Abstract
The glutamine analog, 6-diazo-5-oxo-L-norleucine (DON), is an antibiotic isolated from Streptomyces which has previously been described as an anti-tumor drug. The mechanism of teratogenesis and anti-tumor effects following DON exposure is not yet fully clarified. More specifically, compared to more commonly studied teratogenic subjects such as growth retardation, cleft palate, and limb defects, little has been reported on neurocristopathy and cardiovascular anomalies following maternal exposures to DON. In order to collect basic data for clinical application, prevention and safety, the biologically unique effects of DON and gamma-rays exposure need to be evaluated. In this study, Donryu rats in the experimental groups were given a single intraperitoneal DON injection and/or gamma-ray irradiation on day 10 of gestation. We reported on the relationships between full body maternal exposures to DON and subsequently observed embryonic lethality, external defects, and visceral anomalies, especially of cardiovascular nature. We observed a high frequency of craniofacial defects and cardiovascular anomalies, as well as embryonic lethality in the treated groups following day 10 of maternal exposure. These results indicate sensitivity to DON exposure of rat fetus leading to dysfunction and aberrant development of the neural crest, second heart field (SHF) in formation of neurocristopathy-induced cardiovascular anomalies, especially ventricular septal defects, tetralogy of Fallot, right aortic arch, vascular rings, double aortic arch and aortic arch anomalies. These types of cardiovascular anomalies are similar to those found in humans, termed DiGeorge syndrome, suggesting that similar chemicals and gamma-rays may play a role in dysfunction of neural crest, SHF and formation of human neurocristopathy as well as cardiovascular anomalies. It is crucial to consider their effects involving processes of DNA damage, mitochondrial damage, cell death and cell killing, dysfunction of neural crest, SHF and epithelial to mesenchymal transition (EMT) on the formation of these syndromes, as this animal model is expected to contribute in investigating the mechanism of such teratogenesis in human. The present data also suggests the need for further studies to specifically investigate the role played by the neural crest and SHF in the pathogenesis, prevention, clinical application of cardiovascular diseases and lethality.
