Zangen Sarah W, Ryu Seonghun, 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. 2006 Feb;76(2):107-14. doi: 10.1002/bdra.20227.
We have previously shown that oxidative stress is important in the pathogenesis of diabetes-induced anomalies in Cohen Diabetic sensitive (CDs) rat embryos and seems to interplay with genetic factors. We investigated the role of genetic factors related to the antioxidant defense mechanism in CDs rat embryos.
We studied 11.5- and 12.5-day embryos of Cohen Diabetic resistant (CDr) and CDs rats that were fed a regular diet (RD), and hence not diabetic, compared to rats fed a high-sucrose low-copper diet (HSD) where only the CDs animals became diabetic. Embryos were monitored for growth and congenital anomalies. mRNA of catalase (CAT), glutathione peroxidase (GSHpx), CuZn-SOD (SOD-superoxide dismutase), and Mn-SOD and the extent of nuclear factor kappa B (NF-kappaB) activation were assessed.
Embryos of CDs dams fed RD were significantly smaller and had an increased rate of NTDs compared to embryos of CDr dams fed RD. When CDs dams were fed HSD, >50% of the CDs embryos were dead and 44% of the live embryos had NTDs. Live 11.5-day old embryos of CDs dams fed RD had a statistically significant increase in CAT, CuZn-SOD, and GSHpx mRNA levels compared with the levels in the CDr embryos from dams fed RD. CDs embryos from dams fed HSD showed significant overactivation of NF-kappaB compared with CDr embryos from dams fed HSD (in which activation was decreased), without any increase in the expression of SOD, CAT, and GSHpx.
This study demonstrates that one of the genetic differences between the CDr and CDs strains fed RD is an increased expression of genes encoding for antioxidant enzymes in the CDs but inability for upregulation in diabetes. In addition, while activation of NF-kappaB is decreased in CDr on HSD, it is increased in the CDs. These differences may play a role in the increased sensitivity of the CDs embryos to diabetic-induced teratogenicity.
我们之前已经表明，氧化应激在科恩糖尿病敏感（CDs）大鼠胚胎中糖尿病诱导的异常发病机制中起重要作用，并且似乎与遗传因素相互作用。我们研究了与抗氧化防御机制相关的遗传因素在CDs大鼠胚胎中的作用。
我们研究了喂食常规饮食（RD）的科恩糖尿病抗性（CDr）和CDs大鼠的11.5天和12.5天胚胎，因此它们没有患糖尿病，与喂食高蔗糖低铜饮食（HSD）的大鼠相比，只有CDs动物会患糖尿病。监测胚胎的生长和先天性异常。评估过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GSHpx）、铜锌超氧化物歧化酶（SOD-超氧化物歧化酶）、锰超氧化物歧化酶的mRNA以及核因子κB（NF-κB）的激活程度。
与喂食RD的CDr母鼠的胚胎相比，喂食RD的CDs母鼠的胚胎明显更小，神经管缺陷发生率更高。当CDs母鼠喂食HSD时，超过50%的CDs胚胎死亡，44%的存活胚胎有神经管缺陷。与喂食RD的母鼠所产CDr胚胎相比，喂食RD的CDs母鼠所产存活的11.5天大胚胎的CAT、铜锌超氧化物歧化酶和GSHpx mRNA水平有统计学显著升高。与喂食HSD的母鼠所产CDr胚胎相比（其激活程度降低），喂食HSD的母鼠所产CDs胚胎显示NF-κB显著过度激活，而SOD、CAT和GSHpx的表达没有任何增加。
本研究表明，喂食RD的CDr和CDs品系之间的遗传差异之一是CDs中编码抗氧化酶的基因表达增加，但在糖尿病中无法上调。此外，虽然HSD喂养的CDr中NF-κB的激活降低，但CDs中则增加。这些差异可能在CDs胚胎对糖尿病诱导的致畸性增加的敏感性中起作用。
