Ryu Seonghun, Kohen Roni, Samuni Amram, Ornoy Asher
Laboratory of Teratology, Department of Anatomy and Cell Biology, Hebrew University-Hadassah Medical School, Jerusalem, Israel 91120.
Birth Defects Res A Clin Mol Teratol. 2007 Aug;79(8):604-11. doi: 10.1002/bdra.20383.
Diabetic teratogenicity relates, partly, to embryonic oxidative stress and the extent of the embryonic damage can apparently be reduced by antioxidants. We investigated the effects of superoxide dismutase-mimics nitroxides, 2,2,6,6-tetramethyl piperidine-N-oxyl (TPL) as an effective antioxidant, on diabetes-induced embryopathy.
Embryos (10.5 day old) and their yolk sacs from Sabra female rats were cultured for 28 h in the absence or in the presence of nitroxides at 0.05-0.4 mM in control, diabetic subteratogenic, or diabetic teratogenic media, and monitored for growth retardation and congenital anomalies. The oxidant/antioxidant status was examined by oxygen radical absorbance capacity and lipid peroxidation assays, whereas the yolk sac function was evaluated by endocytosis assay.
Diabetic culture medium inhibited embryonic and yolk sac growth, induced a high rate of NTDs, reduced yolk sac endocytosis and embryonic antioxidant capacity, and increased lipid peroxidation. These effects were more prominent in the embryos with NTD compared to those without NTD. TPL added to diabetic teratogenic medium improved embryonic and yolk sac growth, reduced the rate of NTDs, and improved yolk sac function. The oxidant/antioxidant status of embryos was also improved. TPL at 1 mM did not damage the embryos cultured in control medium.
In diabetic culture medium, oxidative damage is higher in the malformed rat embryos compared to those without anomalies; the nitroxide provides protection against diabetes-induced teratogenicity in a dose-dependent manner. The yolk sac damage, apparently caused by the same mechanism, might be an additional contributor to the embryonic damage observed in diabetes.
糖尿病致畸作用部分与胚胎氧化应激有关，而抗氧化剂显然可降低胚胎损伤程度。我们研究了超氧化物歧化酶模拟物氮氧化物2,2,6,6 - 四甲基哌啶 - N - 氧基（TPL）作为一种有效抗氧化剂对糖尿病诱导的胚胎病的影响。
将来自萨布拉雌性大鼠的胚胎（10.5日龄）及其卵黄囊在对照、糖尿病亚致畸或糖尿病致畸培养基中，于不存在或存在0.05 - 0.4 mM氮氧化物的情况下培养28小时，并监测生长迟缓及先天性异常情况。通过氧自由基吸收能力和脂质过氧化测定来检测氧化/抗氧化状态，而通过内吞作用测定来评估卵黄囊功能。
糖尿病培养基抑制胚胎和卵黄囊生长，诱导高比例的神经管缺陷（NTDs），降低卵黄囊内吞作用和胚胎抗氧化能力，并增加脂质过氧化。与无NTD的胚胎相比，这些影响在有NTD的胚胎中更为显著。添加到糖尿病致畸培养基中的TPL改善了胚胎和卵黄囊生长，降低了NTDs发生率，并改善了卵黄囊功能。胚胎的氧化/抗氧化状态也得到改善。1 mM的TPL未损伤在对照培养基中培养的胚胎。
在糖尿病培养基中，畸形大鼠胚胎的氧化损伤高于无异常的胚胎；氮氧化物以剂量依赖方式提供针对糖尿病诱导的致畸作用的保护。显然由相同机制引起的卵黄囊损伤可能是糖尿病中观察到的胚胎损伤的另一个促成因素。
