Maternal folate depletion and high-fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring

FASEB J. 2013 Aug;27(8):3323-34. doi: 10.1096/fj.12-224121. Epub 2013 Apr 19.

Abstract

The mechanisms through which environmental and dietary factors modulate DNA repair are still unclear but may include dysregulation of gene expression due to altered epigenetic markings. In a mouse model, we investigated the effect of maternal folate depletion during pregnancy and lactation, and high-fat feeding from weaning, on base excision repair (BER) and DNA methylation and expression of selected BER-related genes in the brain of adult offspring. While folate depletion did not affect BER activity of the mothers, BER increased in the offspring at weaning (P=0.052). In the long term, as observed in 6-mo-old offspring, the double insult, i.e., maternal low-folate supply and high-fat feeding from weaning, decreased BER activity significantly in the cortex, cerebellum, hippocampus, and subcortical regions (P≤0.017). This fall in BER activity was associated with small changes in methylation or expression of BER-related genes. Maternal folate depletion led to slightly increased oxidative DNA damage levels in subcortical regions of adult offspring, which may increase sensitivity to oxidative stress and predispose to neurological disorders. In summary, our data suggest that low-folate supply during early life may leave an epigenetic mark that can predispose the offspring to further dietary insults, causing adverse effects during adult life.

Keywords: base excision repair; developmental origin; epigenetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / metabolism
  • Animals
  • Base Sequence
  • Brain / drug effects*
  • Brain / growth & development
  • Brain / metabolism
  • DNA Damage
  • DNA Glycosylases / genetics
  • DNA Methylation / drug effects*
  • DNA Repair / drug effects*
  • DNA-Binding Proteins / genetics
  • Diet, High-Fat
  • Dietary Fats / administration & dosage
  • Dietary Fats / pharmacology*
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid / pharmacology*
  • Gene Expression Regulation, Developmental / drug effects
  • Male
  • Maternal Nutritional Physiological Phenomena*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Pregnancy
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vitamin B Complex / administration & dosage
  • Vitamin B Complex / pharmacology
  • Weaning
  • X-ray Repair Cross Complementing Protein 1

Substances

  • DNA-Binding Proteins
  • Dietary Fats
  • X-ray Repair Cross Complementing Protein 1
  • Vitamin B Complex
  • 5-Methylcytosine
  • Folic Acid
  • DNA Glycosylases
  • Neil1 protein, mouse
  • Ogg1 protein, mouse
  • mutY adenine glycosylase