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Ethanol-induced microphthalmia is not mediated by changes in retinoic acid or sonic hedgehog signaling during retinal neurogenesis.

AbstractBACKGROUND:
Microphthalmia (reduced eye size), generally accompanied by vision defects, is a hallmark of fetal alcohol spectrum disorder (FASD) in humans. In zebrafish, embryonic ethanol exposure over the time of retinal neurogenesis also results in microphthalmia. This microphthalmia is in part the consequence of reduced retinal cell differentiation, including photoreceptors. Here we pursue 2 signaling pathways implicated in other aspects of FASD pathogenesis: retinoic acid (RA) and Sonic hedgehog (Shh).
METHODS:
We evaluated markers for RA and Shh signaling within the eyes of embryos treated with ethanol during the period of retinal neurogenesis. We also performed rescue experiments using administration of exogenous RA and microinjection of cholesterol, which augments Shh signaling.
RESULTS:
Using sequential or co-treatments, RA did not rescue ethanol-induced microphthalmia at any concentration tested. In addition, RA itself caused microphthalmia, although the underlying mechanisms were distinct from those of ethanol. Interestingly, RA treatment appeared to recover photoreceptor differentiation in a concentration-dependent manner. This may be an independent effect of exogenous RA, as ethanol treatment alone did not alter RA signaling in the eye. Cholesterol injection also did not rescue ethanol-induced microphthalmia at any concentration tested, and ethanol treatments did not alter expression of shh, or of ptc-2, which is normally regulated by Shh signaling.
CONCLUSIONS:
Together these findings indicate that, during the time of retinal neurogenesis, effects of ethanol on eye development are likely independent of the RA and Shh signaling pathways. These studies suggest that FASD intervention strategies based upon augmentation of RA or Shh signaling may not prevent ethanol-induced microphthalmia.
AuthorsBhavani Kashyap, Ruth A Frey, Deborah L Stenkamp
JournalAlcoholism, clinical and experimental research (Alcohol Clin Exp Res) Vol. 35 Issue 9 Pg. 1644-61 (Sep 2011) ISSN: 1530-0277 [Electronic] England
PMID21554333 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright2011 by the Research Society on Alcoholism.
Chemical References
  • Central Nervous System Depressants
  • Hedgehog Proteins
  • Vitamins
  • Ethanol
  • Tretinoin
  • Acridine Orange
Topics
  • Abnormalities, Drug-Induced (metabolism, pathology)
  • Acridine Orange (metabolism)
  • Animals
  • Central Nervous System Depressants (toxicity)
  • Dose-Response Relationship, Drug
  • Embryo, Nonmammalian (drug effects, metabolism)
  • Ethanol (toxicity)
  • Female
  • Hedgehog Proteins (metabolism)
  • Microphthalmos (chemically induced, metabolism, pathology)
  • Neurogenesis
  • Retina (embryology, metabolism, pathology)
  • Signal Transduction (drug effects)
  • Transgenes
  • Tretinoin (metabolism, pharmacology, toxicity)
  • Vitamins (metabolism, pharmacology, toxicity)
  • Zebrafish (embryology, genetics, metabolism)

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