Genes and mechanisms that are involved in the effects of teratogens on limb development

Abstract

This review focuses on teratogens that cause limb malformations and the underlying mechanisms they deregulate to cause this. Normal limb development starts with proliferation of the intermediate mesoderm at sites along the body’s antero-posterior axis designated to form limbs. This is followed by axis patterning, bone and cartilage formation, muscle formation and vascular development to form a complete limb. Exposure to retinoic acid, alcohol, thalidomide, warfarin and valproic acid during limb development are known to cause limb malformations. The way in which they function and the type and severity of their effect differ per substance. To prevent teratogens from entering the market and causing limb malformations, it is important to perform predictive developmental toxicity tests. Currently, these tests move from the conventional costly and low-throughput in vivo animal models to more high-throughput models that reduce animal usage, and can be used to investigate the mechanisms by which teratogens alter normal limb development. In the future these methods have to deal with the increasing challenge to provide data on compounds to which humans may be exposed, but for which we lack developmental toxicity data.