Ethanol Induces Endoplasmic Reticulum Stress in the Developing Brain

Authors

  • Zunji Ke,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Xin Wang,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Ying Liu,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Zhiqin Fan,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Gang Chen,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Mei Xu,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Kimberley A. Bower,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Jacqueline A. Frank,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Mingtao Li,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Shengyun Fang,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Xianglin Shi,

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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  • Jia Luo

    1. From the Department of Internal Medicine (ZK, GC, MX, KAB, JAF, JL), University of Kentucky College of Medicine, Lexington, Kentucky; Institute for Nutritional Sciences (ZK, YL, ZF), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Graduate Center for Toxicology (XW, XS), University of Kentucky College of Medicine, Lexington, Kentucky; Department of Pharmacology (ML), Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; and University of Maryland Biotechnology Institute (SF), Baltimore, Maryland.
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Reprint requests: Jia Luo, Department of Internal Medicine, University of Kentucky College of Medicine, 130 Health Sciences Research Building, 1095 Veterans Drive, Lexington, KY 40536; Tel: 859-323-3036; Fax: 859-257-0199; E-mail: jialuo888@uky.edu

Abstract

Background:  Ethanol exposure during brain development causes profound damages to the central nervous system (CNS). The underlying cellular/molecular mechanisms remain unclear. The endoplasmic reticulum (ER) is involved in posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress, which is characterized by translational attenuation, synthesis of ER chaperone proteins, and activation of transcription factors. Sustained ER stress ultimately leads to cell death. ER stress is implicated in various neurodegenerative processes.

Methods:  Using a third trimester equivalent mouse model of ethanol exposure, we tested the hypothesis that ethanol induces ER stress in the developing brain. Seven-day-old C57BL/6 mice were acutely exposed to ethanol by subcutaneous injection and the expression of ER stress-inducible proteins (ERSIPs) and signaling pathways associated with ER stress were examined.

Results:  Ethanol exposure significantly increased the expression of ERSIPs and activated signaling pathways associated with ER stress; these include ATF6, CHOP/GADD153, GRP78, and mesencephalic astrocyte-derived neurotrophic factor as well as the phosphorylation of IRE1α, eIF2α, PERK, and PKR. The ethanol-induced increase in ERSIPs occurred within 4 hours of ethanol injection, and levels of some ERSIPs remained elevated after 24 hours of ethanol exposure. Ethanol-induced increase in phosphorylated eIF2α, caspase-12, and CHOP was distributed in neurons of specific areas of the cerebral cortex, hippocampus, and thalamus.

Conclusions:  Our finding indicates that ethanol induces ER stress in immature neurons, providing novel insight into ethanol’s detrimental effect on the developing CNS.

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