Cellular and Molecular Life Sciences CMLS

, Volume 59, Issue 5, pp 882–893

Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons

  • S.M. de la Monte
  • J.R. Wands

DOI: 10.1007/s00018-002-8475-x

Cite this article as:
de la Monte, S. & Wands, J. CMLS, Cell. Mol. Life Sci. (2002) 59: 882. doi:10.1007/s00018-002-8475-x


Chronic gestational exposure to ethanol has profound adverse effects on brain development. In this regard, studies using in vitro models of ethanol exposure demonstrated impaired insulin signaling mechanisms associated with increased apoptosis and reduced mitochondrial function in neuronal cells. To determine the relevance of these findings to fetal alcohol syndrome, we examined mechanisms of insulin-stimulated neuronal survival and mitochondrial function using a rat model of chronic gestational exposure to ethanol. In ethanol-exposed pups, the cerebellar hemispheres were hypoplastic and exhibited increased apoptosis. Isolated cerebellar neurons were cultured to selectively evaluate insulin responsiveness. Gestational exposure to ethanol inhibited insulin-stimulated neuronal viability, mitochondrial function, Calcein AM retention (membrane integrity), and GAPDH expression, and increased dihydrorosamine fluorescence (oxidative stress) and pro-apoptosis gene expression (p53, Fas-receptor, and Fas-ligand). In addition, neuronal cultures generated from ethanol-exposed pups had reduced levels of insulin-stimulated Akt, GSK-3β, and BAD phosphorylation, and increased levels of non-phosphorylated (activated) GSK-3β and BAD protein expression. The aggregate results suggest that insulin-stimulated central nervous system neuronal survival mechanisms are significantly impaired by chronic gestational exposure to ethanol, and that the abnormalities in insulin signaling mechanisms persist in the early postnatal period, which is critical for brain development.

Key words. Fetal alcohol syndrome; fetal ethanol effects; central nervous system; insulin; neuronal apoptosis; mitochondria; signal transduction. 

Copyright information

© Birkhäuser Verlag, 2002

Authors and Affiliations

  • S.M. de la Monte
    • 1
  • J.R. Wands
    • 1
  1. 1.Departments of Medicine and Pathology, Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, Rhode Island 02903 (USA), Fax: +401 444 2939, e-mail: delamonte@hotmail.comUS

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