Comparative embryolethality and teratogenicity of the all-trans isomers of retinoic acid, 3,4-didehydroretinyl acetate, and retinyl acetate in pregnant rats.
The teratogenic potencies of the all-trans isomers of retinoic acid (RA), 3,4-didehydroretinyl acetate (A2), and retinyl acetate (A1) were compared. Groups of eight timed-pregnant Sprague-Dawley rats were administered single equimolar doses (3.5-352 mumol/kg BW) of the retinoids orally in oil on day 8.5 of pregnancy, and dams and fetuses were sacrificed on day 19. The relative teratogenicity and embryolethality of the three tested retinoids were: RA > A2 > A1. The no-effect level of RA and A2 was 3.5 mumol/kg BW and of A1 was 35 mumol/kg BW. Whereas the adverse effects of RA and A1 were dose dependent, A2 showed biphasic effects, with a peak of embryolethality at 35 mumol/kg BW. Dams also exhibited weight loss and other toxic manifestations from doses of A2 and Ra > or = 35 mumol/kg BW. In dosed dams, (1) Liver concentrations of A1 and A2 increased with the doses of A1 and A2, respectively, (2) RA had little effect on liver A1 except for an increase at the highest toxic dose, and (3) A2 showed a sparing effect on liver A1. RA, although not detected in fetuses from dams treated with A1, was present in significant concentrations (0.5-4.1 nmol/g liver) in fetuses from dams treated with A2. The biphasic change in embryolethality with the dose of A2 correlates with this enhanced concentration 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 inhibiting the catabolism of RA at lower doses and its formation at higher doses.
Duitsman
P K
PK
Department of Biochemistry and Biophysics, Iowa State University, Ames 50011, USA.
Olson
J A
JA
D000818:Animals; D004224:Diterpenes; D005260:Female; D005327:Fetal Resorption; D007536:Isomerism; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D009929:Organ Size; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D000084562:Retinyl Esters; D013723:Teratogens / Q000633:toxicity*; D014212:Tretinoin / Q000633:toxicity*; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000633:toxicity
C105682:3,4-didehydroretinyl acetate; D004224:Diterpenes; D000084562:Retinyl Esters; D013723:Teratogens; D014801:Vitamin A; C009166:retinol acetate; D014212:Tretinoin