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TNF-alpha protects embryos exposed to developmental toxicants
Arkady Torchinsky1, Jeanne Shepshelovich, Hasida Orenstein
1Department of Embryology and Teratology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
Summary
Tumor necrosis factor alpha (TNF-alpha) deficiency surprisingly increased embryo susceptibility to cyclophosphamide-induced birth defects. TNF-alpha appears to protect embryos from teratogenic stress by restoring NF-kappaB activity.
Area of Science:
- Developmental toxicology
- Immunology
- Teratology
Background:
- Tumor necrosis factor alpha (TNF-alpha) is implicated in pregnancy complications.
- Its precise role in embryonic development under toxicant exposure is unclear.
Purpose of the Study:
- To investigate the role of TNF-alpha in mediating embryonic maldevelopment induced by cyclophosphamide (CP).
- To compare the effects of CP on embryos from TNF-alpha knockout and wild-type mice.
Main Methods:
- Pregnant mice (TNF-alpha knockout and wild-type) were exposed to cyclophosphamide (CP) on day 12 of gestation.
- Embryos were examined for malformations, apoptosis, cell proliferation, and NF-kappaB activity in the brain.
Main Results:
- TNF-alpha knockout embryos exhibited significantly higher rates of craniofacial, trunk, and limb malformations after CP exposure.
- Increased apoptosis and suppressed cell proliferation were observed in TNF-alpha knockout embryos.
- CP-induced suppression of NF-kappaB DNA-binding activity was enhanced in TNF-alpha knockout embryos.
Conclusions:
- TNF-alpha acts as a protective factor against teratogenic stress during embryonic development.
- Restoration of NF-kappaB activity in surviving embryonic cells may be a key mechanism of this protection.