The Effect of Adriamycin Exposure on the Notochord of Mouse Embryos

• Published in: Birth defects research. Part B. Developmental and reproductive toxicology 2012-04, Vol.95 (2), p.175-183
• Main Authors: Hajduk, Piotr, May, Alison, Puri, Prem, Murphy, Paula
• Format: Article
• Language: English
• Subjects: Abnormalities, Drug-Induced - embryology; Animals; Cadherins; Disease Models, Animal; Doxorubicin - toxicity; E-cadherin; Embryo, Mammalian - abnormalities; Embryo, Mammalian - drug effects; Embryo, Mammalian - embryology; Esophageal Atresia - chemically induced; Esophageal Atresia - embryology; Esophageal Atresia - pathology; foregut; Immunohistochemistry - methods; Laminin; Laminin - metabolism; Mice; Mice, Inbred CBA; Microscopy, Confocal - methods; notochord; Notochord - abnormalities; Notochord - drug effects; Notochord - embryology; OA/TOF; Studies; Tracheoesophageal Fistula - chemically induced; Tracheoesophageal Fistula - embryology; Tracheoesophageal Fistula - pathology
• ISSN: 1542-9733; 1542-9741
• DOI: 10.1002/bdrb.21002

The notochord has important structural and signaling properties during vertebrate development with key roles in patterning surrounding tissues, including the foregut. The adriamycin mouse model is an established model of foregut anomalies where exposure of embryos in utero to the drug adriamycin leads to malformations including oesophageal atresia and tracheoesophageal fistula. In addition to foregut abnormalities, treatment also causes branching, displacement, and hypertrophy of the notochord. Here, we explore the hypothesis that the notochord may be a primary target of disruption leading to abnormal patterning of the foregut by examining notochord position and structure in early embryos following adriamycin exposure. Treated (n = 46) and control (n = 30) embryos were examined during the crucial period when the notochord normally delaminates away from the foregut endoderm (6–28 somite pairs). Transverse sections were derived from the anterior foregut and analyzed by confocal microscopy following immunodetection of extracellular matrix markers E‐cadherin and Laminin. In adriamycin‐treated embryos across all stages, the notochord was abnormally displaced ventrally with prolonged attachment to the foregut endoderm. While E‐cadherin was normally detected in the foregut endoderm with no expression in the notochord of control embryos, treated embryos up to 24 somites showed ectopic notochordal expression indicating a change in characteristics of the tissue; specifically an increase in intracellular adhesiveness, which may be instrumental in structural changes, affecting mechanical and signaling properties. This is consistent with disruption of the notochord leading to altered signaling to the foregut causing abnormal patterning and congenital foregut malformations.