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

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 4 g/kg EtOH or its saline vehicle, with or without pretreatment with the free radical spin trapping agent alpha-phenyl-N-tert-butylnitrone (PBN; 40 mg/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. (C) 2013 Elsevier Inc. All rights reserved.