Relationship of the notochord to foregut development in the fetal rat model of esophageal atresia☆☆☆

Background/Purpose: The notochord (Nt) is thought to act as a primary organizer for adjacent axial embryonic organs. The current study used the Adriamycin-induced fetal rat model of esophageal atresia and tracheoesophageal fistula (EA-TEF) to determine whether anomalies of the foregut (FG) were associated with an abnormal Nt.

Methods: Eight experimental female Sprague-Dawley rats received intraperitoneal injection of Adriamycin (1.75 mg/kg) on gestational days 6 to 9 inclusive, and 4 control rats received saline injection only. Their embryos were harvested on gestational days 11, 12, 13, and 14. Embryos from each age subgroup were serially sectioned and stained with H&E. The FG and Nt were traced from the primitive pharynx to the level of the stomach.

Results: By day 11, the Nt of control embryos had completely separated from the FG and was located immediately ventral to the neural tube. On gestational day 12, the Nt detached from the neural tube, and the trachea and esophagus were separating. On day 11, in the Adriamycin-treated embryos, the Nt was still attached to an FG that was narrowed or occluded. On day 12, the Nt remained adherent to the FG from the primitive pharynx to the level above the primitive respiratory buds, at which point it became thicker and branched sagittally, with the anterior branch contacting or merging with the FG. The FG usually loses its lumen or continuity when in contact with the Nt.

Conclusions: Exposure of rat embryos to Adriamycin leads to abnormal development of the Nt, including prolonged attachment to or fusion with the FG, and abnormal branching. Traction on the FG by the Nt produces occlusion of its lumen and may result in its complete interruption. Separation of the Nt from the FG would appear to be a prerequisite for the normal development of the FG into its derivatives: the esophagus and trachea.