Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development

Abstract

Background: Moderately high folic acid intake in pregnant women has led to concerns about deleterious effects on the mother and fetus. Common polymorphisms in folate genes, such as methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolaseformyltetrahydrofolate synthetase (MTHFD1) R653Q, may modulate the effects of elevated folic acid intake. Objectives: We investigated the effects of moderate folic acid supplementation on reproductive outcomes and assessed the potential interaction of the supplemented diet with MTHFD1-synthetase (Mthfd1S) deficiency in mice, which is a model for the R653Q variant. Design: Female Mthfd1S +/+ and Mthfd1S +/2 mice were fed a folic acid-supplemented diet (FASD) (5-fold higher than recommended) or control diets before mating and during pregnancy. Embryos and placentas were assessed for developmental defects at embryonic day 10.5 (E10.5). Maternal folate and choline metabolites and gene expression in folate-related pathways were examined. Results: The combination of FASD and maternal MTHFD1-synthetase deficiency led to a greater incidence of defects in E10.5 embryos (diet 3 maternal genotype, P = 0.0016; diet 3 embryonic genotype, P = 0.054). The methylenetetrahydrofolate reductase (MTHFR) protein and methylation potential [ratio of S-adenosylmethionine (major methyl donor):S-adenosylhomocysteine) were reduced in maternal liver. Although 5-methyltetrahydrofolate (methylTHF) was higher in maternal circulation, the methylation potential was lower in embryos. The presence of developmental delays and defects in Mthfd1S +/2 embryos was associated with placental defects (P = 0.003). The labyrinth layer failed to form properly in the majority of abnormal placentas, which compromised the integration of the maternal and fetal circulation and presumably the transfer of methylTHF and other nutrients. Conclusions: Moderately higher folate intake and MTHFD1-synthetase deficiency in pregnant mice result in a lower methylation potential in maternal liver and embryos and a greater incidence of defects in embryos. Although maternal circulating methylTHF was higher, it may not have reached the embryos because of abnormal placental development; abnormal placentas were observed predominantly in abnormally developed embryos. These findings have implications for women with high folate intakes, particularly if they are polymorphic for MTHFD1 R653Q.

Paternal chronic folate supplementation induced the transgenerational inheritance of acquired developmental and metabolic changes in chickens

“…The present study found that chronic FS could actually influence the lipid metabolic process by influencing glycerophospholipid metabolism, glycerolipid metabolism and fatty acid biosynthesis. However, the hepatic TG contents were increased in the breeder cocks and their offspring from the PFS groups, which was in accordance with previous studies [26,27]. Additionally, enhanced glucose metabolic functions, especially glycolysis and gluconeogenesis functions, were identified in breeder cocks and their offspring from the FS groups.…”

“…Previous studies have mostly shown that folate could promote lipoclastic activity by increasing the biosynthesis of phosphatidylcholine and carnitine and by decreasing the expression of lipid synthesis-related genes [11]. However, several recent studies have found that chronic FS could induce increased inactive folate in the body and further induce lipopexia in the liver [26,27]. The present study found that chronic FS could actually influence the lipid metabolic process by influencing glycerophospholipid metabolism, glycerolipid metabolism and fatty acid biosynthesis.…”

Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio

“…A study reported by Rozen’s group has also shown that the lack of MTHFDA synthetase significantly affects embryonic defects in female mice. The study demonstrated that disruption of the maternal MTHFD1 gene damages fetal growth [ 86 ]. There are also ample studies that suggest ANXA2 is closely involved with embryo implantation and breast cancer, by acting as an adhesion molecule on the endometrium [ 87 , 88 , 89 ].…”

Nutritional 1C Imbalance, B12 Tissue Accumulation, and Pregnancy Outcomes: An Experimental Study in Rats

“…Another likely possibility is that the fetal underdevelopment is a result of other components in the 1C imbalanced diet. Excess folate alone has previously been shown to cause placental abnormalities and embryonic defects in mice [ 20 , 21 ]. In addition, low B12 combined with high folate may exacerbate B12 deficiency [ 21 , 22 ].…”