Hydroxyurea was used as a model teratogen to investigate the role of oxidative stress and stress-response pathways in mediating developmental toxicity. When administered to pregnant mice during early organogenesis, hydroxyurea induced fetal death and growth retardation, as well as external and skeletal malformations. The malformed fetuses displayed hindlimb, vertebral column, and tail defects. Hydroxyurea treatment enhanced the production of 4-hydroxynonenal, a lipid peroxidation end product, in malformation sensitive regions of the embryo. Depletion of glutathione, a major cellular antioxidant, specifically enhanced hydroxyurea-induced malformations and elevated the region-specific production of 4--hydroxynonenal protein adducts in the embryo, without affecting the incidence or extent of hydroxyurea-induced fetal death or growth retardation. The major proteins modified by 4-hydroxynonenal were involved in energy metabolism. Thus, oxidative stress is important in the induction of malformations by hydroxyurea. / Exposure to hydroxyurea stimulated the DNA binding activity of activator protein 1 (AP-1), an early response redox-sensitive transcription factor. Activated AP-1 was composed mainly of c-Fos heterodimers. Glutathione depletion did not change the effects of hydroxyurea on AP-1/c-Fos DNA binding activities despite an augmentation of the incidence of embryo malformations. Mitogen-activated protein kinases (MAPKs) activate AP-1 in response to stress by post-transcriptional phosphorylation of AP-1 proteins. Hydroxyurea treatment dramatically enhanced the activation of stress-responsive p38 MAPKs and JNKs (c-Jun N-terminal protein kinases). Selectively blocking p38 MAPKs enhanced the incidence of fetal death, whereas selective inhibition of JNKs specifically elevated the limb defects induced by hydroxyurea. Thus, activation of stress-response pathways impacts on the response of the embryo to a teratogenic insult.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.115897 |
| Date | January 2008 |
| Creators | Yan, Jin, 1972- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002826127, proquestno: AAINR66685, Theses scanned by UMI/ProQuest. |
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