LONG-TERM ADMINISTRATION OF HIGH-DOSE VITAMIN-A TO RATS DOES NOT CAUSE FETAL MALFORMATIONS - MACROSCOPIC, SKELETAL AND PHYSICOCHEMICAL FINDINGS

A rat model was used to investigate whether high oral doses of vitamin A lead to fetal malformations and to what extent retinyl esters (RES) are transferred from the mother to the fetuses. Retinol and RES conce ntrations in plasma behave similarly in rats and humans. When high con centrations of vitamin A are administered, plasma retinol concentratio ns remain relatively constant, whereas plasma RES increased in paralle l with the dose. To achieve an elevation from similar to 150 to >1525 nmol . L(-1) in the experimental group before mating, female Ibm: RORO (spf) rats were fed a maintenance diet enriched with 15.2 x 10(3) ret inol equivalents (RE). kg(-1) at the start and increased stepwise to 5 2.5 x 10(3) for a total of 8 mo. A parallel subgroup was maintained to measure progress in experimental rats without interference by blood t aking. Rats of the control group received the basal diet analyzed to c ontain 4.5 x 10(3) RE . kg(-1). Before mating the mean body weights of experimental and control rats were not significantly different. All-t rans, 13-cis, 4-oxo-all-trans and 5,6-epoxy-all-trans retinoic acid (R A) concentrations were determined in maternal and fetal plasma. With h igh vitamin A intake, 4-oxo- and 5,6-epoxy RA concentrations were sign ificantly higher in the fetuses than in their mothers. Although these high intakes of vitamin A by the rat darns resulted in high maternal a nd fetal plasma concentrations of vitamin A and its metabolites, fetal malformations were not observed. This may be due to the fact that cir culating RES are not teratogenic and that after crossing the placental barrier, they are stored mainly in fetal liver.