Yang X, Borg L A, Eriksson U J
Department of Medical Cell Biology, University of Uppsala, Sweden.
Anat Rec. 1995 Feb;241(2):255-67. doi: 10.1002/ar.1092410212.
Previous studies in vivo and in vitro have suggested that the oxidative metabolism of the embryo may have a role in the teratogenicity of diabetic pregnancy. In particular, the production of reactive oxygen species by the embryonic mitochondria has been implicated in the teratological process. The induction of congenital malformations by the diabetic milieu occurs during the early embryonic development. The present study aimed to estimate the role of the embryonic mitochondria in the teratological process of diabetic pregnancy by studying mitochondrial morphology in the embryos exposed to a diabetic environment in vivo or in vitro during early organogenesis and late fetal development.
For studies in vivo embryos of control or streptozotocin-diabetic rats were taken at gestational days 9-11 and subjected to light and electron microscopical analysis. The brain, heart, and liver of day-15 fetuses were also observed. For studies in vitro day-9 embryos of normal rats were cultured in a whole-embryo culture system for 48 hours. The culture media were supplied with high concentration of diabetes-related substrates and metabolites, and their effect on structure of embryonic neuroepithelial cells determined.
The light microscopical observations demonstrated numerous cytoplasmic vacuoles in the ectoderm of day-9 embryos and in the neuroepithelium and blood cells of day-10 and day-11 embryos of diabetic rats. Ultrastructurally, these vacuoles were found to be mitochondria undergoing large-amplitude swelling with loss of matrix density and disturbed cristae. In contrast, no mitochondrial differences were found in the brain, heart, and liver, when day-15 fetuses from normal and diabetic rats were compared. Ultrastructural analysis of day-9 embryos cultured for 48 hours in the presence of high concentrations of D-glucose, pyruvate, beta-hydroxybutyrate, and alpha-ketoisocaproate also showed high-amplitude mitochondrial swelling in the neuroepithelium. The mitochondrial swelling was, however, not found in embryos cultured in a high concentration of L-glucose, excluding simple osmotic effects of the diabetes-related substrates and metabolites.
The mitochondrial morphological changes appeared in embryos subjected to a diabetic environment during a time period when the congenital malformations in diabetic pregnancy are induced. The results support the notion that embryonic mitochondria are involved in the teratological process of diabetic pregnancy.
先前的体内和体外研究表明，胚胎的氧化代谢可能在糖尿病妊娠的致畸作用中发挥作用。特别是，胚胎线粒体产生的活性氧与致畸过程有关。糖尿病环境诱导先天性畸形发生在胚胎发育早期。本研究旨在通过研究在器官发生早期和胎儿发育后期体内或体外暴露于糖尿病环境的胚胎中的线粒体形态，评估胚胎线粒体在糖尿病妊娠致畸过程中的作用。
对于体内研究，在妊娠第9 - 11天获取对照或链脲佐菌素诱导糖尿病大鼠的胚胎，并进行光镜和电镜分析。还观察了第15天胎儿的脑、心脏和肝脏。对于体外研究，将正常大鼠第9天的胚胎在全胚胎培养系统中培养48小时。培养基中添加高浓度的糖尿病相关底物和代谢物，并确定它们对胚胎神经上皮细胞结构的影响。
光镜观察显示，糖尿病大鼠第9天胚胎的外胚层以及第10天和第11天胚胎的神经上皮和血细胞中有大量细胞质空泡。超微结构上，这些空泡被发现是线粒体，其经历大幅度肿胀，基质密度丧失且嵴紊乱。相比之下，比较正常和糖尿病大鼠第15天胎儿的脑、心脏和肝脏时，未发现线粒体差异。在高浓度的D - 葡萄糖、丙酮酸、β - 羟基丁酸和α - 酮异己酸存在下培养48小时的第9天胚胎的超微结构分析也显示神经上皮中线粒体大幅度肿胀。然而，在高浓度L - 葡萄糖中培养的胚胎中未发现线粒体肿胀，排除了糖尿病相关底物和代谢物的单纯渗透作用。
在糖尿病妊娠诱导先天性畸形的时间段内，暴露于糖尿病环境的胚胎出现了线粒体形态变化。结果支持胚胎线粒体参与糖尿病妊娠致畸过程的观点。
