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Chronic ethanol exposure causes mitochondrial dysfunction and oxidative stress in immature central nervous system neurons

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Abstract

Cerebellar hypoplasia in experimental fetal alcohol syndrome (FAS) is associated with impaired insulin-stimulated survival signaling. In vitro studies demonstrated that ethanol inhibition of neuronal survival is mediated by apoptosis and mitochondrial dysfunction. Since insulin and insulin-like growth factors (IGFs) regulate energy metabolism, and ethanol can exert its toxic effects by causing oxidative damage to DNA and proteins, we further characterized the effects of chronic gestational exposure to ethanol on mitochondrial gene expression, and the degree to which ethanol inhibition of mitochondrial function is mediated by impaired insulin/IGF responsiveness. Pregnant Long-Evans rats were fed isocaloric liquid diets containing 0, 2, 4.5, 6.5, or 9.25% v/v ethanol from gestation day 6 through delivery. Cerebella harvested on postnatal day 1 were examined for indices of oxidative stress, and mRNA levels of mitochondrial, pro-oxidant, and pro-apoptosis gene expression. Rat primary cerebellar neuron cultures were used to characterize the effects of ethanol (50 mM for 96 h) on insulin and IGF stimulated mitochondrial function and ATP production. Ethanol-exposed cerebella had significantly reduced mRNA levels of mitochondrial genes encoding Complexes II-A, IV, and V, increased expression of p53 and NADPH oxidase (NOX) 1 and 3, and increased immunoreactivity for 4-hydroxy-2,3-nonenal (HNE) and 8-OHdG in cerebellar granule cells. The activations of p53 and NOX genes were highest in cerebella from pups exposed to the 6.5 or 9.25% ethanol containing diet, whereas the impairments in mitochondrial Complex IV and V expression were similar at low and high levels of ethanol exposure. In vitro experiments confirmed that ethanol treatment reduces neuronal expression of mitochondrial genes encoding Complexes IV and V, impairs mitochondrial function and ATP production, and increases HNE and 8-OHdG immunoreactivity, but they also showed that these effects were not insulin- or IGF-dependent. Together, the results suggest that mitochondrial dysfunction, oxidative stress, and DNA damage in FAS may be largely due to the toxic effects of ethanol rather than specific impairments in insulin or IGF signaling.

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Acknowledgments

Supported by grants AA02666, AA-02169, AA-11431, AA12908, and K24 AA-16126 from the National Institutes of Health.

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  1. Departments of Pathology, Clinical Neuroscience, and Medicine, Rhode Island Hospital, Pierre Galletti Research Building, Brown Medical School, 55 Claverick Street, Room 419, Providence, RI, 02903, USA

    Jennifer Chu, Ming Tong & Suzanne M. de la Monte

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  1. Jennifer Chu
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Correspondence to Suzanne M. de la Monte.

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Chu, J., Tong, M. & de la Monte, S.M. Chronic ethanol exposure causes mitochondrial dysfunction and oxidative stress in immature central nervous system neurons. Acta Neuropathol 113, 659–673 (2007). https://doi.org/10.1007/s00401-007-0199-4

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  • DOI: https://doi.org/10.1007/s00401-007-0199-4

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