title: Redox and epigenetic regulation of the APE1 gene in the hippocampus of piglets: The effect of early life exposures.
abstract: Oxidative stress via redox reactions can regulate DNA repair pathways. The base excision repair (BER) enzyme apurinic/apyrimidinic endonuclease 1 (APE1) is a key player in the redox regulation of DNA repair. Environmental factors can alter the methylation of DNA repair genes, change their expression and thus modulate BER activity and susceptibility to oxidative DNA damage. Therefore, we hypothesized that epigenetic modifications play a role in the redox regulation of APE1 in hippocampi of newborns and investigated the effect of supplementation of pregnant sows with a diet enriched in antioxidants and other nutrients on oxidative stress, DNA methylation and DNA repair in their offspring. High levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and low levels of glutathione were detected in control piglets after birth compared with supplemented piglets, indicating the presence of oxidative stress. In control animals, this oxidative stress was associated with genomic DNA demethylation, decreased APE1 promoter methylation, increased APE1 expression and with slightly but not statistically significant increased BER-related DNA incision activity. Supplementation of piglets with antioxidants and other nutrients significantly lowered 8-oxodG levels compared to control animals, which was accompanied by overall lower APE1 promoter methylation and enhanced APE1 expression at day 7-28 after birth in supplemented piglets, although DNA incision activity was not significantly different between groups. Preliminary attempts to study the interaction between redox and epigenetic regulatory mechanisms revealed an inverse correlation between APE1 expression and methylation of CpG-sites 11 and 13 in the promoter region, which according to Genomatix "MatInspector" are located in the core binding sites of redox-sensitive transcription factors. We are the first to study methylation of the APE1 promoter and its role in mediating the functional effects of redox reactions induced by oxidative stress. Epigenetic and redox mechanisms may interact in regulating APE1-related DNA repair processes, involving redox-sensitive TFs.
authors.affiliation: Centre for Brain Ageing and Vitality, Human Nutrition Research Centre, Institute for Ageing & Health, Newcastle University, Campus for Ageing and Vitality, NE4 5PL Newcastle upon Tyne, UK. Electronic address: sabine.langie@newcastle.ac.uk.
authors.forename: Sabine A S
authors.initials: SA
authors.lastname: Langie
authors.affiliation: Warsaw University of Life Sciences, Faculty of Agriculture and Biology, Department of Biochemistry, 02-787 Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Kowalczyk
authors.affiliation: Centre for Brain Ageing and Vitality, Human Nutrition Research Centre, Institute for Ageing & Health, Newcastle University, Campus for Ageing and Vitality, NE4 5PL Newcastle upon Tyne, UK.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Tomaszewski
authors.affiliation: Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, Faculty of Health & Life Sciences, University of Liverpool, Liverpool L69 3GA, UK.
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Vasilaki
authors.affiliation: Department of Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Lou M
authors.initials: LM
authors.lastname: Maas
authors.affiliation: Department of Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: Moonen
authors.affiliation: PPES, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Ajay
authors.initials: A
authors.lastname: Palagani
authors.affiliation: Department of Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Roger W L
authors.initials: RW
authors.lastname: Godschalk
authors.affiliation: Institute of Biochemistry and Biophysics PAS, 02-106 Warsaw, Poland; Institute of Genetics and Biotechnology University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tudek
authors.affiliation: Department of Toxicology, Maastricht University, 6200 MD Maastricht, The Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.affiliation: PPES, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Wim Vanden
authors.initials: WV
authors.lastname: Berghe
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, 02-766 Warsaw, Poland.
authors.forename: Romuald
authors.initials: R
authors.lastname: Zabielski
authors.affiliation: Centre for Brain Ageing and Vitality, Human Nutrition Research Centre, Institute for Ageing & Health, Newcastle University, Campus for Ageing and Vitality, NE4 5PL Newcastle upon Tyne, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics* / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D013552:Swine
chemical_list: D000975:Antioxidants; D000080242:8-Hydroxy-2'-Deoxyguanosine; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D003849:Deoxyguanosine; D005978:Glutathione
keywords: Base excision repair; Developmental origin; Epigenetics; Oxidative stress