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

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

Research output: Contribution to journalArticlepeer-review

Abstract

Studies with diverse teratogens implicated the transcription factor NF-κB 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-κB 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-κB (p65 subunit)-DNA binding, IκB kinase beta (IKKβ) activity, expression of p65 and IKKβ proteins, as well as NF-κB inhibitory proteins (IκBs) such as IκBα, IκBβ, and IκBε, and died within the next 24 h. Embryos of females exposed to 15 mg/kg CP exhibited only a decrease in NF-κB-DNA binding and IKKβ activity at 24 h. However, at 48 h, a more prominent decrease in NF-κB activity was observed, accompanied by a decreased expression of p65 and IKKβ 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-κB-DNA binding activity and no alterations in NF-κB signaling. These results suggest that the classical NF-κB 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-κB signaling may culminate in such a final effect as embryonic death.

Original languageEnglish
Pages (from-to)197-205
Number of pages9
JournalToxicology and Applied Pharmacology
Volume229
Issue number2
DOIs
StatePublished - 1 Jun 2008

Keywords

  • Embryo
  • IKKβ
  • IκBs
  • NF-κB
  • Teratogenesis

Fingerprint

Dive into the research topics of 'Teratogen-induced distortions in the classical NF-κB activation pathway: Correlation with the ability of embryos to survive teratogenic stress'. Together they form a unique fingerprint.

Cite this