NF-kappa B DNA-binding activity in embryos responding to a teratogen, cyclophosphamide.
BACKGROUND
The Rel/NF-kappaB transcription factors have been shown to regulate apoptosis in different cell types, acting as inducers or blockers in a stimuli- and cell type-dependent fashion. One of the Rel/NF-kappaB subunits, RelA, has been shown to be crucial for normal embryonic development, in which it functions in the embryonic liver as a protector against TNFalpha-induced physiological apoptosis. This study assesses whether NF-kappaB may be involved in the embryo's response to teratogens. Fot this, we evaluated how NF-KappaB DNA binding activity in embryonic organs demonstrating differential sensitivity to a reference teratogen, cyclophosphamide, correlates with dysmorphic events induced by the teratogen at the cellular level (excessive apoptosis) and at the organ level (structural anomalies).


RESULTS
The embryonic brain and liver were used as target organs. We observed that the Cyclophosphamide-induced excessive apoptosis in the brain, followed by the formation of severe craniofacial structural anomalies, was accompanied by suppression of NF-kappaB DNA-binding activity as well as by a significant and lasting increase in the activity of caspases 3 and 8. However, in the liver, in which cyclophosphamide induced transient apoptosis was not followed by dysmorphogenesis, no suppression of NF-kappaB DNA-binding activity was registered and the level of active caspases 3 and 8 was significantly lower than in the brain. It has also been observed that both the brain and liver became much more sensitive to the CP-induced teratogenic insult if the embryos were exposed to a combined treatment with the teratogen and sodium salicylate that suppressed NF-kappaB DNA-binding activity in these organs.


CONCLUSIONS
The results of this study demonstrate that suppression of NF-kappaB DNA-binding activity in embryos responding to the teratogenic insult may be associated with their decreased resistance to this insult. They also suggest that teratogens may suppress NF-kappaB DNA-binding activity in the embryonic tissues in an organ type- and dose-dependent fashion.
Torchinsky
Arkady
A
Department of Embryology & Teratology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel. arkadyt@post.tau.ac.il
Lishanski
Lucy
L
Wolstein
Orit
O
Shepshelovich
Jeanne
J
Orenstein
Hasida
H
Savion
Shoshana
S
Zaslavsky
Zeev
Z
Carp
Howard
H
Brill
Alexander
A
Dikstein
Rivka
R
Toder
Vladimir
V
Fein
Amos
A
D000015:Abnormalities, Multiple / Q000139:chemically induced; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D003520:Cyclophosphamide / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D012980:Sodium Salicylate / Q000494:pharmacology; D013723:Teratogens / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D013723:Teratogens; D003520:Cyclophosphamide; D012980:Sodium Salicylate