Teratogenic effect of bis‐diamine on embryonic rat heart

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.

Teratogenic effects of bis‐diamine on the developing cardiac conduction system

“…Previous studies showed that cardiovascular anomalies were frequently induced when bis‐diamine was administered to pregnant female rats on ED 10.5, and this animal model has been used to understand the pathogenesis of conotruncal anomalies (Taleporos et al, 1978; Hayakawa et al, 1983; Okamoto et al, 1984; Momma et al, 1990, 1991; Tasaka et al, 1991, 1993; Kuribayashi and Roberts, 1993; Momma and Ando, 1994, 1995; Jackson et al, 1995). Until now, it has been shown that bis‐diamine establishes cardiovascular defects by disturbing the migration of neural crest cells and myocardial differentiation, proliferation, and apoptosis thorough placental transfer (Ikeda et al, 1984; Binder, 1985; Choy et al, 1999; Fujino et al, 1999; Nakagawa et al, 2000; Nishijima et al, 2000; Okamoto et al, 2004). The present study showed that this animal model is useful for understanding the mechanisms of arrhythmias associated with human congenital heart disease.…”

“…N,N′ bis (dichloroacetyl) diamine‐1,8‐octa‐methylene diamine (bis‐diamine) is known to induce characteristic conotruncal anomalies, including patent truncus arteriosus, tetralogy of Fallot, interruption of the aortic arch, and ventricular septal defect in embryos when administered to pregnant female rats (Taleporos et al, 1978; Hayakawa et al, 1983; Okamoto et al, 1984; Momma et al, 1990, 1991; Tasaka et al, 1991, 1993; Kuribayashi and Roberts, 1993; Momma and Ando, 1994, 1995; Jackson et al, 1995). Previous studies using this animal model have shown that bis‐diamine caused anomalous neural crest cell migration into the hearts and subsequent abnormal conotruncal division (Ikeda et al, 1984; Binder, 1985; Choy et al, 1999; Fujino et al, 1999; Nakagawa et al, 2000), pericardial defects (Nishijima et al, 2000), and poor myocardial proliferation and growth (Okamoto et al, 2004). In order to determine the mechanisms of arrhythmias associated with congenital heart defects, we examined the embryonic development of the cardiac conduction system in this animal model.…”

Teratogenic effects of bis‐diamine on the developing myocardium

“…N,N′‐bis (dichloroacetyl) diamine‐1,8‐octa‐methylene diamine (bis‐diamine) is known to induce characteristic cardiovascular anomalies, including such conotruncal anomalies as patent truncus arteriosus, tetralogy of Fallot, interruption of the aortic arch, and ventricular septal defect in rat embryos when administered to the mother (Tareporos et al, 1978; Hayakawa et al, 1983; Okamoto et al, 1984; Momma et al, 1990, 1991; Tasaka et al, 1991, 1993; Kuribayashi and Roberts, 1993; Momma and Ando, 1994, 1995; Jackson et al, 1995). In previous reports, this chemical was proposed to disturb the normal migration of cardiac neural crest cells into the heart, leading to the induction of the conotruncal anomalies (Ikeda et al, 1984; Binder, 1985; Choy et al, 1999; Fujino et al, 1999; Nakagawa et al, 2000; Nishijima et al, 2000). Because the human conotruncal anomalies are also induced by abnormal neural crest cell migration into the heart, this animal model appears useful for studying myocardial cell growth and proliferation or ventricular development in the heart exhibiting a conotruncal anomaly.…”