Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?

Ghunwa A Nakouzi,Joseph H Nadeau

doi:10.1186/s12863-014-0091-x

Abstract

BackgroundNeural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is not understood. In addition, many cases remain resistant to the beneficial effects of folic acid supplementation. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation.ResultsWe examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apob tm1Unc and Vangl2 Lp mice, hereafter referred to as Apob and Lp respectively. The FA supplemented diet did not reduce the incidence or severity of NTDs in Apob or Lp mutant homozygotes or the loop-tail phenotype in Lp mutant heterozygotes, suggesting that mice with these mutant alleles are resistant to FA supplementation. Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.ConclusionSimilar genotypic biases have been reported for several NTD models, but were interpreted as diet-induced increases in the incidence and severity of NTDs that led to increased embryonic lethality. Absence of differences in resorption rates and litter sizes argue against induced embryonic lethality. We suggest an alternative interpretation, namely that FA supplementation led to strongly skewed allelic inheritance, perhaps from disturbances in polyamine metabolism that biases fertilization in favor of wild-type gametes.

Highlights

Neural tube defects (NTDs) are the second most common birth defect in humans
We began by testing whether parental folic acid (FA) supplementation reduced the incidence or severity of NTDs in homozygous mutant embryos or the loop-tail phenotype in Lp heterozygous mutant mice
The proportion of affected embryos did not differ between the two test and control groups (Table 1), suggesting that these NTD mutants are resistant to the beneficial effects of dietary FA supplementation

Summary

Introduction

Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation. Neural tube defects (NTDs) are serious and common birth defects resulting from both genetic and FA plays a role in both the folate cycle for the production of thymidylate and purines mediating cell division, and in the methylation cycle of homocysteine metabolism resulting in epigenetic regulation of gene expression [9,10,11]. The efficacy of FA supplementation is widely accepted, the mechanism by which FA reduces the incidence of NTDs is not understood and whether FA-resistant cases respond to alternative dietary nutrients is not generally known. Our lab sought to expand this body of knowledge by studying the effect of FA on selected NTD mouse models

Results

Discussion

Conclusion