Genetically programmed retinoic acid deficiency during gastrulation phenocopies most known developmental defects due to acute prenatal alcohol exposure in FASD

Abstract

Fetal Alcohol Spectrum Disorder (FASD) arises from maternal consumption of alcohol during pregnancy affecting 2%–5% of the Western population. In Xenopus laevis studies, we showed that alcohol exposure during early gastrulation reduces retinoic acid (RA) levels at this critical embryonic stage inducing craniofacial malformations associated with Fetal Alcohol Syndrome. A genetic mouse model that induces a transient RA deficiency in the node during gastrulation is described. These mice recapitulate the phenotypes characteristic of prenatal alcohol exposure (PAE) suggesting a molecular etiology for the craniofacial malformations seen in children with FASD. Gsc+/Cyp26A1 mouse embryos have a reduced RA domain and expression in the developing frontonasal prominence region and delayed HoxA1 and HoxB1 expression at E8.5. These embryos also show aberrant neurofilament expression during cranial nerve formation at E10.5 and have significant FASD sentinel-like craniofacial phenotypes at E18.5. Gsc+/Cyp26A1 mice develop severe maxillary malocclusions in adulthood. Phenocopying the PAE-induced developmental malformations with a genetic model inducing RA deficiency during early gastrulation strongly supports the alcohol/vitamin A competition model as a major molecular etiology for the neurodevelopmental defects and craniofacial malformations seen in children with FASD.

Risk and Resilience Variants in the Retinoic Acid Metabolic and Developmental Pathways Associated with Risk of FASD Outcomes

“…When taken together, these findings support the proposed hypothesis, wherein PAEinduced RA deficiency is a potential underlying etiology of FASD, particularly during early gastrulation. Animal models have supported this hypothesis, both in studies conducted by our group and others, and now here, with the enrichment of risk alleles of RA metabolism in a human FASD cohort [33,34]. Our FASD cohort is small, and while it supports the hypothesis, these results need to be validated in a larger multiethnic cohort.…”

“…Many variants of these two enzyme families have been associated with increased alcohol consumption, dependence, and altered enzyme activity, but only a few have thus far been associated with FASD [32]. Our group and others have shown in animal models that alcohol-induced RA deficiency during gastrulation can result in most known FASD developmental phenotypes [33,34]. Accordingly, certain genetic variants of RA metabolism may predispose to RA deficiency following PAE, and these same variants would be found with increased allele frequencies in children diagnosed with FASD in this cohort.…”