The role of pro- and anti-apoptotic molecular interactions in embryonic maldevelopment.
OBJECTIVE
Pregnancy loss and the occurrence of inborn structural anomalies are often preceded by excessive apoptosis in targeted embryonic and extraembryonic tissues. Apoptogenic stimuli activate both death and survival, signaling cascades consisting of molecules acting as activators and effectors, or negative regulators of apoptosis. The interplay between these cascades determines whether the cell which is exposed to an apoptogenic stimulus dies or survives. This review summarizes the functioning of pro- and anti-apoptotic molecules in embryos responding to various teratogens. The effect of potentiation of the maternal immune system on these molecules is also discussed.


METHODS
The data on the functioning of various pro- and anti-apoptotic molecules in embryos exposed to various developmental toxicants, and embryos developing in a diabetic environment are reviewed. Techniques such as the TUNEL method, DNA fragmentation assay, electromobility shift assay (EMSA), fluorometric assay, immunohistochemistry, Western blot, In situ hybridization, have been used in our studies to detect apoptosis, and evaluate the functioning of molecules such as TNFalpha, caspases, NF-kappaB and IkappaB, p53, and bcl-2 in different embryonic and extraembryonic tissues.


RESULTS
Our and other data summarized in this review have demonstrated that the doses of developmental toxicants required to induce pregnancy loss and gross structural anomalies induce excessive apoptosis shortly after treatment. Depending on the intensity and type of targeted tissues, this apoptosis was accompanied by alterations in the activity of the molecules which act as activators and effectors (e.g. caspase 3, caspase 8, caspase 2, p53) or negative regulators (bcl-2, NF-kappaB) of apoptosis. Maternal immunopotentiation, which decreases the level of induced and spontaneous pregnancy loss and the incidence and severity of teratogen-induced structural anomalies has been shown to modulate the expression of these molecules both in embryonic tissues and at the feto-maternal interface.


CONCLUSIONS
The data presented in this review suggest that molecules such as TNFalpha, caspase 3, caspase 8, NF-kappaB, p53 and bcl-2, which are involved in the regulation of apoptosis, may also be involved in determining the sensitivity of the embryo to developmental toxicants. Maternal immunopotentiation may modulate the functioning of these molecules.
Toder
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Department of Embryology and Teratology, Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel. toder@post.tau.ac.il
Carp
H
H
Fein
A
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Torchinsky
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000502:physiology*; D005260:Female; D051379:Mice; D011247:Pregnancy / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D013723:Teratogens; D014409:Tumor Necrosis Factor-alpha