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Research ArticleNEUROPHARMACOLOGY

In Utero Ethanol Suppresses Cerebellar Activator Protein-1 and Nuclear Factor-κB Transcriptional Activation in a Rat Fetal Alcohol Syndrome Model

George K. Acquaah-Mensah, James P. Kehrer and Steven W. Leslie
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 277-283; DOI: https://doi.org/10.1124/jpet.301.1.277
George K. Acquaah-Mensah
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James P. Kehrer
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Steven W. Leslie
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Abstract

A model of fetal alcohol syndrome was used to investigate prenatal ethanol effects on cerebellar transcription factors. Pregnant Sprague-Dawley rats were divided into three treatment groups: ethanol-exposed (E), calorically matched pair-fed (PF), and freely fed ad libitum (AL) groups. Ethanol exposure was stopped 2 days before parturition. The DNA binding in neonatal cerebella of the redox-sensitive transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) were determined by electrophoretic mobility shift assays. On the first postnatal day (PD1), there was decreased activation of these transcription factors in the E group relative to the control groups. The PD1 transcriptional effects were reversed as the neonate underwent development without further ethanol exposure. Western blot studies showed no corresponding decreases in protein amounts of both AP-1 and NF-κB components on PD1. Postnatal glutathione levels and catalase activity, as measures of oxidative stress hypothesized to be a probable cause of the transcriptional effects, showed no statistically significant effects attributable to ethanol. Examination of prenatal cerebella on embryonic day 20 (EM20), a time during ethanol exposure, showed DNA-binding trends similar to those of PD1. EM20 Western blot studies showed decreases in the levels of the active form of glycogen synthase kinase-3 (GSK-3). GSK-3 inhibition was reversed by PD1. Blocking of GSK-3 activity with gestational dietary lithium diminished both AP-1 and NF-κB DNA binding. Thus, prenatal ethanol exposure has the effect of diminishing pro-survival transcriptional activation, an effect possibly mediated by changes in GSK-3 activity.

Footnotes

  • Supported by National Institute on Alcohol Abuse and Alcoholism Grant AA05809, National Institutes of Health Grant ES 09791, and the Fred Murphy Jones Fellowship.

  • Abbreviations:
    FAS
    fetal alcohol syndrome
    AP-1
    activator protein-1
    NF-κB
    nuclear factor-κB
    GSK-3
    glycogen synthase kinase-3
    PD
    postnatal day
    EM
    embryonic day
    E
    ethanol-exposed
    PF
    pair-fed
    AL
    ad libitum
    EMSA
    extraction and electrophoretic mobility shift assay
    TTBS
    Tween 20/Tris-buffered saline
    GSH
    glutathione
    GSSG
    glutathione disulfide
    SAPK-1
    stress-activated protein kinase-1
    • Received July 24, 2001.
    • Accepted December 28, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleNEUROPHARMACOLOGY

In Utero Ethanol Suppresses Cerebellar Activator Protein-1 and Nuclear Factor-κB Transcriptional Activation in a Rat Fetal Alcohol Syndrome Model

George K. Acquaah-Mensah, James P. Kehrer and Steven W. Leslie
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 277-283; DOI: https://doi.org/10.1124/jpet.301.1.277

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Research ArticleNEUROPHARMACOLOGY

In Utero Ethanol Suppresses Cerebellar Activator Protein-1 and Nuclear Factor-κB Transcriptional Activation in a Rat Fetal Alcohol Syndrome Model

George K. Acquaah-Mensah, James P. Kehrer and Steven W. Leslie
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 277-283; DOI: https://doi.org/10.1124/jpet.301.1.277
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