title: Maternal folate depletion and high-fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring.
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.
authors.affiliation: Human Nutrition Research Centre, Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK. sabine.langie@gmail.com
authors.forename: Sabine A S
authors.initials: SA
authors.lastname: Langie
authors.forename: Sebastian
authors.initials: S
authors.lastname: Achterfeldt
authors.forename: Joanna P
authors.initials: JP
authors.lastname: Gorniak
authors.forename: Kirstin J A
authors.initials: KJ
authors.lastname: Halley-Hogg
authors.forename: David
authors.initials: D
authors.lastname: Oxley
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.forename: Roger W L
authors.initials: RW
authors.lastname: Godschalk
authors.forename: Jill A
authors.initials: JA
authors.lastname: McKay
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000494:pharmacology; D014886:Weaning; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D004268:DNA-Binding Proteins; D004041:Dietary Fats; D000076105:X-ray Repair Cross Complementing Protein 1; D014803:Vitamin B Complex; D044503:5-Methylcytosine; D005492:Folic Acid; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase
keywords: base excision repair; developmental origin; epigenetics