Gage J C, Sulik K K
Department of Cell Biology and Anatomy, University of North Carolina, Chapel Hill 27599-7090.
Teratology. 1991 Sep;44(3):299-312. doi: 10.1002/tera.1420440307.
Urinary tract abnormalities have been noted to occur in 10-27% of individuals diagnosed as having Fetal Alcohol Syndrome. Among a wide range of functional and structural abnormalities, renal agenesis/hypoplasia, hydronephrosis, and ureteropelvic obstruction feature most prominently. This study was designed to examine the pathogenesis of ethanol-induced urinary tract abnormalities in a mouse model. C57Bl/6J mice were acutely exposed to two doses of ethanol (2.9 g/kg IP) administered 4 hours apart beginning on gestational day (GD) 9, hour 4. This resulted in an incidence of 40.7% urinary tract anomalies among GD18 fetuses. With the exception of duplicate ureter, urinary tract abnormalities consisted exclusively of hydroureter/hydronephrosis. Examination of GD13-17 fetuses revealed that the first grossly detectable differences in the urinary tracts of control vs. affected specimens occurred on GD16 and initially only involved ureteral changes. Hydronephrosis was first detected on GD17. A contributing factor to the development of hydronephrosis appears to be the abnormal location of the ureterovesicle junction which commonly involves duplicate ureteral lumens with resultant functional obstruction to urine flow at the distal end of the ureter. Study of the early pathogenetic changes which appear to result in the urinary tract malformations observed involved utilization of scanning electron microscopy, vital dye (Nile blue sulphate) staining of whole embryos, and analysis of histological sections. These studies revealed that 12 hours following initial maternal ethanol exposure, embryos have excessive amounts of cell death localized in the region of the developing mesonephric duct just proximal to the cloaca. Also affected were premigratory neural crest cells located just proximal to the posterior neuropore. We conclude that excessive amounts of ethanol-induced cell death in these selectively vulnerable populations could account for the subsequently observed urinary tract malformations.
据指出，在被诊断患有胎儿酒精综合征的个体中，10%至27%会出现泌尿系统异常。在众多功能和结构异常中，肾发育不全/发育不良、肾积水和输尿管肾盂梗阻最为突出。本研究旨在检查小鼠模型中乙醇诱导的泌尿系统异常的发病机制。C57Bl/6J小鼠从妊娠第9天第4小时开始，每隔4小时腹腔注射两剂乙醇（2.9克/千克）。这导致18日龄胎儿中泌尿系统异常的发生率为40.7%。除重复输尿管外，泌尿系统异常仅包括输尿管积水/肾积水。对13至17日龄胎儿的检查显示，对照样本与受影响样本的泌尿系统首次在16日龄时出现明显可检测到的差异，最初仅涉及输尿管变化。肾积水在17日龄时首次被检测到。肾积水发展的一个促成因素似乎是输尿管膀胱连接处的异常位置，这通常涉及重复的输尿管腔，从而导致输尿管远端尿液流动的功能性梗阻。对似乎导致所观察到的泌尿系统畸形的早期发病变化的研究涉及使用扫描电子显微镜、对整个胚胎进行活性染料（硫酸尼罗蓝）染色以及对组织切片进行分析。这些研究表明，在母体首次接触乙醇12小时后，胚胎在泄殖腔近端发育中的中肾管区域有过量的细胞死亡。同样受影响的是位于后神经孔近端的迁移前神经嵴细胞。我们得出结论，这些选择性易损群体中过量的乙醇诱导的细胞死亡可能是随后观察到的泌尿系统畸形的原因。
