Fetal Alcohol Spectrum Disorder as a Retinoic Acid Deficiency Syndrome

Abraham Fainsod*, Tali Abbou, Liat Bendelac-Kapon, Tamir Edri, Graciela Pillemer

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

2 Scopus citations

Abstract

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.

Original languageAmerican English
Title of host publicationNeuromethods
Subtitle of host publicationAdvances in Research and Practice
EditorsAlbert E. Chudley, Geoff G. Hicks
Place of Publication New York
PublisherHumana Press Inc.
Pages49-76
Number of pages28
ISBN (Print)1071626124, 9781071626122
DOIs
StatePublished - 2022

Publication series

NameNeuromethods
Volume188
ISSN (Print)0893-2336
ISSN (Electronic)1940-6045

Bibliographical note

Funding 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.

Publisher Copyright:
© 2022, The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

  • Acetaldehyde
  • Craniofacial malformations
  • Embryonic organizer
  • Fetal Growth Restriction
  • Microcephaly
  • Retinaldehyde dehydrogenase
  • Retinoic acid signaling
  • Vertebrate embryogenesis
  • Xenopus

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