The role of teratogen exposure on neural crest cells in the pathogenesis of fetal alcohol spectrum disorders
Carozza, Richard Bohling
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Maternal consumption of ethanol during pregnancy contributes to a set of pathologies, grouped together as the fetal alcohol spectrum disorders, affecting as many as 5% of live births in the United States annually. Ethanol acts widely in the developing embryo, affecting many tissues, but causing deficits in neuronal and neural crest populations particularly. These deleterious effects cause archetypical craniofacial expression and neurological deficits, including microcephaly and neuronal dysfunction. Severity of symptoms is linked to frequency of maternal alcohol consumption as well as the maximum blood alcohol concentration reached by the mother. The teratology of ethanol has been widely researched over the last four decades, with the link between the neural crest pathology and the fetal alcohol spectrum phenotype becoming clearer. Animal model studies have managed to replicate many of the symptoms seen in humans afflicted with fetal alcohol spectrum disorders, and have allowed us to elucidate the biochemical mechanisms behind the disease. There is no singular pathway responsible for the fetal alcohol spectrum disorders: over half a dozen models of dysfunction have been identified, and ethanol’s ability to react with a series of targets means that more pathways are likely to be discovered. Current theories regarding the effects of ethanol on the neural crest have implicated apoptosis of the cephalic neural crest, mediated by G-protein coupled receptors, activation of a phospholipase C pathway, and subsequent release of intracellular calcium; perturbations of the actin cytoskeleton leading to migration dysfunction of neural crest cells in the developing neural tube; lack of functional trophic molecules, specifically Shh, likely due to dysfunction of the cholesterol biosynthetic pathway; lack of retinoic acid production; oxidative stress, production of reactive oxygen species, and iron dysregulation; and genetics, which seems to confer greater susceptibility and resistance to ethanol in certain individuals. Ultimately, a global model for ethanol’s actions on the developing fetus eludes researchers, as do any potential treatments, and more research is required to further elucidate ethanol’s teratogenic mechanism.