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TOXICOLOGY

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

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

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.

Address correspondence to: Dr. Barbara F. Hales, Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir-William-Osler, Montreal, Quebec, Canada H3G 1Y6. E-mail: barbara.hales{at}mcgill.ca