Limb malformations of rat fetuses exposed to a distal inhibitor of cholesterol biosynthesis

Abstract

Triparanol, an inhibitor of desmosterol Δ24 reductase, produces a high rate of limb malformations in rat fetuses exposed at gestational day 10 (gd 10) to a single oral dose (150–200 mg/kg) given to the pregnant dam. AY9944, another efficient distal inhibitor of cholesterol biosynthesis that blocks dehydrocholesterol Δ7 reductase, produces a similar degree of cholesterol depletion but fewer malformations. Gas liquid chromatography–mass spectrometry (GC-MS) profiling of the sterols in the serum of the dams and in extracted embryos shows that in addition to desmosterol Δ24 reductase inhibition the conversion of Δ8 to Δ7 unsaturated sterols is also blocked by Triparanol. Therefore, the inhibitor induces the accumulation of desmosterol (Δ8 cholesten-3β-ol, 8-dehydrocholesterol) and zymosterol (Δ8, Δ24 cholestadien-3β-ol) in embryo tissues. The high concentration of the teratogenic drug assayed in the embryos at three successive gestational days (10–30 μg/g) is thought to cause the blockade in both Δ24 reductase and Δ8-Δ7 isomerase, which results in the particular profile of aberrant sterols.Comparison of the animal model with human syndromes, including limb osseous and skeleton perturbations, suggests a combination of desmosterol and Δ8 unsaturated sterols as being involved in the deleterious influence on limb bone formation.

Keywords

• limb patterning
• Sonic Hedgehog
• osteogenesis
• Indian Hedgehog
• chondrodysplasia
• desmosterolosis