title: Embryonic catalase protects against ethanol-initiated DNA oxidation and teratogenesis in acatalasemic and transgenic human catalase-expressing mice.
abstract: Reactive oxygen species (ROS) are implicated in fetal alcohol spectrum disorders (FASD) caused by alcohol (ethanol, EtOH). Although catalase detoxifies hydrogen peroxide, embryonic catalase activity is only about 5% of maternal levels. To determine the roles of ROS and embryonic catalase in FASD, pregnant mice with enhanced (expressing human catalase, hCat) or deficient (acatalasemic, aCat) catalase activity, or their respective wild-type (WT) controls, were treated ip on gestational day 9 with 4 or 6g/kg EtOH or its saline vehicle, and embryos and fetuses were, respectively, evaluated for oxidatively damaged DNA and structural anomalies. Untreated hCat and aCat dams had, respectively, more and less offspring than their WT controls. hCat progenies were protected from all EtOH fetal anomalies at the low dose (p < .01) and from reduced head diameter and resorptions at the high dose (p < .001). Conversely, aCat progenies were more sensitive to dose-dependent EtOH fetal anomalies (p < .001) and exhibited a 50% increase in maternal lethality (p < .05) at the high dose. Maternal pretreatment of aCat mice with polyethylene glycol-conjugated catalase (PEG-Cat) reduced EtOH fetal anomalies (p < .001). EtOH-initiated embryonic DNA oxidation was reduced in hCat and WT mice pretreated with PEG-Cat and enhanced in aCat mice. Plasma concentrations of EtOH in catalase-altered mice were similar to controls, precluding a pharmacokinetic basis for altered EtOH teratogenesis. Endogenous embryonic catalase, despite its low level, is an important embryoprotective enzyme for EtOH teratogenesis and a likely determinant of individual risk.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lutfiya
authors.initials: L
authors.lastname: Miller
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Shapiro
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000201:enzymology*; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D011247:Pregnancy; D053719:Tandem Mass Spectrometry
chemical_list: D000431:Ethanol; D004247:DNA; D002374:Catalase
keywords: Catalase; DNA oxidation; ethanol; mutant mice; reactive oxygen species; teratogenesis.