title: Increasing maternal or post-weaning folic acid alters gene expression and moderately changes behavior in the offspring.
abstract: BACKGROUND
  Studies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice.
  
  
  METHODS
  Dams were fed FA either at 0.4 mg or 4 mg/kg diet throughout the pregnancy and the resulting pups were maintained on the diet throughout experimentation. Newborn pups brain cerebral hemispheres were used for microarray analysis. To confirm alteration of several genes, quantitative RT-PCR (qRT-PCR) and Western blot analyses were performed. In addition, various behavior assessments were conducted on neonatal and adult offspring.
  
  
  RESULTS
  Results from microarray analysis suggest that the higher dose of FA supplementation during gestation alters the expression of a number of genes in the newborns' cerebral hemispheres, including many involved in development. QRT-PCR confirmed alterations of nine genes including down-regulation of Cpn2, Htr4, Zfp353, Vgll2 and up-regulation of Xist, Nkx6-3, Leprel1, Nfix, Slc17a7. The alterations in the expression of Slc17a7 and Vgll2 were confirmed at the protein level. Pups exposed to the higher dose of FA exhibited increased ultrasonic vocalizations, greater anxiety-like behavior and hyperactivity. These findings suggest that although FA plays a significant role in mammalian cellular machinery, there may be a loss of benefit from higher amounts of FA. Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior.
authors.affiliation: Department of Developmental Biochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Subit
authors.initials: S
authors.lastname: Barua
authors.affiliation: Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Kathryn K
authors.initials: KK
authors.lastname: Chadman
authors.affiliation: Department of Developmental Biochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Salomon
authors.initials: S
authors.lastname: Kuizon
authors.affiliation: Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Diego
authors.initials: D
authors.lastname: Buenaventura
authors.affiliation: Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Stapley
authors.affiliation: Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Felicia
authors.initials: F
authors.lastname: Ruocco
authors.affiliation: Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: Umme
authors.initials: U
authors.lastname: Begum
authors.affiliation: Department of Environmental Health Sciences, Columbia University, New York, United States of America.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Guariglia
authors.affiliation: Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America.
authors.forename: W Ted
authors.initials: WT
authors.lastname: Brown
authors.affiliation: Department of Developmental Biochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States of America; Graduate Center and College of Staten Island, City University of New York, Staten Island, New York, United States of America.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Junaid
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism; D019587:Dietary Supplements; D005247:Feeding Behavior; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D006120:Grooming; D008297:Male; D008431:Maternal-Fetal Exchange; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D012919:Social Behavior; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D005492:Folic Acid