ABSTRACT
Teratogenicity is the most severe side effect of oral retinoids, affecting 1 in 57 women ingesting over 10,000 IUs daily of preformed vitamin A. The majority of malformations induced by isotretinoin treatment during pregnancy primarily affect neural crest cells (NCCs), leading to craniofacial dysmorphic features involving facial, thymic, cardiac, and central nervous system structures. Animal studies have confirmed that administration of isotretinoin increases apoptosis of NCCs. In sebocytes, increased expression of the pro-apoptotic proteins tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL-receptor 1, and insulin-like growth factor-binding protein 3 have been related to isotretinoin-mediated sebocyte apoptosis. Isotretinoin alters the expression of the transcription factors PAX-2 and KROX-20 in macaque embryo NCCs. Isotretinoin-stimulated overactivation of p53-mediated apoptosis of NCCs may represent the molecular basis for craniofacial abnormalities associated with isotretinoin embryopathy. The teratogenicity of isotretinoin can be regarded as the result of upregulated p53 signaling in NCCs, promoting inappropriate excessive NCC apoptosis during embryogenesis.
