(Journal Article): TNF-alpha protects embryos exposed to developmental toxicants.
Torchinsky A, Shepshelovich J, Orenstein H, Zaslavsky Z, Savion S, Carp H, Fein A, Toder V (Department of Embryology & Teratology, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.,
arkadyt(at)post.tau.ac.il
)
IN:
Am J Reprod Immunol
2003; 49(3):159-168
Fulltext: HTML
ABSTRACT: BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) 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-alpha further, a comparative study was performed in TNF-alpha, knockout and TNF-alpha, 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-kappaB DNA-binding activity by electrophoretic mobility shift assay (EMSA) and the expression of Re1lA (an NF-kappaB subunit) and I(kappa)B(alpha) 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-alpha -/- females, than in TNF-alpha,+/+ mice. Excessive apoptosis and suppression of cell proliferation was found in the brain, and they were more prominent in TNF-alpha -/- than TNF-alpha +/+ embryos, when examined 24 hr after CP injection. Finally, CP-induced suppression of NF-kappaB DNA-binding activity was found to be enhanced in the brain of TNF-alpha -/- embryos, and the restoration of NF-kappaB DNA-binding activity was compromised. CONCLUSION: This work demonstrates for the first time that TNF-alpha may act as a protector of embryos exposed to teratogenic stress. One possible mechanism may be restoration of NF-kappaB activity in embryonic cells surviving the teratogenic insult.
TYPE OF PUBLICATION: Original article
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(Journal Article): TNF-alpha acts to prevent occurrence of malformed fetuses in diabetic mice.
Torchinsky A, Gongadze M, Orenstein H, Savion S, Fein A, Toder V (Department of Embryology and Teratology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel,
arkadyt(at)post.tau.ac.il
)
IN:
Diabetologia
2004; 47(1):132-139
Impact Factor(s) of Diabetologia: 5.583 (2004), 5.689 (2003), 5.136 (2002), 6.299 (2001)
ABSTRACT: AIMS/HYPOTHESIS: Activation of apoptosis in embryos is thought to be a key event in the pathogenesis of diabetes-induced embryopathies such as early embryonic death and inborn structural anomalies. TNF-alpha can activate apoptotic and anti-apoptotic signalling cascades, indicating its ability to contribute to and counteract diabetes-induced maldevelopment. To investigate how TNF-alpha regulates the response of embryos to diabetes-induced embryopathic stress, we used streptozotocin-induced diabetic TNF-alpha knockout mice. MATERIALS: To evaluate the reproductive performance, mated diabetic female mice were examined on days 4 and 8 of pregnancy for the presence of blastocysts or embryos in uterine horns. To evaluate the teratogenic effect, the female mice were killed on day 18 of pregnancy and fetuses were examined for gross external anomalies. In addition, apoptotic nuclei were localised by the TUNEL assay and DNA-binding activity of the transcription factor NF-kappaB was evaluated by electrophoretic mobility shift assay in 10- and 11-day-old embryos respectively. RESULTS: Severely diabetic TNF-alpha(+/+) female mice had a much greater decrease in pregnancy rate but a lower incidence of malformed fetuses in litters than severely diabetic TNF-alpha(-/-) female mice. Also, the intensity of excessive apoptosis was higher, but the amount of active NF-kappaB complexes was lower in malformed TNF-alpha(-/-) embryos than in TNF-alpha(+/+) embryos. CONCLUSIONS/INTERPRETATION: TNF-alpha contributes to death of peri-implantation embryos and possibly protects postimplantation embryos exposed to diabetes-induced teratogenic stimuli via activation of NF-kappaB-mediated anti-apoptotic signalling. It seems that TNF-alpha prevents the birth of malformed offspring in severely diabetic mice.
TYPE OF PUBLICATION: Original article
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