title: Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  We examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apobtm1Unc and Vangl2Lp 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.
  
  
  CONCLUSIONS
  Similar 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.
authors.forename: Ghunwa A
authors.initials: GA
authors.lastname: Nakouzi
authors.affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. jnadeau@pnri.org.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Nadeau
mesh_terms: D000483:Alleles; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics; D004032:Diet; D004195:Disease Models, Animal; D020964:Embryo Loss; D005260:Female; D005306:Fertilization / Q000187:drug effects*; D005492:Folic Acid / Q000008:administration & dosage*; D005854:Germ Cells / Q000187:drug effects; D040582:Inheritance Patterns; D008297:Male; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D054259:Neural Tube / Q000196:embryology*; D009436:Neural Tube Defects / Q000235:genetics* / Q000517:prevention & control; D010641:Phenotype
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D005492:Folic Acid