Demonstration of abnormal notochord development by three-dimensional reconstructive imaging in the rat model of esophageal atresia

The notochord (Nt) is believed to have a. role in the development of axial organs. This study was undertaken to reconstruct in three dimensions (3D) t he relationship of the Nt to abnormal development of the foregut (Fg) in th e adriamycin-induced rat model of esophageal atresia (EA). Pregnant Sprague -Dawley rats were given 1.75 mg/kg adriamycin intraperitoneally on gestatio nal days 6-9 inclusive; control rats received i.p. saline of equal volume, or no injection. Rats were killed between days 11 and 14 and their embryos harvested, histologically sectioned serially, and stained with hematoxylin and eosin. Digitized photographs were taken of serial transverse sections; these photos were traced and used as the basis for 3D reconstruction. From day II the normal Nt is no longer in contact with the respiratory or Fg mes enchyme. In adriamycin-treated embryos the Nt branches abnormally as it ent ers the Fg mesenchyme. Adherence of the Nt to the mesenchyme of the Fg exer ts mechanical traction pulling the upper Fig dorsally. The severity of the Fg abnormalities correlates with the length of the ventral extension of the Nt within the Fg mesenchyme: the embryo develops atresia of the esophagus or trachea when the Nt is grossly abnormal. The Nt undergoes reactive thick ening in the absence of Fg structures ventral to it. Thus, structural lesio ns of the Fg (e.g., atresias) are associated with abnormalities of the Nt. The relationship of the Nt to the Fg mesenchyme determines the severity of the abnormality induced by adriamycin: extensive adherence produces trachea l agenesis and EA.