Teratogen-induced oxidative stress targets glyceraldehyde-3-phosphate dehydrogenase in the organogenesis stage mouse embryo.
Exposure during the organogenesis stage of the mouse embryo to the model teratogen, hydroxyurea (HU), induces curly tail and limb malformations. Oxidative stress contributes to the developmental toxicity of HU. Reactive oxygen species (ROS) interact with polyunsaturated bilipid membranes to form α,β-unsaturated reactive aldehydes; 4-hydroxy-2-nonenal (4-HNE), one of the most cytotoxic of these aldehydes, covalently adducts with proteins, lipids, and nucleic acids. The goal of the current study is to determine if HU exposure of CD1 mice on gestation day 9 generates region-specific 4-HNE-protein adducts in the embryo and to identify the proteins targeted. The formation of 4-HNE-protein adducts was elevated in the caudal region of control embryos; HU exposure further increased 4-HNE-protein adduct formation in this area. Interestingly, three of the 4-HNE-modified proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glutamate oxaloacetate transaminase 2, and aldolase 1, A isoform, are involved in energy metabolism. The formation of 4-HNE-GAPDH protein adducts reduced GAPDH enzymatic activity by 20% and attenuated lactate production by 40%. Furthermore, HU exposure induced the nuclear translocation of GAPDH in the caudal region of exposed embryos; this nuclear translocation may be associated with the reactivation of oxidized proteins involved in DNA repair, such as apurinic/apyrimidinic endonuclease-1, and the stimulation of E1A-associated P300 protein/creb-binding protein (p300/CBP) activity, initiating cell death in a p53-dependent pathway. We propose that GAPDH is a redox-sensitive target in the embryo and may play a role in a stress response during development.
Schlisser
Ava E
AE
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada H3G 1Y6.
Yan
Jin
J
Hales
Barbara F
BF
D000014:Abnormalities, Drug-Induced / Q000201:enzymology / Q000209:etiology; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D024442:Aspartate Aminotransferase, Mitochondrial / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology; D047108:Embryonic Development / Q000187:drug effects*; D005634:Fructose-Bisphosphate Aldolase / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006918:Hydroxyurea / Q000633:toxicity*; D051379:Mice; D038081:Organogenesis / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects*; D013723:Teratogens / Q000633:toxicity*; D014178:Translocation, Genetic
D000447:Aldehydes; D013723:Teratogens; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D024442:Aspartate Aminotransferase, Mitochondrial; D005634:Fructose-Bisphosphate Aldolase; C027576:4-hydroxy-2-nonenal; D006918:Hydroxyurea