Histone deacetylases (HDACs) regulate gene expression through modulating chromatin structure and are known to impact many aspects of development in animals. Several compounds have been found to inhibit the action of HDACs leading to various adverse outcomes. This AOP aims to describe the sequence of events by which HDAC inhibition leads to impeded craniofacial development.
The MIE is the inhibition, at early embryonic stages, of histone deacetylases. This leads to inhibition of cranial neural crest cell migration and inhibition of chondrocyte differentiation. The attenuation of chondrocyte differentiation reduces the production of collagen, a key structural component of cartilage, resulting in the reduced size and morphologically distorted facial cartilage features.
This AOP concerns very specific developmental effects of an MIE which has very broad gene regulatory implications. This means that the progression through KEs and AO are mainly applicable at early developmental stages prior to neural crest migration and chondrocyte differentiation.
The AOP is linked to case study 2, concerning the developmental and reproductive toxicity of valproic acid (VPA) and several structural homologs. One of the well-described developmental toxicity effects of fetal VPA exposure is craniofacial deformities.