Teratogenicity of arotinoids (retinoids) in vivo and in vitro

Abstract

The effect of structural modifications on the arotinoid molecule, a new class of retinoids, on their teratogenicity in mice was studied. Animals were treated on days 8 and 9 of gestation, the most susceptible stages to retinoid-induced malformations in rodents. The teratogenic potency of the 13 arotinoids tested varied over a dose range of more than five orders of magnitude. Next, we tested whether the quantitative differences in the teratogenicity of these arotinoids correlates with their activity in high density (micromass) cultures of rat embryonic limb bud and midbrain cells. There was a good quantitative correlation between the in vivo teratogenicity and the in vitro activity in limb bud cells but no correlation was found in midbrain cells. Thus, the limb bud cell culture system may be useful for a preliminary testing to select non-teratogenic retinoids. For the risk assessment in humans, however, the in vitro results should be verified in animals studies.

Teratogenicity of arotinoids (retinoids) in the rat whole embryo culture

“…Five structurally closely related arotinoids with a difference in their in vivo teratogenic potency of approximately 106 (Kistler et al 1990) were tested in rat WEC. Compounds RO 13-7410 and RO 15-1549 were the most potent ones (NOAEL 0.03-0.3 nM) in inhibiting growth and differentiation of the conceptuses and in inducing an increased percentage of dysmorphogenic embryos.…”

“…The potency of 13 structurally closely related arotinoids (retinoids) to induce teratogenicity in mice in vivo after treatment on days 8 and 9 of pregnancy is strikingly different (Kistler et al 1990). The magnitude of the difference was on the order of 106 between the most and the least potent compound.…”

“…The types of anomalies observed in offspring of these dams were typical for retinoid teratogenicity (Kochhar 1967;Geelen 1979;Kistler 1981Kistler , 1987Kistler et al 1990). The potency of retinoids to inhibit rat (Kistler 1987;Kistler et al 1990). Five arotinoids with a free carboxylic endgroup RO 13-7410, RO 19-4788, RO 40-3387, RO 15-1549, and RO 19-4787 (Fig.…”

“…Structural modifications of the arotinoid molecule RO 13-7410 led to a difference in the teratogenic potencies of more than five orders of magnitude in mice in vivo and in micromass cultures of rat embryonic limb bud cells (Kistler et al 1990). Five of these retinoids were selected and tested in rat whole embryo culture to determine the suitability of this in vitro test system for the identification of potentially non-teratogenic derivatives among this class of chemicals.…”

13th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC): alternative testing methodologies for organ toxicity.

“…For a given group of structurally related chemicals, the whole embryo culture assay can be used inhouse for screening purposes. Limb bud cultures, brain cell aggregates, cultures of palatal shelves, embryonic lung, and many other organs both from rodents and even human tissues, and organs from aborted fetuses have been used extensively for mechanistic studies as adjunct tests to standard embryotoxicity tests in rodents (33,34 (65). A standardized protocol micromass assay was tested in an international validation trial, and Flint reported in 1993 that this assay correctly identified chemicals that are known to be teratogenic both in humans and the most common rodent species.…”