Dawrant Michael J, Giles Shay, Bannigan John, Puri Prem
National Children's Hospital, Tallaght, Dublin 24, Ireland.
Pediatr Surg Int. 2007 May;23(5):469-72. doi: 10.1007/s00383-006-1847-9.
A spectrum of tracheo-oesophageal malformations is seen in humans: oesophageal atresia, tracheal agenesis and laryngotracheo-oesophageal clefts. They are thought to share a common but unknown aetiology. These birth defects are frequently associated with other VACTERL anomalies. The adriamycin rat model (ARM) has proved to be a valuable model of the VACTERL anomalies, illustrating the dysmorphogenesis of oesophageal atresia and tracheal agenesis. As organogenesis relies on temporaspatially co-ordinated signalling systems, the next step would be to study the molecular pathogenesis of tracheo-oesophageal malformations. However, the mouse is the foremost mammal studied by developmental biologists, offering an expanding wealth of knowledge and scientific research techniques with which to investigate these anomalies. A limited dose response analysis of the teratogenicity of adriamycin in the mouse has identified a dose and timing of injections that produced tracheo-oesophageal malformations and other VACTERL anomalies. A clear account of the types and variability of the tracheo-oesophageal malformations produced by this dose is essential in order to be able to plan and interpret any future investigations of early gestation fetuses. CBA/Ca mice were accurately time-mated (n = 10). Nine dams received intraperitoneal injections of adriamycin (6 mg/kg) and one control dam received saline injections, on days 7 and 8. Fetuses were harvested on day 18, near term. Tracheo-oesophageal malformations were examined by dissecting microscope and serial transverse sections. Results are reported in the standard teratological manner as mean percentage per litter (+/-SEM). The resorption rate of the adriamycin treated fetuses was 50.4%. There were 29 adriamycin treated fetuses for inspection. Tracheo-oesophageal malformations were found in 29.2% (+/-10.3), affecting five out of nine litters. Oesophageal atresia occurred in 15.6% (+/-8.1), laryngotracheo-oesophageal cleft in 10.4% (+/-7) and tracheal agenesis in 3.1% (+/-3.1). All of these malformations occurred with a tracheo-oesophageal fistula. Unlike the ARM, the AMM can produce fetuses with complete laryngotracheo-oesophageal cleft as well as oesophageal atresia or tracheal agenesis. Their occurrence was found to be reproducible but variable. These are important considerations when planning and interpreting experiments using this model.
食管闭锁、气管发育不全和喉气管食管裂。它们被认为有共同但未知的病因。这些出生缺陷常与其他VACTERL异常相关。阿霉素大鼠模型（ARM）已被证明是VACTERL异常的一个有价值的模型，说明了食管闭锁和气管发育不全的畸形发生过程。由于器官发生依赖于时空协调的信号系统，下一步将是研究气管食管畸形的分子发病机制。然而，小鼠是发育生物学家研究最多的哺乳动物，提供了越来越丰富的知识和科研技术来研究这些异常。对阿霉素在小鼠中的致畸性进行的有限剂量反应分析确定了产生气管食管畸形和其他VACTERL异常的注射剂量和时间。清楚了解该剂量产生的气管食管畸形的类型和变异性对于能够计划和解释未来对早期妊娠胎儿的任何研究至关重要。对CBA/Ca小鼠进行精确的定时交配（n = 10）。9只母鼠在第7天和第8天接受腹腔注射阿霉素（6 mg/kg），1只对照母鼠接受生理盐水注射。在接近足月的第18天收获胎儿。通过解剖显微镜和连续横切片检查气管食管畸形。结果以标准的致畸学方式报告为每窝的平均百分比（±SEM）。阿霉素处理的胎儿的吸收率为50.4%。有29只阿霉素处理的胎儿可供检查。发现29.2%（±10.3）有气管食管畸形，影响了9窝中的5窝。食管闭锁发生率为15.6%（±8.1），喉气管食管裂为10.4%（±7），气管发育不全为3.1%（±3.1）。所有这些畸形都伴有气管食管瘘。与ARM不同，阿霉素小鼠模型（AMM）可以产生完全喉气管食管裂以及食管闭锁或气管发育不全的胎儿。发现它们的发生是可重复的，但存在变异性。在使用该模型计划和解释实验时，这些都是重要的考虑因素。
