Midgut atresias result from abnormal development of the notochord in an Adriamycin rat model

Abstract

Background/Purpose: Prenatal exposure to Adriamycin in a rat model (ARM) has been reported to lead to a spectrum of tracheoesophageal and associated malformations of the gastrointestinal tract, including multiple intestinal atresias. An abnormal relationship of the notochord with the foregut has been implicated in the formation of esophageal atresias. The authors hypothesised that midgut atresias arise from abnormal notochord development in the region of the midgut. This study was designed to examine the gut-notochord relationship during early embryonic development. Methods: Timed pregnant Wistar rats were given 1.75 mg/kg of Adriamycin intraperitoneally on days 7, 8, and 9 of gestation. Embryos were recovered at 12-hour intervals from days 9.5 to 14, and at term. A control group was given saline instead of Adriamycin. Embryos were embedded in resin or wax, sectioned, and studied using light microscopy, paying particular attention to the notochord and surrounding structures. Results: The notochord appeared identical in controls and experimental embryos on day 9.5. However, on day 10.5 the notochord was diffusely abnormal in ARM, distorted, and tethered to foregut as well as midgut compared with controls. This abnormality was not seen in control embryos. On day 12 the notochord abnormalities were more exaggerated in the region of the midgut in ARM embryos. Full-term ARM animals had esophageal and multiple intestinal atresias. Conclusions: The notochord is abnormal in the region of the developing midgut, and this may account for the occurrence of atresias found in this region. J Pediatr Surg 37:719-722. Copyright 2002, Elsevier Science (USA). All rights reserved.