Teratogen-induced distortions in the classical NF-{kappa}B activation pathway: Correlation with the ability of embryos to survive teratogenic stress

Journal Article · Sun Jun 01 04:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.01.011· OSTI ID:21140853

Molotski, Natali; Savion, Shoshana; Gerchikov, Natalie; Fein, Amos; Toder, Vladimir; Torchinsky, Arkady

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, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 229; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CELL PROLIFERATION
DEATH
DNA
EMBRYOS
ENDOXAN
MICE
TERATOGENESIS
TERATOGENS
TRANSCRIPTION FACTORS