title: Maternal dietary uridine causes, and deoxyuridine prevents, neural tube closure defects in a mouse model of folate-responsive neural tube defects.
abstract: BACKGROUND
  Folic acid prevents neural tube closure defects (NTDs), but the causal metabolic pathways have not been established. Serine hydroxymethyltransferase 1 (SHMT1) is an essential scaffold protein in folate-dependent de novo thymidylate synthesis in the nucleus. SHMT1-deficient mice provide a model to investigate folic acid-responsive NTDs wherein disruption of de novo thymidylate synthesis impairs neural tube closure.
  
  
  OBJECTIVE
  We examined the effects of maternal supplementation with the pyrimidine nucleosides uridine, thymidine, or deoxyuridine with and without folate deficiency on NTD incidence in the Shmt1 mouse model.
  
  
  METHODS
  Shmt1(+/+) and Shmt1(-/-) female mice fed folate-replete or folate-deficient diets and supplemented with uridine, thymidine, or deoxyuridine were bred, and litters (n = 10-23 per group) were examined for the presence of NTDs. Biomarkers of impaired folate status and metabolism were measured, including plasma nucleosides, hepatic uracil content, maternal plasma folate concentrations, and incorporation of nucleoside precursors into DNA.
  
  
  RESULTS
  Shmt1(+/-) and Shmt1(-/-) embryos from dams fed the folate-deficient diet were susceptible to NTDs. No NTDs were observed in litters from dams fed the folate-deficient diet supplemented with deoxyuridine. Surprisingly, uridine supplementation increased NTD incidence, independent of embryo genotype and dietary folic acid. These dietary nucleosides did not affect maternal hepatic uracil accumulation in DNA but did affect plasma folate concentrations.
  
  
  CONCLUSIONS
  Maternal deoxyuridine supplementation prevented NTDs in dams fed the folate-deficient diet, whereas maternal uridine supplementation increased NTD incidence, independent of folate and embryo genotype. These findings provide new insights into the metabolic impairments and mechanisms of folate-responsive NTDs resulting from decreased Shmt1 expression.
authors.affiliation: From the Division of Nutritional Sciences, Cornell University, Ithaca, NY.
authors.forename: Lucia
authors.initials: L
authors.lastname: Martiniova
authors.affiliation: From the Division of Nutritional Sciences, Cornell University, Ithaca, NY.
authors.forename: Martha S
authors.initials: MS
authors.lastname: Field
authors.affiliation: From the Division of Nutritional Sciences, Cornell University, Ithaca, NY.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Finkelstein
authors.affiliation: From the Division of Nutritional Sciences, Cornell University, Ithaca, NY.
authors.forename: Cheryll A
authors.initials: CA
authors.lastname: Perry
authors.affiliation: From the Division of Nutritional Sciences, Cornell University, Ithaca, NY.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
mesh_terms: D000818:Animals; D003857:Deoxyuridine / Q000008:administration & dosage* / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000097:blood; D005494:Folic Acid Deficiency / Q000188:drug therapy; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D054259:Neural Tube / Q000187:drug effects; D009436:Neural Tube Defects / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D011247:Pregnancy; D013936:Thymidine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D014498:Uracil / Q000378:metabolism; D014529:Uridine / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood
chemical_list: D014498:Uracil; D005492:Folic Acid; D012696:Glycine Hydroxymethyltransferase; C559685:Shmt1 protein, mouse; D013936:Thymidine; D003857:Deoxyuridine; D014529:Uridine
keywords: SHMT1; deoxyuridine; folic acid; neural tube defects; uridine
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