title: Folic acid supplementation can adversely affect murine neural tube closure and embryonic survival.
abstract: Neural tube defects (NTDs), a common birth defect in humans, result from the failure of the embryonic neural tube (NT) to close properly. NT closure is a complex, poorly understood morphogenetic process influenced by genes and environment. The most effective environmental influence in decreasing the risk for NTDs is folic acid (FA) fortification and supplementation, and these findings led to the recommendation of periconceptual FA intake and mandatory fortification of the US grain supply in 1998. To explore the relationship between genetics and responsiveness to FA supplementation, we used five mouse NTDs models-Zic2, Shroom3, Frem2, Grhl2 (Grainyhead-like 2) and L3P (Line3P)-and a long-term generational FA supplementation scheme. Contrary to expectations, we find that three genetic mutants respond adversely to FA supplementation with increased incidence of NTDs in homozygous mutants, occurrence of NTDs in heterozygous embryos and embryonic lethality prior to NT closure. Because of these unexpected responses, we examined NTD risk after short-term FA supplementation. Our results indicate that, for the same genetic allele, NTD risk can depend on the length of FA exposure. Our data indicate that, depending on the gene mutation, FA supplementation may adversely influence embryonic development and NT closure.
authors.affiliation: HHMI and Department of Pediatrics, Programs in Molecular Biology, University of Colorado AnschutzMedical Campus and Children’s Hospital Colorado, Aurora, CO 80045, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Marean
authors.forename: Amanda
authors.initials: A
authors.lastname: Graf
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lee
authors.initials: L
authors.lastname: Niswander
mesh_terms: D000818:Animals; D019587:Dietary Supplements / Q000009:adverse effects*; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005492:Folic Acid / Q000009:adverse effects*; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D054259:Neural Tube / Q000187:drug effects* / Q000196:embryology*; D009436:Neural Tube Defects / Q000196:embryology / Q000209:etiology* / Q000235:genetics / Q000401:mortality*; D011247:Pregnancy; D013534:Survival
chemical_list: D005492:Folic Acid