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

Abstract

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. The highest concentrations of the compounds with no effects (NOAEL) on general conceptus growth, on differentiation and on the frequency of dysmorphogenic embryos in vitro were compared with the lowest effective teratogenic doses in vivo (LOAEL) or with the concentrations leading to 50% inhibition of limb bud cell differentiation (IC50) in vitro. NOAEL's for the parameters of conceptus development ranged from 10(-5) micrograms/ml (0.03 nM) to 10 micrograms/ml (28.7 microM) for the compounds tested. These correlated very well with LOAEL and IC50 (R greater than 0.95). The types of dysmorphogenesis in vitro were those typical for retinoids, and for the most part resembled the malformations found in vivo. We conclude that the whole embryo culture system is a useful tool for the preliminary testing of retinoids.

The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis

“…In general, the teratogenic potency of a retinoid correlates with its conversion potential to atRA, increasing half‐life/maternal clearance, and its ability to traverse the placenta (Soprano and Soprano,1995; Nau,2001). Teratogenic retinoids must be able to bind RAR, but strength of binding does not correlate well with teratogenic potency (arotinoids are much more potent teratogens than atRA but bind RAR approximately equivalently) (Kistler et al,1990; Bechter et al,1992; Nau,2001). Whereas developing retinoids that have therapeutic value without teratogenicity is problematic, since they would have to bind and activate the RAR, it may be possible to generate retinoids that are unable to be efficiently transferred to the embryo.…”

The Validation and Use of In Vitro Teratogenicity Tests

“…Results of 6 pairs of compounds were compared in the cultured chick and rat embryo and in a brain cell aggregate culture. We reported excellent comparison between in vivo and in vitro data for a series of retinoids (Bechter et al 1992). In an internal prospective validation study, ongoing for the last 10 years, with so far 5 in vivo teratogenic and 49 in vivo non-teratogenic compounds, the specificity of the test system was 90%, the sensitivity 60% and over all accuracy 87% (Bechter 1994, unpublished results). "…”

Reproduction and development.

“…In a validation study on different culture systems, six pairs of coded compounds were tested in chick and rat embryo cultures and in brain cell aggregate cultures (45). Bechter et al (46) reported an excellent agreement between in vivo and in vitro data for a series of retinoids.…”