Experimental production of congenital malformations in the Japanese white rabbits by maternal treatment with hypervitaminosisA

Abstract

Teratogenic effects of excessive vitamin A on the rabbit were examined morphologically. The rabbits used were those of jw/NIBS strain, which have been bred as a closed colony at Nippon Institute for Biological Science, Tokyo for about twenty years. The females were given a single, intraperitoneal injection of water-miscible vitamin A palmitate at a dose of 300,000 IU/kg body weight on day 8, 9, 10, 11, 12, 13, 14 or 15 of pregnancy. The fetuses were removed from the mothers by cesarean section on day 28 of pregnancy, and were examined for gross and skeletal malformations. The skeletal checks were done after clearing the soft tissues with KOH and stainning the bones with alizarin red S. In the group treated on day 8, all embryos died. In the groups treated from day 9 today 15, various gross and skeletal malformations were observed. General retardation of growth was also evident. The gross malformations manifested were cranio-facial malformations, auricular malformations, cleft palate, pseudomacroglossia, open-eyelid, short-tailedness, club foot, micromelia, ectrodactylism, syndactylism and brachydactylism. In the groups treated on day 9, 10 or 11, the malformations were produced with high frequencies. Their incidences reduced as the developmental stage of treatment advanced. The cranial malformations in the groups treated in the early stages of organogenesis showed a hypoplasia of the skull bones ; while those in the groups treated in the later stages revealed fusions or protuberances of the parietal and frontal bones. These findings suggested that the types of cranial malformations would vary according to the developmental stages at which the embryos were being insulted. The facial malformations showed hypoplasias of the nasal bones, maxillas, premaxillas and mandibles. The micromelias showed a shortening and thickening of the long bones. Fusion of the humerus and radius the elbow joint was also found in some cases of micromelia.