PUBLICATION

Fetal alcohol exposure impairs hedgehog cholesterol modification and signaling

Authors
Li, Y.X., Yang, H.T., Zdanowicz, M., Sicklick, J.K., Qi, Y., Camp, T.J., and Diehl, A.M.
ID
ZDB-PUB-070210-18
Date
2007
Source
Laboratory investigation; a journal of technical methods and pathology   87(3): 231-240 (Journal)
Registered Authors
Camp, Terese
Keywords
fetal alcohol syndrome, fetal alcohol spectrum defects, hedgehog, cholesterol, post-translational modification, signal transduction
MeSH Terms
  • Cholesterol/administration & dosage
  • Cholesterol/metabolism*
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian/drug effects*
  • Ethanol/administration & dosage*
  • Ethanol/toxicity
  • Female
  • Fetal Alcohol Spectrum Disorders/metabolism
  • Hedgehog Proteins/metabolism*
  • Humans
  • Immunohistochemistry
  • In Vitro Techniques
  • Pregnancy
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction/drug effects*
  • Teratogens/toxicity
PubMed
17237799 Full text @ Lab Invest.
Abstract
Consumption of alcohol by pregnant women can cause fetal alcohol spectrum defects (FASD), a congenital disease, which is characterized by an array of developmental defects that include neurological, craniofacial, cardiac, and limb malformations, as well as generalized growth retardation. FASD remains a significant clinical challenge and an important social problem. Although there has been great progress in delineating the mechanisms contributing to alcohol-induced birth defects, gaps in our knowledge still remain; for instance, why does alcohol preferentially induce a spectrum of defects in specific organs and why is the spectrum of defects reproducible and predictable. In this study, we show that exposure of zebrafish embryos to low levels of alcohol during gastrulation blocks covalent modification of Sonic hedgehog by cholesterol. This leads to impaired Hh signal transduction and results in a dose-dependent spectrum of permanent developmental defects that closely resemble FASD. Furthermore, supplementing alcohol-exposed embryos with cholesterol rescues the loss of Shh signal transduction, and prevents embryos from developing FASD-like morphologic defects. Overall, we have shown that a simple post-translational modification defect in a key morphogen may contribute to an environmentally induced complex congenital syndrome. This insight into FASD pathogenesis may suggest novel strategies for preventing these common congenital defects.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping