Differential teratogenic response of TNFα+/+ and TNFα-/- mice to cyclophosphamide: The possible role of NF-κB

Arkady Torchinsky, Maka Gongadze, Shoshana Savion, Amos Fein, Vladimir Toder

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: We observed previously that tumor necrosis factor α (TNFα)-knockout embryos are more sensitive to a cyclophosphamide (CP)-induced teratogenic insult than their TNFα-positive counterparts, implicating molecules acting in TNFα-activated antiapoptotic pathways in the mechanisms underlying this phenomenon. The main goal of this study was to assess whether the transcription factor nuclear factor κB (NF-κB) may be 1 of those molecules. Such a choice is based by evidence demonstrating TNFα as a powerful activator of NF-αB and a key role of the transcription factor in the most effective TNFα-activated antiapoptotic cascade. Also, the expression pattern of active caspases 3, 8, and 9 was researched to assess the sensitivity of TNFα+/+ and TNFα-/- embryos to CP-induced apoptotic stimuli. METHODS: TNFα-knockout mice were exposed to CP on day 12 of pregnancy, with or without an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC) and sacrificed on day 18 of pregnancy to evaluate the CP-induced teratogenic effect. Embryos harvested 24 or 48 hr after the CP treatment were used to evaluate NF-κB DNA-binding and activity of caspases 3, 8, and 9. RESULTS: PDTC potentiated the CP-induced teratogenic effect and augmented the CP-induced suppression of NF-κB DNA-binding. These effects were more prominent in TNFα-/- than TNFα+/+ embryos. CP-induced caspase activation was found to be similar in TNFα-/- and TNFα+/+ embryos at 24 hr after treatment. At 48 hr, TNFα-/- embryos exhibited higher levels of active caspases 8 and 9 than their TNFα-positive counterparts. CONCLUSIONS: The results of our study allow us to hypothesize that NF-κB may be a component of mechanisms underlying differential sensitivity of TNFα-/- and TNFα+/+ mice to CP-induced teratogenic insult.

Original languageEnglish
Pages (from-to)437-444
Number of pages8
JournalBirth Defects Research Part A - Clinical and Molecular Teratology
Volume76
Issue number6
DOIs
StatePublished - Jun 2006

Keywords

  • Caspases
  • Cyclophosphamide
  • NF-κB
  • TNFα
  • Teratogenesis

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