Ethanol exposure during neurogenesis induces persistent effects on neural maturation: evidence from an ex vivo model of fetal cerebral cortical neuroepithelial progenitor maturation

Gene Expr. 2008;14(3):159-71.

Abstract

Ethanol is a significant neuroteratogen. We previously used fetal cortical-derived neurosphere cultures as an ex vivo model of the second trimester ventricular neuroepithelium, and showed that ethanol directly induced fetal stem and progenitor cell proliferation and maturation without inducing death. However, ethanol is defined as a teratogen because of its capacity to persistently disrupt neural maturation beyond a specific exposure period. We therefore utilized a simplified neuronal maturation paradigm to examine the immediate and persistent changes in neuronal migration following ethanol exposure during the phase of neuroepithelial proliferation. Our data indicate that mRNA transcripts for migration-associated genes RhoA, Paxillin (Pxn), and CDC42 were immediately induced following ethanol exposure, whereas dynein light chain, LC8-type 1 (DYNLL1), and growth-associated protein (Gap)-43 were suppressed. With the exception of Gap43, ethanol did not induce persistent changes in the other mRNAs, suggesting that ethanol had an activational, rather than organizational, impact on migration-associated mRNAs. However, despite this lack of persistent effects on these mRNAs, ethanol exposure during the proliferation period significantly increased subsequent neuronal migration. Moreover, differentiating neurons, pretreated with ethanol during the proliferation phase, exhibited reduced neurite branching and an increased length of primary neurites, indicating a persistent destabilization of neuronal maturation. Collectively, our data indicate that ethanol-exposed proliferating neuroepithelial precursors exhibit subsequent differentiation-associated increases in migratory behavior, independent of mRNA transcript levels. These data help explain the increased incidence of cerebral cortical neuronal heterotopias associated with the fetal alcohol syndrome.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Movement / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Central Nervous System Depressants / pharmacology
  • Cerebral Cortex* / cytology
  • Cerebral Cortex* / drug effects
  • Cerebral Cortex* / embryology
  • Ethanol / pharmacology*
  • Female
  • Fetal Alcohol Spectrum Disorders
  • Fetus* / anatomy & histology
  • Fetus* / drug effects
  • Fetus* / physiology
  • Gene Expression Regulation / drug effects
  • Humans
  • Mice
  • Neuroepithelial Cells / cytology
  • Neuroepithelial Cells / drug effects*
  • Neuroepithelial Cells / physiology*
  • Pregnancy
  • Random Allocation
  • Stem Cells / cytology
  • Stem Cells / drug effects*
  • Stem Cells / physiology*
  • Teratogens / pharmacology

Substances

  • Central Nervous System Depressants
  • Teratogens
  • Ethanol