Asher Ornoy1, Shiran Bahat Rand, Noa Bischitz. 1. Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem, Israel. ornoy@cc.huji.ac.il <ornoy@cc.huji.ac.il>
Abstract
BACKGROUND: Hyperglycemia and hypoxia are well-known teratogens that may affect many animal species, including man. One of the main mechanisms of teratogenic action of both seems to be increased oxidative stress. The purpose of this study was to evaluate the hypothesis that in the developing embryo hyperglycemia also leads to hypoxia, both resulting in oxidative damage. METHODS: The study was performed on 10.5-day-old rat embryos of the regular Sabra strain cultured for 28 hours in hyperglycemic or hypoxic conditions. Embryonic growth and rate of anomalies was assessed at the end of the culture period. The embryonic oxidative damage was investigated by studying the levels of Malondialdehyde (MDA) to determine the lipid peroxidation. The redox status was studied by measuring the activity of Catalase-like (CAT) and Super Oxide Dismutase (SOD) enzymes and the amount of Low Molecular Weight Antioxidants (LMWA). In addition, we studied by immunohistochemistry in the embryos and yolk sacs the amount of nitrotyrosine as an additional marker for the extent of oxidative stress. The amounts of the redox and hypoxia sensitive transcription factors HIF1alpha, NFkB, and IkB were also studied by immunohistochemistry. RESULTS: Both hyperglycemia and hypoxia increased the rate of congenital anomalies mainly of the heart, neural tube, and brain. Embryonic growth and scoring were decreased only by hypoxia. Both hyperglycemia and hypoxia increased embryonic oxidative stress as evidenced by increased lipid peroxidation, increased nitrotyrosine and LMWA, but only minimal changes in CAT and SOD activity. Severe hyperglycemia also caused hypoxia, as evidenced by increased HIF1alpha. Thus, there seems to be an interrelation between hyperglycemia and hypoxia, both resulting in embryonic damage apparently by enhanced oxidative stress. CONCLUSIONS: Both hyperglycemia and hypoxia seem to exert their embryotoxicity through a similar mechanism of increased oxidative stress in the embryo in a stage when its antioxidant capacity is still weak. Moreover, hyperglycemia also seems to induce hypoxia, intensifying diabetes-induced embryopathy. 2010 Wiley-Liss, Inc.
BACKGROUND:Hyperglycemia and hypoxia are well-known teratogens that may affect many animal species, including man. One of the main mechanisms of teratogenic action of both seems to be increased oxidative stress. The purpose of this study was to evaluate the hypothesis that in the developing embryo hyperglycemia also leads to hypoxia, both resulting in oxidative damage. METHODS: The study was performed on 10.5-day-old rat embryos of the regular Sabra strain cultured for 28 hours in hyperglycemic or hypoxic conditions. Embryonic growth and rate of anomalies was assessed at the end of the culture period. The embryonic oxidative damage was investigated by studying the levels of Malondialdehyde (MDA) to determine the lipid peroxidation. The redox status was studied by measuring the activity of Catalase-like (CAT) and Super Oxide Dismutase (SOD) enzymes and the amount of Low Molecular Weight Antioxidants (LMWA). In addition, we studied by immunohistochemistry in the embryos and yolk sacs the amount of nitrotyrosine as an additional marker for the extent of oxidative stress. The amounts of the redox and hypoxia sensitive transcription factors HIF1alpha, NFkB, and IkB were also studied by immunohistochemistry. RESULTS: Both hyperglycemia and hypoxia increased the rate of congenital anomalies mainly of the heart, neural tube, and brain. Embryonic growth and scoring were decreased only by hypoxia. Both hyperglycemia and hypoxia increased embryonic oxidative stress as evidenced by increased lipid peroxidation, increased nitrotyrosine and LMWA, but only minimal changes in CAT and SOD activity. Severe hyperglycemia also caused hypoxia, as evidenced by increased HIF1alpha. Thus, there seems to be an interrelation between hyperglycemia and hypoxia, both resulting in embryonic damage apparently by enhanced oxidative stress. CONCLUSIONS: Both hyperglycemia and hypoxia seem to exert their embryotoxicity through a similar mechanism of increased oxidative stress in the embryo in a stage when its antioxidant capacity is still weak. Moreover, hyperglycemia also seems to induce hypoxia, intensifying diabetes-induced embryopathy. 2010 Wiley-Liss, Inc.
Authors: Rodney D Britt; Arij Faksh; Elizabeth Vogel; Richard J Martin; Christina M Pabelick; Y S Prakash Journal: Expert Rev Respir Med Date: 2013-10-03 Impact factor: 3.772