(Journal Article): Diabetes-Induced Fetal Growth Retardation is Associated with Suppression of NF-κB Activity in Embryos
 
Mammon K, Keshet R, Savion S, Pekar O, Zaslavsky Z, Fein A, Toder V, Torchinsky A (Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel, arkadyt(at)post.tau.ac.il )
 
IN: Rev Diabetic Stud 2005; 2(1):27-34
Impact Factor(s) of Rev Diabetic Stud: 0.125 (2006)

Fulltext:    HTML  PDF

ABSTRACT: BACKGROUND: Mechanisms underlying diabetes-induced fetal growth retardation remain largely undefined. Two events such as the persistent activation of apoptosis or suppression of cell proliferation in embryos might directly result in fetal growth retardation. Evidence implicating the transcription factor NF-κB in the regulation of the physiological and teratogen-induced apoptosis as well as cell proliferation suggests that it may be a component of mechanisms underlying this pathology. To address this issue, this study was designed to test: 1) whether diabetes-induced fetal growth retardation is preceded by the modulation of NF-κB activity in embryos at the late stage of organogenesis and 2) whether apoptosis is altered in these embryos. METHODS: The embryos and placentas of streptozotocin-induced diabetic mice collected on days 13 and 15 of pregnancy were used to evaluate the expression of NF-κB, IκBα and phosphorylated (p)-IκBα proteins by Western blot analysis and NF-κB DNA binding by an ELISA-based method. The detection of apoptotic cells was performed by the TUNEL assay and the expression of a proapoptotic protein Bax was evaluated by the Western blot. RESULTS: The embryos of diabetic mice were significantly growth retarded, whereas the placental weight did not differ in diabetic or control females. Levels of NF-κB and p-IκBα proteins as well as the amount of NF-κB DNA binding was lower in embryos of diabetic mice as compared to those in controls. However, neither excessive apoptosis nor an increased Bax expression was found in growth-retarded embryos and their placentas. CONCLUSION: The study herein revealed that diabetes-induced fetal growth retardation is associated with the suppression of NF-κB activity in embryos, which seems to be realized at the level of IκB degradation.

TYPE OF PUBLICATION: Original article

REFERENCES:

