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XB-ART-55483
Sci Rep January 1, 2018; 8 (1): 347.

Acetaldehyde inhibits retinoic acid biosynthesis to mediate alcohol teratogenicity.

Shabtai Y , Bendelac L , Jubran H , Hirschberg J , Fainsod A .


Abstract
Alcohol consumption during pregnancy induces Fetal Alcohol Spectrum Disorder (FASD), which has been proposed to arise from competitive inhibition of retinoic acid (RA) biosynthesis. We provide biochemical and developmental evidence identifying acetaldehyde as responsible for this inhibition. In the embryo, RA production by RALDH2 (ALDH1A2), the main retinaldehyde dehydrogenase expressed at that stage, is inhibited by ethanol exposure. Pharmacological inhibition of the embryonic alcohol dehydrogenase activity, prevents the oxidation of ethanol to acetaldehyde that in turn functions as a RALDH2 inhibitor. Acetaldehyde-mediated reduction of RA can be rescued by RALDH2 or retinaldehyde supplementation. Enzymatic kinetic analysis of human RALDH2 shows a preference for acetaldehyde as a substrate over retinaldehyde. RA production by hRALDH2 is efficiently inhibited by acetaldehyde but not by ethanol itself. We conclude that acetaldehyde is the teratogenic derivative of ethanol responsible for the reduction in RA signaling and induction of the developmental malformations characteristic of FASD. This competitive mechanism will affect tissues requiring RA signaling when exposed to ethanol throughout life.

PubMed ID: 29321611
Article link: Sci Rep
Grant support: [+]
Genes referenced: aldh1a1 aldh1a2 aldh1a3 aldh1b1 aldh2 chrd.1 cyp26a1 dhrs3 gsc hoxa1 hoxb1 hoxb4 rdh10

Disease Ontology terms: fetal alcohol syndrome
OMIMs: ALCOHOL SENSITIVITY, ACUTE

Article Images: [+] show captions
References:
Ang, 1999, Pubmed, Xenbase [+]


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