Ethanol exposure affects gene expression in the embryonic organizer and reduces retinoic acid levels.
Fetal Alcohol Spectrum Disorder (FASD) is a set of developmental malformations caused by alcohol consumption during pregnancy. Fetal Alcohol Syndrome (FAS), the strongest manifestation of FASD, results in short stature, microcephally and facial dysmorphogenesis including microphthalmia. Using Xenopus embryos as a model developmental system, we show that ethanol exposure recapitulates many aspects of FAS, including a shortened rostro-caudal axis, microcephally and microphthalmia. Temporal analysis revealed that Xenopus embryos are most sensitive to ethanol exposure between late blastula and early/mid gastrula stages. This window of sensitivity overlaps with the formation and early function of the embryonic organizer, Spemann's organizer. Molecular analysis revealed that ethanol exposure of embryos induces changes in the domains and levels of organizer-specific gene expression, identifying Spemann's organizer as an early target of ethanol. Ethanol also induces a defect in convergent extension movements that delays gastrulation movements and may affect the overall length. We show that mechanistically, ethanol is antagonistic to retinol (Vitamin A) and retinal conversion to retinoic acid, and that the organizer is active in retinoic acid signaling during early gastrulation. The model suggests that FASD is induced in part by an ethanol-dependent reduction in retinoic acid levels that are necessary for the normal function of Spemann's organizer.
Yelin
Ronit
R
Department of Cellular Biochemistry and Human Genetics, Faculty of Medicine, Hebrew University, POB 12272, Jerusalem 91120, Israel.
Schyr
Racheli Ben-Haroush
RB
Kot
Hadas
H
Zins
Sharon
S
Frumkin
Ayala
A
Pillemer
Graciela
G
Fainsod
Abraham
A
D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D036703:Blastula / Q000187:drug effects; D017931:DNA Primers; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000473:pathology; D005775:Gastrula / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D023421:Models, Animal; D009024:Morphogenesis / Q000187:drug effects; D010957:Plasmids; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology*
D017931:DNA Primers; D049452:Green Fluorescent Proteins; D000431:Ethanol; D014212:Tretinoin