p38 and c-Jun N-terminal kinase mitogen-activated protein kinase signaling pathways play distinct roles in the response of organogenesis-stage embryos to a teratogen.
Mitogen-activated protein kinase (MAPK) signaling plays an important role during embryo development. We hypothesize that MAPK activation is a determinant of the fate of organogenesis-stage embryos exposed to insult. To test this hypothesis, CD1 mice were exposed to a model teratogen, hydroxyurea, on gestational day 9. Hydroxyurea exposure triggered a dramatic, transient increase in the activation of p38 MAPKs and c-Jun N-terminal kinases (JNKs) in embryos, without activating extracellular signal-regulated kinases 1 and 2. Selectively blocking p38 MAPKs with 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) enhanced hydroxyurea-induced fetal mortality without affecting growth retardation or the incidence of deformities among surviving fetuses. In contrast, selectively blocking JNKs with JNK peptide inhibitor 1, L-stereoisomer did not affect hydroxyurea-induced fetal death but increased the incidence of the hindlimb defects observed. Thus, p38 MAPKs and JNKs play distinct roles in protecting the conceptus against insult. Pharmacological inhibition of teratogen exposure induced MAPK activation has adverse consequences on the embryo.
Yan
Jin
J
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec, Canada H3G 1Y6.
Hales
Barbara F
BF
D000014:Abnormalities, Drug-Induced / Q000196:embryology* / Q000201:enzymology*; D000818:Animals; D004622:Embryo, Mammalian / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D005260:Female; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D038081:Organogenesis / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D013723:Teratogens; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D007093:Imidazoles; D011725:Pyridines; D013723:Teratogens; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580