Moderately high intake of folic acid has a negative impact on mouse embryonic development

Abstract

BACKGROUND:The incidence of neural tube defects has diminished considerably since the implementation of food fortification with folic acid (FA). However, the impact of excess FA intake, particularly during pregnancy, requires investigation. In a recent study, we reported that a diet supplemented with 20-fold higher FA than the recommended intake for rodents had adverse effects on embryonic mouse development at embryonic days (E)10.5 and 14.5. In this report, we examined developmental outcomes in E14.5 embryos after administering a diet supplemented with 10-fold higher FA than recommended to pregnant mice with and without a mild deficiency of methylenetetrahydrofolate reductase (MTHFR). METHODS: Pregnant mice with or without a deficiency in MTHFR were fed a control diet (recommended FA intake of 2 mg/kg diet for rodents) or an FA-supplemented diet (FASD; 10-fold higher than the recommended intake [20 mg/kg diet]). At E14.5, mice were examined for embryonic loss and growth retardation, and hearts were assessed for defects and for ventricular wall thickness. RESULTS: Maternal FA supplementation was associated with embryonic loss, embryonic delays, a higher incidence of ventricular septal defects, and thinner left and right ventricular walls, compared to mothers fed control diet. CONCLUSIONS: Our work suggests that even moderately high levels of FA supplementation may adversely affect fetal mouse development. Additional studies are warranted to evaluate the impact of high folate intake in pregnant women. Birth Defects Research (Part A) 97:47À52,

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

“…In previous murine studies, we observed more developmental delays and heart defects in embryos (17) and more liver damage in adults (16) fed a diet containing 10 times the recommended diet content for folic acid, which is equivalent to current recommendations for high-risk women (3). In light of those findings, we used a diet that contained one-half that amount in the current study to be more relevant to elevated folic acid intakes that are commonly observed in pregnant women (12)(13)(14).…”

“…MethylTHF rose w1.7-fold in the plasma of mice fed the FASD. In previous studies, we showed that total plasma folate rose w2.5-fold and w10-fold in pregnant mice fed a 103FASD and an FASD with 20-fold the recommended diet content, respectively (17,29). For comparison, total plasma folate was reported to increase 2-fold in women who were taking 1.1 mg folic acid/d and 3.4-fold in women who were taking 5 mg folic acid/d (54).…”

“…Mice fed the 103FASD had lower methylTHF and SAM in the liver and liver damage (16). Incidences of heart defects, developmental delays, and embryonic loss were higher in litters of mice fed this diet (17). In the liver, the combination of the 103FASD and MTHFR deficiency (Mthfr +/2 mice) was more severe than the diet alone, which suggested that the UL for folic acid intake should take into account genetic variants such as MTHFR 677C.T.…”

Effect of genetic polymorphisms involved in folate metabolism on the concentration of serum folate and plasma total homocysteine (p-tHcy) in healthy subjects after short-term folic acid supplementation: a randomized, double blind, crossover study

“…It was also reported that women with the highest quartile folate and the lowest quartile zinc were vulnerable to fetomaternal complications (Mukherjee et al 1984). Recently, it was demonstrated that high-dose folic acid supplements were associated with adverse effects on fetal mouse development (Mikael et al 2013). It was also shown that folic acid supplements (400 lg) given every other day to individuals who were consuming diet providing about 3.5 mg zinc were associated with increased loss of zinc via faces .…”

Folate therapy optimization in complicated pregnancy

“…Так, у потомства самок мышей, полу-чавших диету с дозой фолиевой кислоты, экви-валентной дозе 4 мг/сут у людей, наблюдалось увеличение гибели эмбрионов, задержка эмбрио-нального роста, повышение риска появления по-роков сердца по сравнению с животными, полу-чавшими контрольную диету [25]. Было отмечено значительное увеличение риска развития опухо-лей молочной железы у потомства самок крыс, получавших диету с повышенным в 2,5 раза со-держанием фолиевой кислоты [23].…”