title: Hyperglycemia and hypoxia are interrelated in their teratogenic mechanism: studies on cultured rat embryos.
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.
authors.affiliation: Department of Medical Neurobiology, Hebrew University Hadassah Medical School, Jerusalem, Israel. ornoy@cc.huji.ac.il <ornoy@cc.huji.ac.il>
authors.forename: Asher
authors.initials: A
authors.lastname: Ornoy
authors.forename: Shiran Bahat
authors.initials: SB
authors.lastname: Rand
authors.forename: Noa
authors.initials: N
authors.lastname: Bischitz
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism*; D047108:Embryonic Development / Q000502:physiology*; D019084:Fluorescent Antibody Technique, Indirect; D006943:Hyperglycemia / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology; D008315:Malondialdehyde / Q000378:metabolism; D008970:Molecular Weight; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D002374:Catalase; D013482:Superoxide Dismutase