Research article

NF-κB DNA-binding activity in embryos responding to a teratogen, cyclophosphamide

Arkady Torchinsky¹ , Lucy Lishanski¹ , Orit Wolstein² , Jeanne Shepshelovich¹ , Hasida Orenstein¹ , Shoshana Savion¹ , Zeev Zaslavsky¹ , Howard Carp¹ , Alexander Brill¹ , Rivka Dikstein² , Vladimir Toder¹ and Amos Fein¹

¹  Department of Embryology & Teratology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel

²  Department of Biological Chemistry, Weismann Institute of Sciences, Rehovot, Israel

author email corresponding author email

BMC Developmental Biology 2002, 2:2doi:10.1186/1471-213X-2-2

Published:	5 February 2002

Abstract

Background

The Rel/NF-κB 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-κB subunits, RelA, has been shown to be crucial for normal embryonic development, in which it functions in the embryonic liver as a protector against TNFα-induced physiological apoptosis. This study assesses whether NF-κB may be involved in the embryo's response to teratogens. Fot this, we evaluated how NF-KappaB DNA binding activity in embryonic organs demonstraiting 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-κB 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-κB 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-κB DNA-binding activity in these organs.

Conclusion

The results of this study demonstrate that suppression of NF-κB 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-κB DNA-binding activity in the embryonic tissues in an organ type- and dose-dependent fashion.