Ethanol induces endoplasmic reticulum stress in the developing brain

Zunji Ke, Xin Wang, Ying Liu, Zhiqin Fan, Gang Chen, Mei Xu, Kimberley A. Bower, Jacqueline A. Frank, Mingtao Li, Shengyun Fang, Xianglin Shi, Jia Luo

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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 24hours 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.

Original languageEnglish
Pages (from-to)1574-1583
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Issue number9
StatePublished - Sep 2011


  • Cell signaling
  • Development
  • Fetal alcohol syndrome
  • Neurodegeneration
  • Oxidative stress

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health


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