Embryogenesis in cultured whole rat embryos after combined exposures to 3,3',5-triiodo-L-thyronine (T3) plus all-trans-retinoic acid and to T3 plus 9-cis-retinoic acid.
Retinoid-induced malformations of the jaw, ears, face, skull, eyes, and heart in humans and rodents are well known. Data on nuclear receptors and developmental toxicity bioassays indicate that thyroid hormones can modulate the biologic activity of retinoids. The present investigation concerned the potential for interactions of all-trans-retinoic acid (RA) with 3,3'5-triiodo-L-thyronine (T3) and of 9-cis-retinoic acid (9-cis-RA) with T3 in the morphogenesis of cultured whole rat embryos. Varying concentrations of retinoids or T3 were microinjected into the amniotic fluid or placed in the culture medium alone or in combinations of T3 with each retinoid. At 200 ng/ml, T3 increased the incidence of branchial arch defects produced by either RA or 9-cis-RA but did not elicit branchial arch defects alone except at concentrations significantly compromising survival (2,000 ng/ml; 32% mortality). Similarly high culture medium concentrations of T3 alone were associated with failure of neural tube closure in the rhombencephalon (rhombencephalic schisis). At this concentration, other dysmorphia were minimal and at 670 ng/ml T3, no dysmorphogenic or embryotoxic effects could be detected. Modulation of T3 effects by the yolk sac placenta was suggested by failure of microinjected T3 to elicit dysmorphia at very high amniotic fluid concentrations. RA (300 ng/ml) or 9-cis-RA (600 ng/ml) alone elicited no or minimal rhombencephalic schisis at the highest concentrations studied. RA plus T3 produced a much greater than additive effect on rhombencephalic schisis, whereas 9-cis-RA plus T3 produced a less than additive effect. Conversely, much greater than additive effects on anterior schisis were observed for 9-cis-RA plus T3 whereas combined effects of RA and T3 were approximately additive. For most other dysmorphia, the combined effects of each retinoid with T3 were greater than additive and were particularly striking for cephalic defects.
Kraft
J C
JC
Department of Pharmacology, School of Medicine, University of Washington, Seattle 98195.
Willhite
C C
CC
Juchau
M R
MR
D000014:Abnormalities, Drug-Induced; D000650:Amnion; D000818:Animals; D001934:Branchial Region / Q000187:drug effects; D003470:Culture Media; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects*; D007536:Isomerism; D009436:Neural Tube Defects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012249:Rhombencephalon / Q000187:drug effects; D014212:Tretinoin / Q000008:administration & dosage / Q000494:pharmacology*; D014284:Triiodothyronine / Q000008:administration & dosage / Q000494:pharmacology*
D003470:Culture Media; D014284:Triiodothyronine; D014212:Tretinoin