Early molecular effects of ethanol during vertebrate embryogenesis

Ronit Yelin, Hadas Kot, Dvir Yelin, Abraham Fainsod*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Fetal alcohol spectrum disorder (FASD) is the combination of developmental, morphological, and neurological defects that result from exposing human embryos to ethanol (EtOH). Numerous embryonic structures are affected, leading to a complex viable phenotype affecting among others, the anterior/posterior axis, head, and eye formation. Recent studies have provided evidence suggesting that EtOH teratogenesis is mediated in part through a reduction in retinoic acid (RA) levels, targeting mainly the embryonic organizer (Spemann's organizer) and its subsequent functions. EtOH-treated Xenopus embryos were subjected to an analysis of gene expression patterns. Analysis of organizer-specific genes revealed a transient delay in the invagination of gsc- and chordin-positive cells that eventually reach their normal rostro-caudal position. Dorsal midline genes show defects along the rostro-caudal axis, lacking either their rostral (Xbra and Xnot2) or caudal (FoxA4b and Shh) expression domains. Head-specific markers like Otx2, en2, and Shh show abnormal expression patterns. Otx2 exhibits a reduction in expression levels, while en2 becomes restricted along the dorsal/ventral axis. During neurula stages, Shh becomes up-regulated in the rostral region and it is expressed in an abnormal pattern. These results and histological analysis suggest the existence of malformations in the brain region including a lack of the normal fore brain ventricle. An increase in the size of both the prechordal plate and the notochord was observed, while the spinal cord is narrower. The reduction in head and eye size was accompanied by changes in the eye markers, Pax6 and Tbx3. Our results provide evidence for the early molecular changes induced by EtOH exposure during embryogenesis, and may explain some of the structural changes that are part of the EtOH teratogenic phenotype also in FASD individuals.

Original languageAmerican English
Pages (from-to)393-403
Number of pages11
JournalDifferentiation
Volume75
Issue number5
DOIs
StatePublished - Jun 2007

Bibliographical note

Funding Information:
Acknowledgments We thank Eddy De Robertis, Yoshiki Sasai, Dale Frank, Herbert Steinbeisser, and Randall Moon for plasmids and probes. We are indebted to Graciela Pillemer for critically reading the manuscript. This work was funded in part by grants from the March of Dimes, Birth Defects Foundation, the State of Lower-Saxony and the Volkswagen Foundation, Hannover, Germany, and the Israel Cancer Research Fund to AF.

Keywords

  • Craniofacial malformations
  • Eye formation
  • Fetal alcohol syndrome
  • Head development
  • Microcephaly
  • Microphthalmia
  • Neural tube
  • Notochord
  • Prechordal plate
  • Spemann's organizer
  • Teratogen
  • XCG1

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