High Gestational Folic Acid Supplementation Alters Expression of Imprinted and Candidate Autism Susceptibility Genes in a sex-Specific Manner in Mouse Offspring

J Mol Neurosci. 2016 Feb;58(2):277-86. doi: 10.1007/s12031-015-0673-8. Epub 2015 Nov 7.


Maternal nutrients play critical roles in modulating epigenetic events and exert long-term influences on the progeny's health. Folic acid (FA) supplementation during pregnancy has decreased the incidence of neural tube defects in newborns, but the influence of high doses of maternal FA supplementation on infants' brain development is unclear. The present study was aimed at investigating the effects of a high dose of gestational FA on the expression of genes in the cerebral hemispheres (CHs) of 1-day-old pups. One week prior to mating and throughout the entire period of gestation, female C57BL/6J mice were fed a diet, containing FA at either 2 mg/kg (control diet (CD)) or 20 mg/kg (high maternal folic acid (HMFA)). At postnatal day 1, pups from different dams were sacrificed and CH tissues were collected. Quantitative RT-PCR and Western blot analysis confirmed sex-specific alterations in the expression of several genes that modulate various cellular functions (P < 0.05) in pups from the HMFA group. Genomic DNA methylation analysis showed no difference in the level of overall methylation in pups from the HMFA group. These findings demonstrate that HMFA supplementation alters offsprings' CH gene expression in a sex-specific manner. These changes may influence infants' brain development.

Keywords: Autism; DNA methylation; Epigenetics; Folic acid; Imprinting; Prenatal nutrition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / genetics*
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / embryology
  • Cerebral Cortex / metabolism
  • DNA Methylation
  • Dietary Supplements
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid / pharmacology*
  • Genetic Predisposition to Disease
  • Genomic Imprinting*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Prenatal Exposure Delayed Effects / genetics*
  • Prenatal Nutritional Physiological Phenomena / genetics*
  • Sex Factors
  • Vitamin B Complex / administration & dosage
  • Vitamin B Complex / pharmacology*


  • Vitamin B Complex
  • Folic Acid