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Long-Term Administration of High Dose Vitamin A to Rats Does Not Cause Fetal Malformations: Macroscopic, Skeletal and Physicochemical Finds^1,2,

Hans K. Biesalski^*,3, Christian Hemmes^*, Magdy el Hanafy^*, Harald Weiser, Horst Zschaebitz^** and Eckart Stofft^**

^* Department of Biological Chemistry and Nutrition, University of Hohenheim, D-70593 Stuttgart, Germany Department of Vitamin and Nutrition Research, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland ^** Department of Anatomy, University of Mainz, D-55099 Mainz, Germany

A rat model was used to investigate whehter 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 elevantion from 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 10³ retinol equivalents (RE) · kg^-1 at the start and increased stepwise to 52.5 x 10³ 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 10³ RE · 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.

KEY WORDS: • vitamin A • retinyl esters • retinoic acid • teratogenicity • rats

¹ Supported in part by DFG grant B1313/5-1.

² The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

³ To whom reprint requests should be addressed.

Manuscript received 7 June 1995. Revision accepted 21 December 1995.