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Teratogenicity of arotinoids (retinoids) in vivo and in vitro
A Kistler1, T Tsuchiya, M Tsuchiya
1Pharmaceutical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
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.
Insights
Structural modifications of arotinoids affect their teratogenicity. Limb bud cell cultures show promise for predicting retinoid safety, but further animal studies are needed for human risk assessment.
Area of Science:
- Developmental toxicology
- Retinoid research
- Pharmacology
Background:
- Retinoids are crucial for development but can be teratogenic.
- Arotinoids represent a new class of retinoids with potential therapeutic applications.
- Understanding the structure-teratogenicity relationship is vital for drug safety.
Purpose of the Study:
- To investigate the teratogenic effects of structural modifications in arotinoids in mice.
- To correlate in vivo teratogenicity with in vitro activity in embryonic cell cultures.
- To evaluate the utility of limb bud and midbrain cell cultures for predicting retinoid teratogenicity.
Main Methods:
- Administered 13 arotinoids to mice on gestation days 8 and 9.
- Assessed teratogenic potency across a wide dose range.
- Evaluated arotinoid activity in high-density (micromass) cultures of rat embryonic limb bud and midbrain cells.
Main Results:
- Significant variation in teratogenic potency among the 13 arotinoids tested.
- A strong quantitative correlation observed between in vivo teratogenicity and in vitro activity in limb bud cell cultures.
- No correlation found between in vivo teratogenicity and in vitro activity in midbrain cell cultures.
Conclusions:
- The rat embryonic limb bud cell micromass culture system shows potential for preliminary screening of non-teratogenic retinoids.
- In vitro findings require validation through animal studies for accurate human risk assessment.
- Structural modifications significantly influence arotinoid teratogenicity, necessitating careful evaluation.