Skeletal cranio-facial dysmorphogenesis : Suggestions for a new AOP

Among congenital anomalies, oral cleft (OC, cleft lip and/or palate alone or associated with other jaw deformities) are one of the most frequent (1:700 live births). OC have multifactorial origin, involving both genetic and environmental risk factors (i.e. maternal active and passive smoking, diabetes, some antiepileptic drugs). An adverse outcome pathway (AOP) describes a linear sequence of key events (KEs, change in biological cell, tissue, organ, organism state, measurable and interconnected by scientifically based relationships named KERs) beginning with a molecular initiating event (MIE, the initial point of chemical interaction on molecular level) and culminating with the AO. The elucidation of the different potential chemical actors switching on the same or different MIEs/ KEs but contributing to the same AO (for our purposes OC) is fundamental in order to plan research on the contribution of multiple exposures for facial cleftings. The proposed AOP for skeletal craniofacial defects includes: 1) CYP26 inhibition (MIE), 2) imbalance of retinoic acid dependent gene expression (KE, 3) imbalance of retinoic acid regulated protein expression (KE), 4) altered hindbrain neural crest cell migration and compaction (KE), 5) embryonic branchial arch defects (KE), 6) craniofacial skeletal defects (AO). Previously published and new experimental data (morphological and molecular data, mainly obtained by Milan unit using in vitro postimplantation rat whole embryo culture and in utero exposure followed by embryofetal examination) support the suggested KE/KERs. It is likely that other MIEs and KEs may be involved in the AO with the respective AOPs sharing one or more KEs.