Different dietary combinations of folic acid and vitamin B12 in parental diet results in epigenetic reprogramming of IGF2R and KCNQ1OT1 in placenta and fetal tissues in mice

Abstract

Genomic imprinting is important for mammalian development and its dysregulation can cause various developmental defects and diseases. The study evaluated the effects of different dietary combinations of folic acid and B12 on epigenetic regulation of IGF2R and KCNQ1OT1 ncRNA in C57BL/6 mice model. Female mice were fed diets with nine combinations of folic acid and B12 for 4 weeks. They were mated and off‐springs born (F1) were continued on the same diet for 6 weeks postweaning and were allowed to mate. The placenta and fetal (F2) tissues were collected at day 20 of gestation. Dietary deficiency of folate (BNFD and BOFD) and B12 (BDFN) with either state of other vitamin or combined deficiency of both vitamins (BDFD) in comparison to BNFN, were overall responsible for reduced expression of IGF2R in the placenta (F1) and the fetal liver (F2) whereas a combination of folate deficiency with different levels of B12 revealed sex‐specific differences in kidney and brain. The alterations in the expression of IGF2R caused by folate‐deficient conditions (BNFD and BOFD) and both deficient condition (BDFD) was found to be associated with an increase in suppressive histone modifications. Over‐supplementation of either folate or B12 or both vitamins in comparison to BNFN, led to increase in expression of IGF2R and KCNQ1OT1 in the placenta and fetal tissues. The increase in the expression of IGF2R caused by folate over‐supplementation (BNFO) was associated with decreased DNA methylation in fetal tissues. KCNQ1OT1 noncoding RNA (ncRNA), however, showed upregulation under deficient conditions of folate and B12 only in female fetal tissues which correlated well with hypomethylation observed under these conditions. An epigenetic reprograming of IGF2R and KCNQ1OT1 ncRNA in the offspring was evident upon different dietary combinations of folic acid and B12 in the mice.

The protective effect of folic acid against valproate-induced neurological and skeletal congenital anomalies in mice

“…In the current study, FA was effective in preventing the intrauterine growth restriction induced by VPA. This was in line with previous results proved the importance of supplementation to improve fetal growth and to prevent the incidence of low birth weight [38]. According to previous studies, folic acid supplementation during early pregnancy improves the growth of the fetus and placenta through enhancement of cell proliferation, DNA and RNA synthesis and amino acids metabolism [39,40].…”

Impact of Methyl-Donor Micronutrient Supplementation on DNA Methylation Patterns: A Systematic Review and Meta-Analysis of in vitro, Animal, and Human Studies

“…The route of supplement administration included adding to water [33, 34, 43] or diet (chow) [35–38, 40, 42–45, 47, 49–56, 58, 59, 61–67], oral gavage [41] and subcutaneous injection [57]. Nineteen studies supplemented only folic acid [35, 39, 41–45, 48, 50, 54, 56, 59, 60, 62, 64–67], four only choline [33, 57, 61, 63], three only betaine [47, 49, 55], three only methionine [37, 38, 58], and six studies used a mix of methyl-donor supplements [34, 36, 40, 51–53]. Samples included maternal placenta and diverse fetal or own animal tissues such as liver, brain, kidney, adipose tissue.…”

“…Of the 35 animal model studies, 14 were conducted with mice (C57BL/6J, CBA/J, Swiss Albino, C57BL/6, AxinFu/þ, and/or INS-GAS) [33][34][35][36][37][38][39][40][41][42][43][44][45][46] and 21 with rats (Sprague-Dawley, Long-Evans and Wistar) . The route of supplement administration included adding to water [33,34,43] or diet (chow) [35-38, 40, 42-45, 47, 49-56, 58, 59, 61-67], oral gavage [41] and subcutaneous injection [57].…”

Altered dietary ratio of folic acid and vitamin B12 during pregnancy influences the expression of imprinted H19/IGF2 locus in C57BL/6 mice

“…parameters (43,44) . To study this, statistical analysis was performed by using two-way ANOVA and pairwise comparisons using oneway ANOVA (α = 0•05) along with Tukey's post hoc test was carried out only after confirming the significant interaction of folic acid and B 12 with the parameters studied.…”