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Redox and epigenetic regulation of the APE1 gene in the hippocampus of piglets: The effect of early life exposures

Lookup NU author(s): Dr Sabine Langie, Bartlomiej Tomaszewski, Professor John Mathers


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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. (C) 2014 Elsevier B.V. All rights reserved.

Publication metadata

Author(s): Langie SAS, Kowalczyk P, Tomaszewski B, Vasilaki A, Maas LM, Moonen EJ, Palagani A, Godschalk RWL, Tudek B, van Schooten FJ, Berghe WV, Zabielski R, Mathers JC

Publication type: Article

Publication status: Published

Journal: DNA Repair

Year: 2014

Volume: 18

Pages: 52-62

Print publication date: 01/06/2014

Online publication date: 29/04/2014

Acceptance date: 26/03/2014

ISSN (print): 1568-7864

ISSN (electronic): 1568-7856



DOI: 10.1016/j.dnarep.2014.03.011

PubMed id: 24794400


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Funder referenceFunder name
Lifelong Health
FOOD-CT-2005-513943European Network of Excellence (NoE) "Environmental Cancer risk, Nutrition and Individual Susceptibility" (ECNIS) within European Union sixth Framework Programme (FP6), Priority 5: "Food Quality and Safety"
PBZ-KBN-093/P06/2003Polish Ministry of Science and Higher Education