title: High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.
abstract: Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C > T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex. Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.
authors.affiliation: Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Renata H
authors.initials: RH
authors.lastname: Bahous
authors.affiliation: Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada.
authors.forename: Nafisa M
authors.initials: NM
authors.lastname: Jadavji
authors.affiliation: Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Liyuan
authors.initials: L
authors.lastname: Deng
authors.affiliation: Pharmacology Unit, Faculty of Pharmacy, Institut de Neurociència Universitat de Barcelona (IBUB), Nucli Universitari de Pedralbes, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cosín-Tomás
authors.affiliation: Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lu
authors.affiliation: Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Malysheva
authors.affiliation: Developmental Biology and Cancer Programme, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Kit-Yi
authors.initials: KY
authors.lastname: Leung
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Ming-Kai
authors.initials: MK
authors.lastname: Ho
authors.affiliation: Pharmacology Unit, Faculty of Pharmacy, Institut de Neurociència Universitat de Barcelona (IBUB), Nucli Universitari de Pedralbes, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
authors.affiliation: Institute of Biomedical Investigation of Barcelona, Spanish National Research Council, Barcelona, Spain.|Center for Mind and Brain, University of California Davis, Davis, CA, USA.
authors.forename: Perla
authors.initials: P
authors.lastname: Kaliman
authors.affiliation: Developmental Biology and Cancer Programme, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Nicholas D E
authors.initials: NDE
authors.lastname: Greene
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Bedell
authors.affiliation: Division of Nutritional Sciences and Genomics, Cornell University, Ithaca, NY, USA.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Caudill
authors.affiliation: Departments of Human Genetics and Pediatrics, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000109:Acetylcholine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004032:Diet / Q000009:adverse effects; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000009:adverse effects*; D006712:Homocystinuria / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008569:Memory Disorders / Q000139:chemically induced / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects*; D008745:Methylation; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D009128:Muscle Spasticity / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D011247:Pregnancy; D011618:Psychotic Disorders / Q000235:genetics / Q000473:pathology
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D005492:Folic Acid; C000609029:MTHFR protein, mouse; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000109:Acetylcholine