Adriamycin mouse model: a variable but reproducible model of tracheo-oesophageal malformations.

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.

Embryologic and anatomic basis of esophageal surgery.

The embryogenesis, congenital anomalies, and surgical anatomy and applications of the esophagus for benign and malignant processes are detailed in this article. Emphasis is placed on the role of embryology and the anatomy involved in surgical decisions.

Timing and embryology of esophageal atresia and tracheo-esophageal fistula.

BACKGROUND: The embryology of tracheo-esophageal anomalies is controversial. The development of an adriamycin-treated animal model has enabled improved understanding of the embryogenesis of these anomalies. Using this model, we aimed to describe the events leading to esophageal atresia and tracheo-esophageal fistula. METHODS: Timed-pregnant Sprague-Dawley rats were injected daily with adriamycin intraperitoneally at a dose of 2 mg/Kg on days 6-9 of gestation. Histological sections were prepared from 96 experimental and 34 control rat embryos at 11-14 days gestation (plug day = day 0). RESULTS: The tracheal bud failed to develop normally from the foregut, leaving the foregut to give origin to both bronchi and differentiate into the respiratory system, and then continue as a fistula to the lower esophageal segment. Dorsal pouching of the proximal foregut, which is seen clearly on day 13, is responsible for the development of the upper esophageal segment. CONCLUSIONS: We conclude that failure of the tracheal bud to develop normally from the primitive foregut is the main event which leads to the tracheo-esophageal anomalies. As the proximal part of the primitive foregut develops primarily into a trachea rather than an esophagus, the anomaly of the esophagus could be described as agenesis instead of atresia.

Restitution of swallowing in the fetal sheep restores intestinal growth after midgestation esophageal obstruction.

We have shown that, in the fetal sheep, abolition of fluid ingestion early in gestation results in a profound gastrointestinal tract (GIT)-specific growth retardation and that these effects can be reversed if fetal swallowing is restored, even for relatively short periods (15 days). The fetal esophagus was ligated at 60-65 days of gestation in 11 fetal sheep (term is 145-148 days). At 136 days of gestation, body and tissue growth of six fetuses were compared to eight age-matched control fetuses. There were no effects on body growth, but the growth of the GIT was significantly retarded. The small intestine was the most severely affected region; villi were smaller in both proximal and distal regions, and villus density was increased and crypt density decreased. The growth-retarding effects are progressive such that they become more pronounced as the period of absence of swallowed input to the GIT is increased. Thus the effects observed in our study (ingestion abolished for approximately 80 days) are much more marked than those in our earlier short-term studies (40-50 days). Five of the fetuses with esophageal ligations underwent further surgery at approximately 120 days' gestation to correct the esophageal obstruction so as to allow the resumption of fluid ingestion. By 136 days, the values of most intestinal morphological parameters had begun to move toward control values.(ABSTRACT TRUNCATED AT 250 WORDS)