title: Long-term administration of high dose vitamin A to rats does not cause fetal malformations: macroscopic, skeletal and physicochemical findings.
abstract: 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 concentrations in plasma behave similarly in rats and humans. When high concentrations of vitamin A are administered, plasma retinol concentrations remain relatively constant, whereas plasma RES increased in parallel with the dose. To achieve an elevation from approximately 150 to > 1525 nmol x 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) retinol equivalents (RE) x kg(-1) at the start and increased stepwise to 52.5 x 10(3) for a total of 8 mo. A parallel subgroup was maintained to measure progress in experimental rats without interference by blood taking. Rats of the control group received the basal diet analyzed to contain 4.5 x 10(3) RE x kg(-1). Before mating the mean body weights of experimental and control rats were not significantly different. All-trans, 13-cis, 4-oxo-all-trans and 5,6-epoxy-all-trans retinoic acid (RA) concentrations were determined in maternal and fetal plasma. With high vitamin A intake, 4-oxo- and 5,6-epoxy RA concentrations were significantly higher in the fetuses than in their mothers. Although these high intakes of vitamin A by the rat dams resulted in high maternal and fetal plasma concentrations of vitamin A and its metabolites, fetal malformations were not observed. This may be due to the fact that circulating RES are not teratogenic and that after crossing the placental barrier, they are stored mainly in fetal liver.
authors.affiliation: Department of Biological Chemistry and Nutrition, University of Hohenheim, Stuttgart, Germany.
authors.forename: H K
authors.initials: HK
authors.lastname: Biesalski
authors.forename: C
authors.initials: C
authors.lastname: Hemmes
authors.forename: M
authors.initials: M
authors.lastname: El Hanafy
authors.forename: H
authors.initials: H
authors.lastname: Weiser
authors.forename: H
authors.initials: H
authors.lastname: Zschaebitz
authors.forename: E
authors.initials: E
authors.lastname: Stofft
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004224:Diterpenes; D004952:Esters / Q000097:blood; D005260:Female; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D051381:Rats; D000084562:Retinyl Esters; D014801:Vitamin A / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000633:toxicity*
chemical_list: D004224:Diterpenes; D004952:Esters; D000084562:Retinyl Esters; D014801:Vitamin A; C014794:retinol palmitate; C042811:retinyl stearate; C042067:retinol oleate