TNF-α protects embryos exposed to developmental toxicants

Arkady Torchinsky, Jeanne Shepshelovich, Hasida Orenstein, Zeev Zaslavsky, Shoshana Savion, Howard Carp, Amos Fein, Vladimir Toder

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Tumor necrosis factor α (TNF-α) has been implicated in mediating post-implantation embryo loss or the embryonic maldevelopment induced by development toxicants or maternal metabolic imbalances. In order to clarify the role of TNF-α further, a comparative study was performed in TNF-α knockout and TNF-α positive mice, exposed to a reference teratogen, cyclophosphamide (CP). Methods: Cyclophosphamide was injected on day 12 of pregnancy and 18-day fetuses were examined for external structural anomalies. Apoptosis and cell proliferation were measured by TdT-mediated biotin-dUTP nick-end labeling and 5′-bromo-2′-deoxyuridine incorporation, respectively, in the brain (an organ, sensitive to the teratogen) of embryos 24 hr after CP injection. NF-κB DNA-binding activity by electrophoretic mobility shift assay (EMSA) and the expression of Re1A (an NF-κB subunit) and IκBα proteins by Western blot analysis were assessed in the-brain of embryos tested 24 and 48 hr after CP treatment. Results: Surprisingly, the proportion of fetuses with craniofacial, trunk and severe limb reduction anomalies were significantly higher in TNF-α-/- females, than in TNF-α+/+ mice. Excessive apoptosis and suppression of cell proliferation was found in the brain, and they were more prominent in TNF-α-/- than TNF-α+/+ embryos, when examined 24 hr after CP injection. Finally, CP-induced suppression of NF-κB DNA-binding activity was found to be enhanced in the brain of TNF-α-/- embryos, and the restoration of NF-κB DNA-binding activity was compromised. Conclusion: This work demonstrates for the first time that TNF-α may act as a protector of embryos exposed to teratogenic stress. One possible mechanism may be restoration of NF-κB activity in embryonic cells surviving the teratogenic insult.

Original languageEnglish
Pages (from-to)159-168
Number of pages10
JournalAmerican Journal of Reproductive Immunology
Volume49
Issue number3
DOIs
StatePublished - 1 Mar 2003

Keywords

  • Birth defects
  • Embryo
  • NF-κB
  • Teratogenesis
  • Tumor necrosis factor α

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