Framework of thalidomide teratogenicity. Thalidomide is broken down into active byproducts. The antiangiogenic byproduct inhibits new blood vessel formation in forming tissues and organs (but not mature, vascular smooth muscle coated vessels). The endothelial cells are prevented from proliferating and migrating due to actin cytoskeleton changes. Cell death and localised reactive oxygen species (ROS) are induced and gene signalling pathways are affected resulting in further cell death. In rapidly forming tissues and organs, such as a limb, this is devastating causing tissue loss, for example, of chondrogenic precursor cells, and deformity. The damaged and malformed tissues would then fail to recruit or result in failed secondary cell population migrations, such as nerves and muscles. Such migrating cell types would be mispositioned resulting in a worsening of the defect. The framework could also be applied to tissues and organs that have formed and been patterned before thalidomide exposure. In this case new vessel formation would be inhibited and localised cell death/gene changes would occur as the tissue tries to mature and grow resulting in reduced size and/or reduced physiological function.
