Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy.
Reactive oxygen species (ROS) are involved in the etiology of numerous diseases including cardio-vascular diseases and diabetes mellitus. There is evidence that several teratogens affect the developing embryo by increasing its oxidative stress and, because of its relatively weak antioxidant defense, especially at the early stages of organogenesis, result in severe embryonic damage. This mechanism seems to operate in diabetes-induced embryonic damage as well as in the mechanism of teratogenicity caused by ionizing radiation, hypoxia, alcohol and cocaine use and cigarette smoking. We studied the role of oxidative stress in diabetic induced embryopathy, both in vivo and in vitro. Under diabetic condition there was a significant decrease in the activity of endogenous antioxidant enzymes and of vitamins C and E in the embryos and their yolk sacs. The lowest activity was observed in the malformed experimental embryos when compared to experimental embryos without anomalies. Similar results were obtained in the Cohen diabetic rats, where the diabetic prone (CDs) rats were unable to increase their antioxidant enzyme activity in spite of the diabetes. Studies performed by other investigators show similar results. Human and animal studies show that the main mechanism of fetal damage induced by high levels of ionizing irradiation, cocaine and alcohol abuse, hypoxia and cigarette smoking is also by increased embryonic oxidative stress. Similarly, several drugs exert their teratogenic activity via embryonic oxidative stress. Abnormal placentation may also cause enhanced placental oxidative stress, resulting in embryonic death, preeclampsia or congenital anomalies. Inability of the developing embryo to cope with that stress may result in embryonic death and/or congenital anomalies. Animal studies also show that a variety of antioxidants are effective in decreasing the damaging effects of heightened oxidative stress induced by teratogens. Effective antioxidants, which might also be of clinical use, include vitamins C and E, carotenoids, folic acid, as well as synthetic products. Appropriate clinical studies with antioxidants in pregnancies of high risk to develop oxidative stress are needed, since non-toxic antioxidants might prove an efficient and inexpensive way to reduce the rate of some serious and sometimes fatal congenital anomalies.
Ornoy
Asher
A
Laboratory of Teratology, Department of Anatomy and Cell Biology, Hebrew University--Hadassah Medical School, Jerusalem, Israel. Ornoy@cc.huji.ac.il
D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D003042:Cocaine / Q000009:adverse effects; D003920:Diabetes Mellitus / Q000196:embryology / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D000431:Ethanol / Q000009:adverse effects; D005260:Female; D005315:Fetal Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D000860:Hypoxia / Q000196:embryology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000528:radiation effects; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D013723:Teratogens / Q000633:toxicity*
D000975:Antioxidants; D017382:Reactive Oxygen Species; D013723:Teratogens; D000431:Ethanol; D003042:Cocaine