Malformations in offspring of diabetic rats: morphometric analysis of neural crest-derived organs and effects of maternal vitamin E treatment.

Abstract

We have previously reported on a malformation-prone Sprague-Dawley rat substrain (U), which presents a high frequency of micrognathia in the offspring of diabetic mothers. This malformation is related to impaired development of the cranial neural crest cells (NCC); the defect may be prevented by antioxidative treatment of the mother. We have therefore investigated whether fetuses of diabetic rats display other malformations associated with altered cranial NCC development and whether maternal vitamin E supplementation may affect such malformations. Fetuses of diabetic rats showed low-set external ears, severely malformed Meckel's cartilage, small thyroid and thymus, and absence of parathyroid glands. Cardiac anomalies were frequently observed, including rightward displacement of the aorta, double outlet right ventricle (DORV), persistent truncus arteriosus (PTA) combined with ventricular septal defects due to a malaligned outlet septum. The malformations in the outflow tract included abnormalities of the great arteries; right-sided aortic arch/descending aorta, and double aortic arches. These defects tended to occur together within individual fetuses. Maternal dietary treatment with 2% vitamin E markedly reduced the severity of the malformations. The phenotypic appearance of these defects is strikingly similar to the DiGeorge anomaly in humans, which has been found in children of diabetic mothers together with an overrepresentation of PTA and DORV. The malformations associated with defective NCC development in the offspring of diabetic U rats show several morphological similarities to those in humans; hence the teratogenic mechanisms may be similar and accessible for study.