Weksler-Zangen Sarah, Yaffe Pirhiya, Ornoy Asher
Laboratory of Teratology, Department of Anatomy and Cell Biology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Birth Defects Res A Clin Mol Teratol. 2003 Jun;67(6):429-37. doi: 10.1002/bdra.10043.
The role of reactive oxygen species in the etiology of diabetes-induced anomalies was studied in a genetic model of nutritionally induced Type 2 diabetes mellitus: the Cohen diabetic sensitive (CDs) and resistant (CDr) rats. We have previously shown in this model that embryopathy may be induced by a combination of genetic and environmental factors. In our study we investigated the role of the antioxidant defense mechanism, genetic predisposition or environmental factors in embryos cultured under diabetic conditions.
CDs, CDr and Sabra rat 11.5-day old embryos were studied after 28 hr of culture in control (low glucose), high glucose, diabetic sub-teratogenic, and diabetic teratogenic media. Embryos were monitored for growth retardation and congenital anomalies. Activity of superoxide dismutase (SOD) and catalase-like (CAT) enzymes was measured in embryonic homogenates.
In control medium, CDs embryos were significantly underdeveloped but exhibited no anomalies and SOD activity was not significantly different from that of CDr embryos. In high glucose medium, CDs embryos were smaller than CDr and Sabra embryos and smaller than CDs embryos cultured in control medium. Neural tube defects (NTD) were found predominantly in the CDs embryos starting from 14% in the high glucose medium and increasing to 29% in the sub-teratogenic medium. In the teratogenic medium, < 50% of the CDs and Sabra embryos were alive whereas all (100%) of the CDr embryos were alive. SOD activity significantly increased in CDs embryos when cultured in the high glucose medium but was significantly reduced in the sub-teratogenic medium. SOD activity was increased significantly in the Sabra embryos cultured in the sub-teratogenic medium but did not change in CDr embryos cultured in either one of the different culture media. CAT activity did not show any significant trend in either one of the rat strains or in any of the different culture conditions.
Our results suggest that genetic susceptibility plays an important role in inducing underdevelopment and NTD in cultured CDs embryos in sub-teratogenic medium and in protecting the CDr embryos under the same conditions. The combination of a sub-teratogenic environment with genetic susceptibility is sufficient to reduce the activity of SOD, hence decreasing the ability of the CDs embryos to cope with diabetic sub-teratogenic environment and prevent NTD.
在营养诱导的2型糖尿病遗传模型——科恩糖尿病敏感（CDs）大鼠和抗性（CDr）大鼠中，研究了活性氧在糖尿病诱导异常病因中的作用。我们之前在该模型中表明，胚胎病可能由遗传和环境因素共同诱导。在我们的研究中，我们调查了抗氧化防御机制、遗传易感性或环境因素在糖尿病条件下培养的胚胎中的作用。
将CDs、CDr和萨布拉大鼠11.5天大的胚胎在对照（低糖）、高糖、糖尿病亚致畸和糖尿病致畸培养基中培养28小时后进行研究。监测胚胎的生长迟缓情况和先天性异常。在胚胎匀浆中测量超氧化物歧化酶（SOD）和过氧化氢酶样（CAT）酶的活性。
在对照培养基中，CDs胚胎明显发育不全，但未出现异常，且SOD活性与CDr胚胎无显著差异。在高糖培养基中，CDs胚胎比CDr和萨布拉胚胎小，且比在对照培养基中培养的CDs胚胎小。神经管缺陷（NTD）主要在CDs胚胎中发现，从高糖培养基中的14%开始，在亚致畸培养基中增加到29%。在致畸培养基中，不到50%的CDs和萨布拉胚胎存活，而所有（100%）的CDr胚胎存活。在高糖培养基中培养时，CDs胚胎的SOD活性显著增加，但在亚致畸培养基中显著降低。在亚致畸培养基中培养的萨布拉胚胎的SOD活性显著增加，但在任何一种不同培养基中培养的CDr胚胎中SOD活性均未改变。在任何一种大鼠品系或任何不同培养条件下，CAT活性均未显示出任何显著趋势。
我们的结果表明，遗传易感性在亚致畸培养基中诱导培养的CDs胚胎发育不全和NTD以及在相同条件下保护CDr胚胎方面起着重要作用。亚致畸环境与遗传易感性的结合足以降低SOD的活性，从而降低CDs胚胎应对糖尿病亚致畸环境和预防NTD的能力。
