title: Embryonic catalase protects against ethanol embryopathies in acatalasemic mice and transgenic human catalase-expressing mice in embryo culture.
abstract: Reactive oxygen species (ROS) have been implicated in the mechanism of ethanol (EtOH) teratogenicity, but the protective role of the embryonic antioxidative enzyme catalase is unclear, as embryonic activity is only about 5% of maternal levels. We addressed this question in a whole embryo culture model. C57BL/6 mouse embryos expressing human catalase (hCat) or their wild-type (C57BL/6 WT) controls, and C3Ga.Cg-Cat(b)/J catalase-deficient, acatalasemic (aCat) mouse embryos or their wild-type C3HeB/FeJ (C3H WT) controls, were explanted on gestational day (GD) 9 (plug=GD 1), exposed for 24h to 2 or 4mg/mL EtOH or vehicle, and evaluated for functional and morphological changes. hCat and C57BL/6 WT vehicle-exposed embryos developed normally, while EtOH was embryopathic in C57BL/6 WT embryos, evidenced by decreases in anterior neuropore closure, somites developed, turning and head length, whereas hCat embryos were protected (p<0.001). Maternal pretreatment of C57BL/6 WT dams with 50kU/kg PEG-catalase (PEG-cat) 8h prior to embryo culture, which increases embryonic catalase activity, blocked all EtOH embryopathies (p<0.001). Vehicle-exposed aCat mouse embryos had lower yolk sac diameters compared to WT controls, suggesting that endogenous ROS are embryopathic. EtOH was more embryopathic in aCat embryos than WT controls, evidenced by reduced head length and somite development (p<0.01), and trends for reduced anterior neuropore closure, turning and crown-rump length. Maternal pretreatment of aCat dams with PEG-Cat blocked all EtOH embryopathies (p<0.05). These data suggest that embryonic catalase is a determinant of risk for EtOH embryopathies.
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-Pinsler
authors.affiliation: Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: pg.wells@utoronto.ca.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Wells
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D020642:Acatalasia / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004249:DNA Damage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D000431:Ethanol / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D006801:Humans; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D011092:Polyethylene Glycols / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; C070295:catalase-polyethylene glycol; D000431:Ethanol; D011092:Polyethylene Glycols; D002374:Catalase
keywords: Antioxidative enzyme; Catalase; Embryopathies; Ethanol; Fetal alcohol spectrum disorder; Reactive oxygen species; Teratogenicity