Abstract
Prenatal alcohol exposure (PAE) causes distinctive facial characteristics in some pregnancies and not others; genetic factors may contribute to this differential vulnerability. Ethanol disrupts multiple events of neural crest development, including induction, survival, migration, and differentiation. Animal models and genomic approaches have substantially advanced our understanding of the mechanisms underlying these facial changes. PAE during gastrulation produces craniofacial changes corresponding with human fetal alcohol syndrome. These result because PAE reduces prechordal plate extension and suppresses sonic hedgehog, leading to holoprosencephaly and malpositioned facial primordia. Haploinsufficiency in sonic hedgehog signaling increases vulnerability to facial deficits and may influence some PAE pregnancies. In contrast, PAE during early neurogenesis produces facial hypoplasia, preceded by neural crest reductions due to significant apoptosis. Factors mediating this apoptosis include intracellular calcium mobilization, elevated reactive oxygen species, and loss of trophic support from β-catenin/calcium, sonic hedgehog, and mTOR signaling. Genome-wide SNP analysis links PDGFRA with facial outcomes in human PAE. Multiple genomic-level comparisons of ethanol-sensitive and – resistant early embryos, in both mouse and chick, independently identify common candidate genes that may potentially modify craniofacial vulnerability, including ribosomal proteins, proteosome, RNA splicing, and focal adhesion. In summary, research using animal models with genome-level differences in ethanol vulnerability, as well as targeted loss-and gain-of-function mutants, has clarified the mechanisms mediating craniofacial change in PAE. The findings additionally suggest that craniofacial deficits may represent a gene–ethanol interaction for some affected individuals. Genetic-level changes may prime individuals toward greater sensitivity or resistance to ethanol’s neurotoxicity.
Highlights
It is indisputable that genetic factors modulate individual risk for alcoholism
Multiple mechanisms contribute to this apoptosis, including the production of reactive oxygen species (Chen et al, 2013), generation of intracellular calcium transients (Debelak-Kragtorp et al, 2003), and the loss of tropic support from β-catenin (Flentke et al, 2011) and/or from sonic hedgehog (Ahlgren et al, 2002)
Animal models confirm that loss-of-function mutations in ribosome proteins or effectors of ribosome biogenesis can cause cell cycle arrest and p53-mediated apoptosis within neural crest progenitors, the best described of these being Treacher-Collins syndrome (Trainor, 2010)
Summary
It is indisputable that genetic factors modulate individual risk for alcoholism (see Edenberg and Foroud, 2013, for a recent review). Multiple genomic-level comparisons of ethanol-sensitive and – resistant early embryos, in both mouse and chick, independently identify common candidate genes that may potentially modify craniofacial vulnerability, including ribosomal proteins, proteosome, RNA splicing, and focal adhesion. ETHANOL INFLUENCES CRANIOFACIAL OUTCOMES IN FASD Insights into how genetic factors may modify vulnerability to PAE are informed by an understanding of ethanol’s mechanisms of action.
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