title: High levels of iron supplementation prevents neural tube defects in the Fpn1ffemouse model.
abstract: Periconception maternal nutrition and folate in particular are important factors influencing the incidence of neural tube defects (NTDs). Many but not all NTDs are prevented by folic acid supplementation and there is a pressing need for additional strategies to prevent these birth defects. Other micronutrients such as iron are potential candidates, yet a clear role for iron deficiency in contributing to NTDs is lacking. Our previous studies with the flatiron (ffe) mouse model of Ferroportin1 (Fpn1) deficiency suggest that iron is required for neural tube closure and forebrain development raising the possibility that iron supplementation could prevent NTDs.
  
  
  
  We determined the effect of periconception iron and/or folic acid supplementation on the penetrance of NTDs in the Fpn1ffemouse model. Concurrently, measurements of folate and iron were made to ensure supplementation had the intended effects.
  
  
  
  High levels of iron supplementation significantly reduced the incidence of NTDs in Fpn1ffemutants. Fpn1 deficiency resulted in reduced folate levels in both pregnant dams and embryos. Yet folic acid supplementation did not prevent NTDs in the Fpn1ffemodel. Similarly, forebrain truncations were rescued with iron. Surprisingly, the high levels of iron supplementation used in this study caused folate deficiency in wild-type dams and embryos.
  
  
  
  Our results demonstrate that iron supplementation can prevent NTDs and forebrain truncations in the Fpn1ffemodel. Surprisingly, high levels of iron supplementation and iron overload can cause folate deficiency. If iron is essential for neural tube closure, it is possible that iron deficiency might contribute to NTDs. Birth Defects Research 109:81-91, 2017. © 2016 The Authors Birth Defects Research Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Biology, The George Washington University, Washington, DC.|Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC.
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Stokes
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Sabatino
authors.affiliation: Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC.
authors.forename: Irene E
authors.initials: IE
authors.lastname: Zohn
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics*; D003433:Crosses, Genetic; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D005494:Folic Acid Deficiency / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D007501:Iron / Q000008:administration & dosage*; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D008822:Mice, Transgenic; D054259:Neural Tube / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism; D009436:Neural Tube Defects / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019683:Penetrance; D011247:Pregnancy; D016548:Prosencephalon / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D000098742:Ferroportin; D005492:Folic Acid; D007501:Iron
keywords: exencephaly; folic acid supplementation; iron deficiency; neural tube defects; spina bifida