title: Deprenyl enhances the teratogenicity of hydroxyurea in organogenesis stage mouse embryos.
abstract: Hydroxyurea, an antineoplastic drug, is a model teratogen. The administration of hydroxyurea to CD1 mice on gestation day 9 induces oxidative stress, increasing the formation of 4-hydroxy-2-nonenal adducts to redox-sensitive proteins such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the caudal region of the embryo. GAPDH catalytic activity is reduced, and its translocation into the nucleus is increased. Because the nuclear translocation of GAPDH is associated with oxidative stress-induced cell death, we hypothesized that this translocation plays a role in mediating the teratogenicity of hydroxyurea. Deprenyl (also known as selegiline), a drug used as a neuroprotectant in Parkinson's disease, inhibits the nuclear translocation of GAPDH. Hence, timed pregnant CD1 mice were treated with deprenyl (10mg/kg) on gestation day 9 followed by the administration of hydroxyurea (400 or 600mg/kg). Deprenyl treatment significantly decreased the hydroxyurea-induced nuclear translocation of GAPDH in the caudal lumbosacral somites. Deprenyl enhanced hydroxyurea-mediated caudal malformations, inducing specifically limb reduction, digit anomalies, tail defects, and lumbosacral vertebral abnormalities. Deprenyl did not augment the hydroxyurea-induced inhibition of glycolysis or alter the ratio of oxidized to reduced glutathione. However, it did dramatically increase cleaved caspase-3 in embryos. These data suggest that nuclear GAPDH plays an important, region-specific, role in teratogen-exposed embryos. Deprenyl exacerbated the developmental outcome of hydroxyurea exposure by a mechanism that is independent of oxidative stress. Although the administration of deprenyl alone did not affect pregnancy outcome, this drug may have adverse consequences when combined with exposures that increase the risk of malformations.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Ava E
authors.initials: AE
authors.lastname: Schlisser
authors.forename: Barbara F
authors.initials: BF
authors.lastname: Hales
mesh_terms: D000818:Animals; D004357:Drug Synergism; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D006918:Hydroxyurea / Q000633:toxicity*; D051379:Mice; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D011256:Pregnancy Outcome; D012642:Selegiline / Q000633:toxicity*; D013723:Teratogens / Q000633:toxicity*
chemical_list: D008996:Monoamine Oxidase Inhibitors; D013723:Teratogens; D012642:Selegiline; D006918:Hydroxyurea
keywords: 4-hydroxy-2-nonenal; apoptosis; caspase-3.; cell death; glutathione; glyceraldehyde-3-phosphate dehydrogenase; nuclear translocation; oxidative stress; teratogen