1. Eriksson UJ, Borg LA, Forsberg H, Styrud J. Diabetic embryopathy. Studies with animal and in vitro models. Diabetes 1991. 40 Suppl 2:94-98. [DOD]
2. Reece EA, Homko CJ. Multifactorial basis of the syndrome of diabetic embryopathy. Teratology 1996. 54:171-182. [DOD]
3. Moley KH. Hyperglycemia and apoptosis: mechanisms for congenital malformation and pregnancy loss in diabetic women. Trends Endocrinol Metab 2001.12:78-82. [DOD]
4. Sun F, Kawasaki E, Akazawa S, Hishikawa Y, Sugahara K, Kamihira S, Koji T, Eguchi K. Apoptosis and its pathway in early post-implantation embryos of diabetic rats. Diabetes Res Clin Pract 2005. 67:110-118. [DOD]
5. Chen FE, Ghosh G. Regulation of DNA binding by Rel/NF-κB transcription factors: structural views. Oncogene 1999. 18: 6845-6852. [DOD]
6. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 2000. 18:621-633. [DOD]
7. Pahl HL. Activators and target genes of Rel/ NF-kB transcription factors. Oncogene 1999. 18:6853-6866. [DOD]
8. Karin M, Lin A. NF-κB at the crossroad of life and death. Nut Immunol 2002. 3:221-227. [DOD]
9. Kucharczak J, Simmons MJ, Fan Y, Gelinas C. To be, or not to be: NF-kappaB is the answer- role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 2003. 22:8961-8982.
10. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B. Nature 1995. 376:167-170. [DOD]
11. Hansen JM, Gong SG, Philbert M, Harris C. .Misregulation of gene expression in the redox-sensitive NF-kappaB-dependent limb outgrowth pathway by thalidomide. Dev Dyn 2002. 225:186-194. [DOD]
12. Torchinsky A, Lishanski L, Wolstein O, Shepshelovich J, Orenstein H, Savion S, Zaslavsky Z, Carp H, Brill A, Dikstein R, Toder V, Fein A. NF-kappaB DNA-binding activity in embryos responding to a teratogen, cyclophosphamide. BMC Dev Biol 2002. 2:2. [DOD]
13. Torchinsky A, Shepshelovich J, Orenstein H, Zaslavsky Z, Savion S, Carp H, Fein A, Toder V. TNF-alpha protects embryos exposed to developmental toxicants. Am J Reprod Immunol 2003. 49:159-168. [DOD]
14. Acquaah-Mensah GK, Kehrer JP, Leslie SW. In utero ethanol suppresses cerebellar activator protein-1 and nuclear factor-kappa B transcriptional activation in a rat fetal alcohol syndrome model. J Pharmacol Exp Ther 2002. 301:277-283. [DOD]
15. Kennedy JC, Memet S, Wells PG. Antisense evidence for nuclear factor-kappaB-dependent embryopathies initiated by phenytoin-enhanced oxidative stress. Mol Pharmacol. 2004. 66:404-412. [DOD]
16. Pampfer S, Cordi S, Cikos S, Picry B, Vanderheyden I, Hertogh RD. Activation of nuclear factor kappaB and induction of apoptosis by tumor necrosis factor-alpha in the mouse uterine epithelial WEG-1 cell line. Biol Reprod 2000. 63:879- 886. [DOD]
17. Torchinsky A, Gongadze M, Orenstein H, Savion S, Fein A, Toder V. TNF-alpha acts to prevent occurrence of malformed fetuses in diabetic mice. Diabetologia 2004. 47:132-139. [DOD]
18. Takagi TN, Matsui KA, Yamashita K, Ohmori H, Yasuda M. Pathogenesis of cleft palate in mouse embryos exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). Teratog Carcinog Mutagen 2000. 20:73-86. [DOD]
19. Chen F, Castranova V, Shi X. New insights into the role of nuclear factor-kappa B in cell growth regulation. Am J Pathol 2001. 159:387-397. [DOD]
20. Gagnon R. Placental insufficiency and its consequences. Eur J Obstet Gynecol Reprod Biol. 2003. 110 Supp.l:S99-107. [DOD]
21. Moley KH, Chi MM, Knudson CM, Korsmeyer SJ, Mueckler M. M. Hyperglycemia induces apoptosis in pre-implantation embryos through cell death effector pathways. Nat. Med 1998. 4:1421–1424. [DOD]
22. Reece EA, Ma XD, Zhao Z, Wu YK, Dhanasekaran D. Aberrant patterns of cellular communication in diabetes-induced embryopathy in rats: II, apoptotic pathways. Am J Obstet Gynecol 2005. 192:967-972. [DOD]
23. Bojunga J, Nowak D, Mitrou PS, Hoelzer D, Zeuzem S, Chow KU. Antioxidative treatment prevents activation of death-receptor- and mitochondrion-dependent apoptosis in the hearts of diabetic rats. Diabetologia 2004. 47:2072-2080. [DOD]
24. Torchinsky A, Toder V, Carp H, Orenstein H, Fein A. In vivo evidence for the existence of a threshold for hyperglycemia-induced major fetal malformations: relevance to the etiology of diabetic teratogenesis. Early Pregnancy 1997. 3:27-33. [DOD]
25. Torchinsky A, Fein A, Toder V. Immunoteratology: I. MHC involvement in the embryo response to teratogens in mice. Am J Reprod Immunol 1995. 34:288-298. [DOD]
26. Phelan SA, Ito M, Loeken MR. Neural tube defects in embryos of diabetic mice: role of the Pax-3 gene and apoptosis. Diabetes 1997. 46:1189-1197. [DOD]
27. Forsberg H, Eriksson UJ, Welsh N. Apoptosis in embryos of diabetic rats. Pharmacol Toxicol 1998. 83:104-111.
28. Torchinsky A, Brokhman I, Shepshelovich J, Orenstein H, Savion S, Zaslavsky Z, Koifman M, Dierenfeld H, Fein A, Toder V. Increased TNF-alpha expression in cultured mouse embryos exposed to teratogenic concentrations of glucose. Reproduction 2003. 125:527-534. [DOD]
29. Jaffe R. Identification of fetal growth abnormalities in diabetes mellitus. Semin Perinatol 2002. 26:190-195. [DOD]
30. Husain SM, Frost R, Mughal ZM. Effect of diabetes mellitus on rat placenta cellularity. Early Hum Dev 2001. 60:207-214. [DOD]
31. Padmanabhan R, Shafiullah M. Intrauterine growth retardation in experimental diabetes: possible role of the placenta. Arch Physiol Biochem 2001. 109:260-271. [DOD]
32. Takenaka Y, Toyoda N. The effect of alpha 1-blocking vasodilator on fetal growth and uteroplacental blood flow in streptozotocin-induced diabetic rats. Life Sci 1995. 56:1127-1134. [DOD]
33. Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor-kappaB: its role in health and disease. J Mol Med 2004.82:434-448. [DOD]
34. Torchinsky A, Toder V. To die or not to die: the function of the transcription factor NF-kappaB in embryos exposed to stress. Am J Reprod Immunol 2004. 51:138-143. [DOD]
35. Chan SL, Yu VC. Proteins of the bcl-2 family in apoptosis signaling: from mechanistic insights to therapeutic opportunities. Clin Exp Pharmacol Physiol 2004. 31:119-128. [DOD]
36. Green DR. Apoptotic pathways: the roads to ruin. Cell 1998. 94:695-698. [DOD]
37. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 2003. 52:1-8. [DOD]
38. Podesta F, Romeo G, Liu WH, Krajewski S, Reed JC, Gerhardinger C, Lorenzi M. Bax is increased in the retina of diabetic subjects and is associated with pericyte apoptosis in vivo and in vitro. Am J Pathol 2000. 156:1025-1032. [DOD]
39. Li ZG, Zhang W, Sima AA. The role of impaired insulin/IGF action in primary diabetic encephalopathy. Brain Res 2005. 1037:12-24. [DOD]
40. Bacher S, Schmitz ML. The NF-kappaB pathway as a potential target for autoimmune disease therapy. Curr Pharm Des 2004. 10:2827-2837. [DOD]