Comparative teratogenic activities of two retinoids: Effects on palate and limb development

Abstract

Two closely related retinoids, all-trans and 13-cis retinoic acids, were assessed for their relative activities as teratogens in ICR mice by monitoring the frequency with which either isomer produced discrete dysmorphogenesis of the embryonic limb and the secondary palate. A single oral dose of all-trans retinoic acid at 100 mg/kg on either day 11.5 or 12.0 of gestation (plug day = day one) was maximally effective; more than 90% of the treated embryos developed reduction defects of the limb bones and an equally high percentage also had cleft palate. The limb development was most sensitive on day 11.5 of gestation while the peak susceptibility for palatal clefts began on day 12.0. Under identical experimental conditions, treatment with 100 mg/kg 13-cis retinoic acid produced no apparent teratogenic effects. By assessing the relative incidence of readily identifiable malformations of the limb and palate associated with various doses of the two isomers, we found that 13-cis retinoic acid was four to eight times less embryopathic than all-trans retinoic acid. Since the mechanism of teratogenic action of retinoids is still far from clear, it is suggested that further studies on causative factors will be greatly assisted by the use of these two closely related retinoids, which substantially differ from each other in their teratogenic potency.

Spatial and temporal pattern of expression of the cellular retinoic acid-binding protein and the cellular retinol-binding protein during mouse embryogenesis.

“…USA (86,(8813)(8814)(8815)(8816)(8817), the following printer's error should be noted. The grey background was not removed as directed from color figures 1 (Upper Left) Bright-field photomicrograph on which arrows specify certain areas: tel, telecephalon; mes, mesencephalon; mye, myelencephalon; sc, spinal cord; drg, dorsal root ganglia; sn, spinal nerves; h, heart; t, tongue; Iv, liver; da, dorsal aorta. (u) In the eye, CRABP is expressed in the retinal layer, and CRBP is expressed in both retinal and pigmented layers.…”

A novel method for retinoic acid administration reveals differential and dose‐dependent downregulation of Fgf3 in the developing inner ear and anterior CNS

“…An incidence of 65-82% affected embryos have been reported using a 100-mg/kg dose of RA (Kochhar et al, 1984;Campbell et al, 2004;Abbott et al, 2005). Clefting of the palate was presented in embryos with 100 mg/kg of RA administered by both gavage (n¼4) and sugar pellets (n¼5) in all embryos analysed.…”

Structure-activity relationships of retinoids in developmental toxicology

“…13-lli-RA is one-half as teratogenic as all-!mru.-RA in the hamster (ED5o = 22.3 mg / kg for 13-lli-RA; ED5o = 10.5 mg/ kg for a!Hra.n.s.-RA, 66) and four to eight times less embryopathic than all-!mru.-RA in the mouse (Kochhar et al, 1984b). However, it is still unknown if binding of retinoids to cRABP is imperative for teratogenic activity.…”

“…When treated with retinylidene methyl nitrone, hamsters were afflicted with a more severe syndrome of malformation than mice (Willhite and Balogh-Nair, 1984;Willhite and Balogh-Nair, 1985). A dose of 100 mg/ kg 13-lli-RA failed to induce limb malformations in ICR mice on day II (Kochhar et al, 1984b), but 25 mg/ kg 13-lli-RA significantly increased the number of affected litters in hamsters on day 8 (Willhite and Balogh-Nair, 1984). The species differences may be related to differential absorption from the gut, species-specific biotransformation patterns, pharmacokinetic or disposition differences, or to differential levels of or binding affinity for embryonic cRABP.…”

“…Because the teratogenic effective dose 50 (ED 5o) is 22.3 and 10.5 mg/kg for isotretinoin (13-ili-RA) and all-!rlllli.-RA, respectively, and because the dose-response curves are parallel, it can be concluded the 13-ili-RA is approximately onehalf as potent a teratogen as all-t.mM-RA in hamsters (Willhite and Shealy, 1984). And 13-ili-RA is four to eight times less embryopathic than all-lli!lli.-RA in the mouse (Kochhar et al, 1984b). However, it is unknown if binding to cRABP is obligatory for teratogenic activity.…”