Teratogen-induced distortions in the classical NF-{kappa}B activation pathway: Correlation with the ability of embryos to survive teratogenic stress
Studies with diverse teratogens implicated the transcription factor NF-{kappa}B in mechanisms determining teratological susceptibility of embryos. Here, a teratogen such as cyclophosphamide (CP) was used to test whether teratogenic insult alters the classical NF-{kappa}B activation pathway, and how these alterations correlate with the ability of mouse embryos to resist the teratogen-induced process of maldevelopment. We observed that embryos tested 24 h after the exposure of females to 40 mg/kg CP exhibited a dramatic decrease in the level of NF-{kappa}B (p65 subunit)-DNA binding, I{kappa}B kinase beta (IKK{beta}) activity, expression of p65 and IKK{beta} proteins, as well as NF-{kappa}B inhibitory proteins (I{kappa}Bs) such as I{kappa}B{alpha}, I{kappa}B{beta}, and I{kappa}B{epsilon}, and died within the next 24 h. Embryos of females exposed to 15 mg/kg CP exhibited only a decrease in NF-{kappa}B-DNA binding and IKK{beta} activity at 24 h. However, at 48 h, a more prominent decrease in NF-{kappa}B activity was observed, accompanied by a decreased expression of p65 and IKK{beta} proteins. These embryos died within the next 24 h. After treatment with 10 mg/kg CP, embryos survived until the end of the antenatal period of development, demonstrating a transient decrease in NF-{kappa}B-DNA binding activity and no alterations in NF-{kappa}B signaling. These results suggest that the classical NF-{kappa}B activation pathway may be among targets that teratogens engage to initiate abnormal development. Besides, the observation that embryos destined to be dead exhibited a dramatically decreased rate of cell proliferation suggests a pathway, whereby teratogen-induced alterations in NF-{kappa}B signaling may culminate in such a final effect as embryonic death.
- OSTI ID:
- 21140853
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 229, Issue 2; Other Information: DOI: 10.1016/j.taap.2008.01.011; PII: S0041-008X(08)00026-4; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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