COMPARATIVE EMBRYOLETHALITY AND TERATOGENICITY OF THE ALL-TRANS ISOMERS OF RETINOIC ACID, 3,4-DIDEHYDRORETINYL ACETATE, AND RETINYL ACETATEIN PREGNANT RATS

The teratogenic potencies of the all-trans isomers of retinoic acid (R A), 3,4-didehydroretinyl acetate (A2), and retinyl acetate (Al) were c ompared. Groups of eight timed-pregnant Sprague-Dawley rats were admin istered single equimolar doses (3.5-352 mu mol/kg BW) of the retinoids orally in oil on day 8.5 of pregnancy, and dams and fetuses were sacr ificed on day 19. The relative teratogenicity and embryolethality of t he three tested retinoids were: RA > A2 > A1. The no-effect level of R A and A2 was 3.5 mu mol/kg BW and of Al was 35 mu mol/kg BW. Whereas t he adverse effects of RA and Al were dose dependent, A2 showed biphasi c effects, with a peak of embryolethality at 35 mu mol/kg BW. Dams als o exhibited weight loss and other toxic manifestations from doses of A 2 and RA greater than or equal to 35 mu mol/kg BW. In dosed dams, II) Liver concentrations of Al and A2 increased with the doses of Al and A 2, respectively, (2) RA had little effect on liver Al except for an in crease at the highest toxic dose, and (3) A2 showed a sparing effect o n liver A1. RA, although not detected in fetuses from dams treated wit h Al, was present in significant concentrations (0.5-4.1 nmol/g liver) in fetuses from dams treated with A2. The biphasic change in embryole thality with the dose of A2 correlates with this enhanced concentratio n of fetal RA. We hypothesize that the actual teratogen in the fetuses of A2-dosed dams is RA. A2 might induce this biphasic effect by inhib iting the catabolism of RA at lower doses and its formation at higher doses. (C) 1996 Wiley-Liss, Inc.