title: The free radical spin trapping agent phenylbutylnitrone reduces fetal brain DNA oxidation and postnatal cognitive deficits caused by in utero exposure to a non-structurally teratogenic dose of ethanol: a role for oxidative stress.
abstract: Reactive oxygen species (ROS), although implicated in morphological birth defects caused by ethanol (EtOH) during pregnancy, have not been directly linked to its behavioral deficits. To determine this, a pathogenic oxidative DNA lesion was measured in fetal brain, and a passive avoidance learning test was assessed postnatally in the progeny of CD-1 mice treated once on gestational day 17 with 4g/kg EtOH or its saline vehicle, with or without pretreatment with the free radical spin trapping agent α-phenyl-N-tert-butylnitrone (PBN; 40mg/kg). EtOH-exposed CD-1 progeny, unlike C57BL/6 progeny, had no morphological birth defects, but exhibited a learning deficit at 12 weeks of age (p<0.001), which continued to 16 weeks in males (p<0.01). Peak blood EtOH concentrations were 2.5-fold higher in C57BL/6 mice compared to CD-1 mice given the same dose. PBN pretreatment of CD-1 dams blocked both EtOH-initiated DNA oxidation in fetal brain (p<0.05) and postnatal learning deficits (p<0.01), providing the first direct evidence for ROS in the mechanism of EtOH-initiated neurodevelopmental deficits.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Lutfiya
authors.initials: L
authors.lastname: Miller
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Shapiro
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000008:administration & dosage* / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D005260:Female; D005333:Fetus / Q000378:metabolism; D005609:Free Radicals / Q000302:isolation & purification / Q000378:metabolism / Q000633:toxicity*; D007858:Learning / Q000187:drug effects; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D011247:Pregnancy; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019097:Spin Trapping
chemical_list: D003497:Cyclic N-Oxides; D005609:Free Radicals; D017382:Reactive Oxygen Species; C029217:phenyl-N-tert-butylnitrone; D000431:Ethanol; D004247:DNA