Hypervitaminosis A resulting in DNA aberration in fetal transgenic mice (Muta ™ Mouse)

Abstract

Treatment with excessive amounts of Vitamin A during maternity induces fetal malformations. However, it is unclear whether these malformations are due to gene mutations or not. Using transgenic mice (containing lacZ gene showing β-galactosidase enzymatic activity), we planned to observe whether gene mutations occur in the fetal tissues after treatment during maternity with Vitamin A (retinol palmitate). On the 11th day of pregnancy, mothers were given 30 mg (group 2), 150 mg (group 3) and 300 mg (group 4) of Vitamin A/kg body weight orally. Fetuses obtained on the 18th day of gestation showed malformations, such as cleft palate, origodactyly, brachydactyly and ectromeria. Most notably, cleft palate occurred dose dependently. The incidental rates were 100% in group 4, 58% in group 3 and 6% in group 2. The number of dead and absorbed fetuses also increased dose dependently with the treatments. DNA (integrated vectors containing lacZ genes) extracted from each fetus showed Vitamin A-induced lacZ mutations, especially in the malformed fetuses. The mutation frequencies were 4.99 × 10 −5 in group 4, 5.28 × 10 −5 in group 3 and 4.26 × 10 −5 in group 2. The frequencies of group 3 were significantly higher ( p < 0.05) than that of the controls (group 1), 2.79 × 10 −5. Maternal treatment with Vitamin A (150 mg/kg of body weight) was carried out on the 11th day of pregnancy. Fetuses obtained on the 14th day of gestation showed a much higher incidence of mutation, approximately 8.91 × 10 −5 (group 6) that was significantly highter ( p < 0.0001) than those from the controls (group 5), 2.94 × 10 −5. The present study indicates a possibility that hypervitaminosis A-induced fetal malformation and death might be caused by gene mutations.