title: Folate deficiency and over-supplementation causes impaired folate metabolism: Regulation and adaptation mechanisms in Caenorhabditis elegans.
abstract: METHODS
  Impaired folate metabolism increases the risk of birth defects, neurodegenerative and cardiovascular disease, osteoporosis and cancer. We used Caenorhabditis elegans to investigate impaired folate metabolism by RNA interference of key enzymes in the methionine synthase (MS) and thymidylate synthase (TS) cycle and by folate deficiency and over-supplementation feeding studies.
  
  
  RESULTS
  Folate status is influenced by genetic variations (polymorphisms), folate deficiency and supplementation. Single RNAi of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR) and MS revealed that gene regulation is largely affected in both folate cycles. Adaptation requires a close transcriptional connection between TS and MS cycle. Coupled DHFR and MS expression is required to balance both cycles, but seems to reduce the overall rate of folate conversion. Feeding studies showed that folate over-supplementation to functioning metabolism inactivates MS and MTHFR expression and enhances TS activity, which favors DNA synthesis over methylation reactions. Folate deficiency disrupted homeostasis by favoring TS cycle and led to malformation in C. elegans offspring. Embryos show aneuploidy and are nonviable lacking DNA repair during meiotic stage of diakinesis.
  
  
  CONCLUSIONS
  Single gene silencing alters gene expression in both cycles and disrupts folate homeostasis. Folate over-supplementation and deficiency favors TS over MS cycle and causes prophase DNA damage.
authors.affiliation: Department of Nutritional Sciences, University of Vienna, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Ortbauer
authors.affiliation: Department of Nutritional Sciences, University of Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Ripper
authors.affiliation: Department of Nutritional Sciences, University of Vienna, Austria.|Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fuhrmann
authors.affiliation: Department of Nutritional Sciences, University of Vienna, Austria.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Lassi
authors.affiliation: Department of Nutritional Sciences, University of Vienna, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Auernigg-Haselmaier
authors.affiliation: Department of Nutritional Sciences, University of Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Stiegler
authors.affiliation: Department of Nutritional Sciences, University of Vienna, Austria.
authors.forename: Jürgen
authors.initials: J
authors.lastname: König
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D052284:Clutch Size; D004260:DNA Repair; D019587:Dietary Supplements; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase
keywords: Folate deficiency; Folic acid over-supplementation; Impaired folate metabolism; Polymorphisms; RNAi