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Published on: April 24, 2013
TNF-alpha acts to prevent occurrence of malformed fetuses in diabetic mice
A Torchinsky1, M Gongadze, H Orenstein
1Department of Embryology and Teratology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel. arkadyt@post.tau.ac.il
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.
Insights
Tumor necrosis factor-alpha (TNF-alpha) contributes to early embryo death in diabetic mice but protects later embryos from malformations by activating anti-apoptotic pathways. TNF-alpha appears to prevent malformed offspring in severely diabetic conditions.
Area of Science:
- Reproductive biology
- Developmental toxicology
- Immunology
Background:
- Diabetes-induced embryopathies, including early embryonic death and structural anomalies, are linked to apoptosis.
- Tumor necrosis factor-alpha (TNF-alpha) has dual roles in apoptosis, potentially causing or preventing maldevelopment.
Purpose of the Study:
- To investigate the role of TNF-alpha in regulating embryonic response to diabetes-induced stress.
- To examine how TNF-alpha influences early embryonic death and malformations in diabetic conditions.
Main Methods:
- Used streptozotocin-induced diabetic TNF-alpha knockout mice.
- Assessed reproductive performance and fetal teratogenic effects.
- Localized apoptotic nuclei using TUNEL assay and evaluated NF-kappaB activity via electrophoretic mobility shift assay.
Main Results:
- Diabetic wild-type (TNF-alpha+/+) mice showed lower pregnancy rates but fewer malformed fetuses than diabetic TNF-alpha knockout (TNF-alpha-/-) mice.
- Malformed TNF-alpha-/- embryos exhibited higher apoptosis intensity and lower active NF-kappaB levels compared to TNF-alpha(+/+) embryos.
Conclusions:
- TNF-alpha promotes peri-implantation embryo death but protects post-implantation embryos from diabetes-induced teratogenic stimuli.
- Activation of NF-kappaB-mediated anti-apoptotic signaling by TNF-alpha appears crucial for preventing malformed offspring in diabetic mice.
