Teratogenic effect of bis-diamine on embryonic rat heart


Department of Pediatrics, Shiga University of Medical Science, Seta, Otsu, Shiga 520–2192, Japan. E-mail:masao@belle.shiga-med.ac.jp


ABSTRACT  Bis-diamine induces conotruncal anomalies including persistent truncus arteriosus, tetralogy of Fallot, interruption of the aortic arch, and ventricular septal defect in rat embryos when administered to the mother. Bis-diamine also induces extracardiac malformations including thymic hypoplasia, facial dysmorphism, forelimb anomalies and diaphragmatic hernia. However, the teratogenic mechanisms of this chemical in early developing rat hearts have not been fully established. Chimeric studies in chick and quail embryos demonstrated that the cranial neural crest cells reached the cardiac outflow tract, contributing to aorticopulmonary and truncal septation. Since an ablation of the cranial neural crest also produced the conotruncal anomalies, bis-diamine is proposed to disturb the normal migration of cardiac neural crest cells to the heart. Based on our data concerning cardiac anomalies induced by bis-diamine, we reviewed how the cardiac malformations were morphologically established in early developing rat hearts. Our data showed that 1) cardiovascular anomalies induced by bis-diamine are time- and species or strain- dependent. 2) bis-diamine reduces the number of neural crest cells migrating to participate in the conotruncal septation, 3) bis-diamine induces anomalous coronary arteries, thin ventricular walls and epicardial defects, and 4) some embryos cultured in the medium containing bis-diamine had extra-cardiac abnormalities including abnormal location of the otic placodes and delay in mid brain closure. Conclusively, bis-diamine does not appear to merely affect the cardiac development, but rather disturbs normal development of all the organs contributed to by neural crest cells.