Ethanol induces embryonic malformations by competing for retinaldehyde dehydrogenase activity during vertebrate gastrulation

Abstract

SUMMARYHuman 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.

Effects of prenatal alcohol exposure (PAE): insights into FASD using mouse models of PAE

“…Both acute and chronic first trimester models of PAE clearly indicate that one of the most sensitive windows for craniofacial malformations, the sentinel diagnostic and most recognizable features for FAS, is at early gastrulation. This appears to recapitulate in mammalian models what has already been well-demonstrated more broadly in other vertebrate models (Kot-Leibovich and Fainsod 2009; Lovely et al 2016). These PAE studies suggest that binge alcohol exposure(s) during early gestation can lead to severe FASD outcomes.…”

A missense mutation in ALDH1A3 causes isolated microphthalmia/anophthalmia in nine individuals from an inbred Muslim kindred

“…20,21 We could assume that A/M, caused by defects in ALDH1A3, is the genetic alternative of this disorder.…”

Alcohol-Induced Morphological Deficits in the Development of Octavolateral Organs of the Zebrafish (Danio rerio)

“…For example, acute embryonic alcohol exposure reduces expression of the raldh2 gene that is required to activate retinoic acid signalling at the beginning of gastrulation. 53,54 Retinoic acid deficiency affects induction of the otic vesicle of zebrafish, 55 and retinoic acid supplement can partially rescue alcohol-induced morphological defects of the otic vesicle. 26 Previous zebrafish studies have revealed many genes that are responsible for morphogenesis of key structures/organs of the octavolateral system, particularly formation of the otic vesicle and otoliths.…”