Pattern of retinoid-induced teratogenic effects: Possible relationship with relative selectivity for nuclear retinoid receptors RARα, RARβ, and RARγ

Abstract

Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development. Excess as well as deficiency of retinoids were found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RAR's and RXR's, which exhibit a specific temporal and spatial expression during development. The significance of the retinoid receptors was investigated here by studying the teratogenic effects of retinoid ligands with relative selectivity for binding and transactivation of the retinoic acid receptors RARα, RARβ and RARγ. Pregnant NMRI mice were administered 5 or 15 mg/kg of CD 336 (Am 580) (α‐ligand), CD 2019 (β‐ligand), CD 437 (γ‐ligand) or 37.5 mg/kg all‐trans‐retinoic acid in 25% Cremophor EL on day 8.25 or day 11 of gestation by gastric intubation. External, visceral and skeletal malformations were observed on day 18 of gestation. The order of teratogenic potency was: α‐ligand>β‐ligand>γ‐ligand. In addition, these retinoids also produced a different spectrum of defects. The α‐ligand induced the most varied defects including severe ear, mandible, and limb malformations. The β‐ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The γ‐ligand preferentially induced ossification deficiencies and defects of the sternebrae and vertebral body. Our results show that these three retinoids, which were previously demonstrated to exhibit retinoid‐like activities in several systems, exert differing teratogenic activities, in regard to both potency and regioselectivity: we hypothesize that the relative selectivity for binding and transactivation of the three retinoic acid receptors could possibly be related to the differences of teratogenic effects observed in this study. The low potency of the γ‐ligand may lead the way to interesting new retinoids with improved therapeutic ratio. © 1996 Wiley‐Liss, Inc.

Retinoic acid-induced developmental defects are mediated by RARβ/RXR heterodimers in the pharyngeal endoderm

“…First, it has been shown that synthetic retinoids that are unable to activate RARs are non-teratogenic (Kochhar et al, 1996), whereas RAR isotype-selective retinoids produce a distinct spectrum of defects (Elmazar et al, 1996;Arafa et al, 2000). Second, overexpression of RARγ in Xenopus embryos potentiates the RA-induced loss of cranial structures, whereas expression of a dominant-negative form of RARs results in a resistance to RAinduced malformations (Old et al, 1996;Blumberg et al, 1997;van der Wees et al, 1998).…”

“…Moreover, the ligand-bound RXR is transcriptionally active only if its RAR partner is also ligand-bound (the so-called RXR subordination) (Lotan et al, 1995;Roy et al, 1995;Horn et al, 1996;Taneja et al, 1996;Botling et al, 1997;Chiba et al, 1997;Minucci et al, 1997;Altucci and Gronemeyer, 2001). Along the same lines, RXR-selective ligands, which are inactive on their own, synergize in vivo with RARα-and RARγ-selective ligands to generate congenital malformations (Kochhar et al, 1996;Lu et al, 1997;Elmazar et al, 1996;Elmazar et al, 1997;Elmazar et al, 2001). In our experiments, the panRXR agonist BMS649 (SR11237) had no effect on its own, indicating that neither RXR homodimers, nor other heterodimers in which the RXR partner is transcriptionally active on its own, mediate the teratogenic effects of retinoids on the branchial region.…”

Protective Effect of Quercetin on Histomorphometric Changes in Kidney of Retinoid Acid-Treated Rat Fetuses

“…We demonstrated astRA (at dose 25 mg/kg, IP) decreased number of renal corpuscles and increased periglomerular space and diameter of renal corpuscles. Elmazar et al (1996) found hypoplasia of kidney, hydronephrosis and hydroureter after administration of RA (37.5 mg/kg body weight). In the present study we focused on the effects of RA on histological structure of fetal kidney.…”

Disruption of Retinoic Acid Receptor Signaling by Environmental Pollutants

“…RARα ligands cause deformities of the ear, mandible and limb, RARβ ligands cause defects of the urinary system and liver, and RARγ ligands cause ossification deficiencies and defects of the sternebrae and vertebral body. [33][34][35] Excess intake of retinoids can cause deleterious effects not only in wild animals but also in humans.…”