altered dietary ratio of folic acid and vitamin B-12 during pregnancy influences the expression of imprinted H19/IGF2 locus in C57BL/6 mice

Maternal folic acid and vitamin B-12 (B-12) status during pregnancy influence fetal growth. This study elucidated the effect of altered dietary ratio of folic acid and B-12 on the regulation of H19/IGF2 locus in C57BL/6 mice. Female mice were fed diets with nine combinations of folic acid and B-12 for 4 weeks. They were mated and the offspring born (F1) were continued on the same diet for 6 weeks post-weaning and were allowed to mate. The placenta and fetal (F2) tissues were collected at day 20 of gestation. H19 overexpression observed under dietary deficiency of folate combined with normal B-12 (B-12 normal folic acid-deficient, BNFD) was associated with an increased expression of microRNA-675 (miR-675) in maternal and fetal tissues. Insulin-like growth factor 2 (IGF2) expression was decreased under folic acid-deficient conditions combined with normal, deficient or over-supplemented state of B-12 (BNFD, BDFD and BOFD) in fetal tissues along with B-12 deficiency combined with normal folic acid (BDFN) in the placenta. The altered expression of imprinted genes under folic acid-deficient conditions was related to decreased serum levels of folate and body weight (F1). Hypermethylation observed at the H19 differentially methylated region (DMR) (in BNFD) might be responsible for the decreased expression of IGF2 in female fetal tissues. IGF2 DMR2 was found to be hypomethylated and associated with low serum B-12 levels with B-12 deficiency in fetal tissues. Results suggest that the altered dietary ratio of folic acid and B-12 affects the in utero development of the fetus in association with altered epigenetic regulation of H19/IGF2 locus.