title: Oxidative DNA damage in the in utero initiation of postnatal neurodevelopmental deficits by normal fetal and ethanol-enhanced oxidative stress in oxoguanine glycosylase 1 knockout mice.
abstract: Studies in mice with deficient antioxidative enzymes have shown that physiological levels of reactive oxygen species (ROS) can adversely affect the developing embryo and fetus. Herein, DNA repair-deficient progeny of oxoguanine glycosylase 1 (ogg1)-knockout mice lacking repair of the oxidative DNA lesion 8-oxo-2'-deoxyguanosine (8-oxodGuo) exhibited enhanced postnatal neurodevelopmental deficits, revealing the pathogenic potential of 8-oxodGuo initiated by physiological ROS production in fetal brain and providing the first evidence of a pathological phenotype for ogg1-knockout mice. Moreover, when exposed in utero to ethanol (EtOH), ogg1-knockout progeny exhibited higher levels of 8-oxodGuo in fetal brain and more severe postnatal neurodevelopmental deficits than wild-type littermates, both of which were blocked by pretreatment with the free radical trapping agent phenylbutylnitrone. These results suggest that ROS-initiated DNA oxidation, as distinct from altered signal transduction, contributes to neurodevelopmental deficits caused by in utero EtOH exposure, and fetal DNA repair is a determinant of risk.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine.
authors.forename: Lutfiya
authors.initials: L
authors.lastname: Miller-Pinsler
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Pinto
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine; Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada. Electronic address: pg.wells@utoronto.ca.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000254:growth & development*; D002492:Central Nervous System Depressants / Q000633:toxicity; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000502:physiology*; D004260:DNA Repair / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology* / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000188:drug therapy; D017382:Reactive Oxygen Species
chemical_list: D002492:Central Nervous System Depressants; D003497:Cyclic N-Oxides; D017382:Reactive Oxygen Species; C029217:phenyl-N-tert-butylnitrone; D000431:Ethanol; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D003849:Deoxyguanosine
keywords: Behavioral deficits; DNA oxidation; Ethanol; Free radicals; Neurodevelopmental deficits; OGG1 mice; Passive avoidance; Phenylbutylnitrone; Reactive oxygen species