Multiple models were proposed to explain the mechanism(s) of alcohol (ethanol) teratogenesis inducing the wide range of developmental defects, neurobehavioral anomalies, and mental disabilities known collectively as Fetal Alcohol Spectrum Disorder (FASD). Competition between alcohol clearance and retinoic acid (RA) biosynthesis was proposed as both processes employ the same families of enzymes. Excess of ethanol or its clearance metabolite, acetaldehyde, will compete with vitamin A (retinol) or retinaldehyde and hamper the production of RA with teratogenic outcomes. Taking advantage of the ease of manipulation, external development, and large clutch sizes in Xenopus, we have been studying and characterizing the alcohol/RA competition model. Xenopus embryos recapitulate many of the developmental malformations of Fetal Alcohol Syndrome (FAS), the more severe form of FASD. The effect of ethanol on development is most severe during gastrula stages and continues, but with milder outcomes throughout development. Ethanol targets the “embryonic organizer,” the earliest site of RA signaling. To support the connection between ethanol and RA, we show that all abnormal embryonic processes or molecular events induced by ethanol can be reproduced by reducing RA signaling levels. Importantly, the effects of ethanol can be rescued by increasing RA signaling, and RA reduction hypersensitizes the embryo to alcohol exposure. Biochemical studies demonstrated that RA biosynthetic enzymes can readily function in ethanol clearance. Additional syndromes linked to reduced RA signaling with partially overlapping phenotypes with FASD are discussed.
|Title of host publication
|Subtitle of host publication
|Advances in Research and Practice
|Albert E. Chudley, Geoff G. Hicks
|Place of Publication
|Humana Press Inc.
|Number of pages
|Published - 2022
Bibliographical noteFunding Information:
This work was funded in part by grants to AF from the US-Israel Binational Science Foundation (2013422 and 2017199), The Israel Science Foundation (668/17), the Manitoba Liquor and Lotteries (RG-003-21), and the Wolfson Family Chair in Genetics.
© 2022, The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
- Craniofacial malformations
- Embryonic organizer
- Fetal Growth Restriction
- Retinaldehyde dehydrogenase
- Retinoic acid signaling
- Vertebrate embryogenesis