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Human embryos exposed to alcohol (ethanol) develop a complex developmental phenotype known as fetal alcohol spectrum disorder (FASD). In Xenopus embryos, ethanol reduces the levels of retinoic acid (RA) signaling during gastrulation. RA, a metabolite of vitamin A (retinol), is required for vertebrate embryogenesis, and deviation from its normal levels results in developmental malformations. Retinaldehyde dehydrogenase 2 (RALDH2) is required to activate RA signaling at the onset of gastrulation. We studied the effect of alcohol on embryogenesis by manipulating retinaldehyde dehydrogenase activity in ethanol-treated embryos. In alcohol-treated embryos, we analyzed RA signaling levels, phenotypes induced and changes in gene expression. Developmental defects that were characteristic of high ethanol concentrations were phenocopied by a low ethanol concentration combined with partial RALDH inhibition, whereas Raldh2 overexpression rescued the developmental malformations induced by high ethanol. RALDH2 knockdown resulted in similar RA signaling levels when carried out alone or in combination with ethanol treatment, suggesting that RALDH2 is the main target of ethanol. The biochemical evidence that we present shows that, at the onset of RA signaling during early gastrulation, the ethanol effect centers on the competition for the available retinaldehyde dehydrogenase activity. In light of the multiple regulatory roles of RA, continued embryogenesis in the presence of abnormally low RA levels provides an etiological explanation for the malformations observed in individuals with FASD.
Fig. 2. Manipulation of ALDH activity modulates the EtOH-induced phenotype. Embryos were subjected to different manipulations of ALDH activity in combination with EtOH treatment. Embryos were allowed to develop to early tailbud stages (st. 29) and were analyzed further by in situ hybridization with the XAG1 (cement gland) and Pax6 (eyes and midbrain) probes. (A) Control embryo; at the early tailbud stage, the developing cement gland, eyes and midbrain are clearly discernible as the stained areas to the left of the image. (B) Partial ALDH inhibition with 20 μM DEAB. (C) Low EtOH (1.3%) treatment. (D) Combined EtOH and DEAB treatment. (E) Control embryos. (F) Embryos treated with 2% EtOH. (G) Embryos overexpressing Raldh2. (H) Rescue of the EtOH effect by overexpression of Raldh2.
Fig. 5. Manipulation of RALDH modulates the effect of EtOH on gene expression domains during gastrulation. Sensitization to EtOH exposure by RALDH knockdown was shown by using DEAB to enhance the sensitivity to EtOH. Embryos were analyzed by in situ hybridization during early/mid gastrula stages (st. 10.5). Embryos were hybridized with the chordin (A–D,Q–T), gsc (E–H,M–P) and Cyp26A1 (I–L,U–X) probes. (A,E,I) Control embryos. (B,F,J) DEAB-treated (20 μM) embryos. (C,G,K) Embryos exposed to EtOH (1.5%). (D,H,L) Combined treatment with DEAB and EtOH shows enhanced sensitivity to the EtOH exposure. Rescue of the EtOH effect was achieved by Raldh2 overexpression. (M,Q,U) Control embryos. (N,R,V) Embryos injected with Raldh2 mRNA. (O,S,W) EtOH-treated (1.5%) embryos. (P,T,X) Raldh2 overexpression rescues the EtOH-induced effects.
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