Effects of hypervitaminosis A on the fetus of several species of experimental animals, with special reference to the oculofacial syndrome

Abstract

The present authors carried out a parallel experiment of hypervitaminosis A using CF#1 mice, Sprague-Dawley rats and Japanese white rabbits. Special attention was paid to 1) the relationship between the time of administration and the frequency of fetal deaths as well as oculofacial syndrome in the three species (stage-response experiment) and 2) the relationship between dose administered and the incidence of oculofacial syndrome in the three species (dose-response experiment). Prior to the present study the equivalent ages in the rat and rabbit embryos for each successive mean age in the mouse embryos (the 8th-13th day of pregnancy) were determined by grossly comparing some morphogenetic patterns. In the stage-response experiment, mice were given a single, intraperitoneal injection of vitamin A palmitate at a dose of 600,000 IU/kg from the 8th to the 13th day of pregnancy, rats were given at a dose of 500,000 IU/kg from the 10th to the 15th day and rabbits were administered 300,000 IU/kg from the 8th to the 16th day. In the dose-response experiment, various dose levels of vitamin A (50,000-250.000 IU/kg) were administered on the 8th day of pregnancy in mice and rabbits and on the 10th day in rats. The results are summarized as follows: 1. The susceptibility expressed by the frequency of fetal deaths including embryonic losses was the highest in rabbits, next in mice and the lowest in rats. 2. Oculofacial syndrome was produced in all species treated on earlier stage, i.e. , 8th-10th day in mice, 10th-11th day in rats and 9th-10th day in rabbits. 3. The minimal teratogenic dose for the production of oculofacial syndrome as well as anomalous craniofacial bones was almost the same in the three species. (50,000-75,000 IU/kg). while the dose-response relationship of those anomalies was the greatest in the rat, next in the mouse and the smallest in the rabbit. 4. Though many other characteristic malformations such as exencephalia, spina bifida, cleft palate, abdominal hernia, anal atresia, tail abnormalities and malformations of vertebrae and ribs were also produced mainly in mice and rats according to the stage injected, no clear dose-response was found except a case of cleft palate. or. The minimal teratogenic dose and the dose-response relationship were depended upon the stage injected. Therefore, more reliable study on the equivalent age in the three species will be necessary for the determination of the species-difference in the teratogenic effect of hypervitaminosis A.