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Multiple gastrointestinal atresias result from disturbed morphogenesis
L Fourcade1, H Shima, E Miyazaki
1Children's Research Centre, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland.
Abstract:
Multiple gastrointestinal atresias (MGA) have been reported to account for 6% to 32% of all intestinal atresias. Controversy exists regarding the pathogenesis. Many investigators believe MGA to be the result of multiple ischemic infarctions of the intestinal tract. However, some have suggested that MGA results from a malformative process early in fetal life. Prenatal exposure to adriamycin in a rat model has been reported to lead to a spectrum of tracheoesophageal and associated malformations of the gastrointestinal tract, including intestinal atresias, identical to these observed in humans. The aim of this study was to determine the incidence and histopathologic findings of MGA in order to understand the pathogenesis. Timed-pregnant Sprague-Dawley rats were injected with adriamycin (1.75 mg/kg) in nine different gestational-day protocols. MGA was only seen in those rats who received adriamycin on gestational days 7, 8, and 9. The litters were recovered on day 21 by cesarean section. The digestive tracts (DT) of the fetuses were harvested for macroscopic and microscopic examination. Ten rats who received adriamycin on gestational days 7, 8, and 9 produced 87 newborns; 1 was damaged during dissection. DT anomalies occurred in 80 (93%) of the 86 newborns; 94% of these demonstrated MGA. There was a very high incidence of associated anomalies in newborns with MGA. Histologically, the blind-ending atresias showed different degrees of villous hyperplasia with or without intraluminal material. This is the first report demonstrating a high rate of occurrence of MGA in the adriamycin rat model. The injection of adriamycin early in gestation, the high incidence of associated malformations, and the anatomic and histologic findings in MGA indicate that MGA is a result of a malformative rather than an ischemic process.
Insights
Multiple gastrointestinal atresias (MGA) in rats result from early gestation adriamycin exposure, indicating a malformative, not ischemic, process. This study highlights MGA
Area of Science:
- Developmental biology
- Toxicology
- Gastroenterology
Background:
- Multiple gastrointestinal atresias (MGA) represent a significant portion of intestinal atresias, with ongoing debate regarding their cause.
- The prevailing theories suggest either multiple ischemic events or a malformative process during fetal development.
Purpose of the Study:
- To investigate the incidence and histopathologic features of MGA in a rat model.
- To elucidate the pathogenesis of MGA by examining the effects of prenatal adriamycin exposure.
Main Methods:
- Timed-pregnant Sprague-Dawley rats were administered adriamycin (1.75 mg/kg) across nine different gestational protocols.
- Fetuses were delivered via cesarean section on day 21, and their digestive tracts were examined macroscopically and microscopically.
- MGA incidence was specifically analyzed in litters exposed on gestational days 7, 8, and 9.
Main Results:
- Adriamycin exposure on gestational days 7, 8, and 9 induced MGA in 94% of affected newborns (80/86 fetuses).
- Newborns with MGA exhibited a high frequency of associated congenital anomalies.
- Histological examination revealed varying degrees of villous hyperplasia in atretic segments, sometimes with intraluminal material.
Conclusions:
- Prenatal adriamycin exposure during critical early gestation periods reliably induces MGA in rats.
- The findings strongly support a malformative etiology for MGA, rather than an ischemic cause.
- This rat model provides valuable insights into the developmental origins of MGA and associated anomalies.