In fetal alcohol spectrum disorder (FASD) a complex phenotype results from exposure of human embryos to alcohol (ethanol) during pregnancy. When extreme, FASD is also known as fetal alcohol syndrome (FAS) and is characterized by facial defects, including mid-facial malformations, reduced head circumference, short stature, central nervous system defects, and behavioral and psychological problems. It is thought that ethanol may compete with the biosynthesis of retinoic acid (RA), which is necessary for correct anterior/posterior patterning during development. RA is normally produced from vitamin A (retinol) by two oxidation steps. The first is mediated by alcohol dehydrogenase (ADH) and produces retinaldehyde, and the second is mediated by aldehyde dehydrogenase (ALDH) and produces RA. The same two enzymatic steps are required for the clearance of alcohol from the body through a process that produces acetaldehyde followed by acetic acid.
This study uses Xenopus embryos as a model system to understand the influence of ethanol on the biosynthesis of RA during the gastrula stage of embryogenesis. The authors identify RA-synthesizing enzymes that are affected by competitive inhibition with alcohol. As seen with ALDH inhibition, ethanol exposure limited retinaldehyde dehydrogenase (RALDH) activity in frog embryos. Partial inhibition of RALDH activity caused an exaggerated phenotype in embryos exposed to low ethanol concentrations. RALDH2 appears in vertebrate embryos at the onset of gastrulation, when the embryo is most sensitive to ethanol exposure. Supplementation of the embryo with RALDH2 ameliorated the effects of high ethanol exposure during early gastrulation. This provides biochemical evidence that ethanol competes with the enzymes necessary for the normal synthesis of RA during gastrulation, which may result in the developmental abnormalities associated with FASD.
RA is important for the direction, differentiation and survival of cells during early embryogenesis. Abnormal changes in RA levels result in developmental malformations, and reduced RA signaling causes a phenotype similar to FAS. This work shows that alcohol competes for enzymes in the RA biosynthesis pathway, suggesting that many alcohol-induced developmental malformations are caused by continued embryonic development in the presence of abnormally low RA levels.
