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Research ArticleToxicology

The Repressor Element 1-Silencing Transcription Factor Is a Novel Molecular Target for the Neurotoxic Effect of the Polychlorinated Biphenyl Mixture Aroclor 1254 in Neuroblastoma SH-SY5Y Cells

Luigi Formisano, Natascia Guida, Stefania Cocco, Agnese Secondo, Rossana Sirabella, Luca Ulianich, Flora Paturzo, Gianfranco Di Renzo and Lorella M. T. Canzoniero
Journal of Pharmacology and Experimental Therapeutics September 2011, 338 (3) 997-1003; DOI: https://doi.org/10.1124/jpet.111.181289
Luigi Formisano
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Natascia Guida
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Stefania Cocco
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Agnese Secondo
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Rossana Sirabella
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Luca Ulianich
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Flora Paturzo
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Gianfranco Di Renzo
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Lorella M. T. Canzoniero
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Abstract

Chronic exposure to polychlorinated biphenyls (PCBs), a class of ubiquitous environmental toxicants, causes neurocognitive anomalies. The transcription factor repressor element 1-silencing transcription factor (REST) plays a critical role in neuronal phenotype elaboration in both neural progenitor cells and non-neuronal cells. Here, we investigated the possible relationship between PCBs and REST in neuroblastoma SH-SY5Y cells. In these cells, chronic exposure to the PCB mixture Aroclor 1254 (A-1254; 5–30 μg/ml) caused dose-dependent cell death via the induction of calpain but not caspase-3. Intriguingly, this effect was prevented by the calpain inhibitor calpeptin. Furthermore, A-1254 enhanced REST mRNA and protein expression levels after both 24 and 48 h. REST down-regulation by small interfering RNA prevented A-1254-induced cell death. In addition, A-1254 enhanced the binding of REST to the synapsin 1 gene promoter, and synapsin 1 knockdown potentiated A-1254-induced cell death. A-1254 (10 μg/ml) also increased the expression of the two REST cofactors, the REST corepressor and the mammalian SIN3 homolog A transcription regulator. Moreover, the PCB mixture decreased acetylation of the histone proteins H3 and H4. It is noteworthy that the histone deacetylase inhibitor trichostatin A prevented such decreases and reduced the A-1254-induced neurotoxic effect. Collectively, these results suggest that A-1254 exerts its toxic effect via REST by down-regulating synapsin 1 and decreasing H3 and H4 acetylation.

Footnotes

  • This work was supported by COFIN 2008; the Ministero della Salute, Ricerca Sanitaria [Grant RF-FSL352059]; Ricerca Finalizzata 2006; the Ministero della Salute, Ricerca Oncologica 2006; the Ministero della Salute, Progetto Strategico 2007; and the Ministero della Salute, Progetto Ordinario 2007.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.181289.

  • ABBREVIATIONS:

    PCB
    polychlorinated biphenyl
    A-1254
    Aroclor 1254
    RE1
    repressor element 1
    REST
    RE1-silencing transcription factor
    CoREST
    REST corepressor
    siREST
    small interfering RNA against REST
    siCTL
    scrambled control
    HDAC
    histone deacetylase
    TSA
    trichostatin A
    DMSO
    dimethyl sulfoxide
    MTT
    3[4,5-dimethylthiazol-2-y1]-2,5-diphenyltetrazolium bromide
    ChIP
    chromatin immunoprecipitation
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    RNAi
    RNA interference
    FACS
    fluorescence-activated cell-sorting analysis
    FITC
    fluorescein isothiocyanate
    PI
    propidium iodide
    ODN-AS
    antisense oligonucleotides
    mSin3A
    mammalian Sin3 homolog A.

  • Received March 3, 2011.
  • Accepted June 20, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 3
1 Sep 2011
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Research ArticleToxicology

The Repressor Element 1-Silencing Transcription Factor Is a Novel Molecular Target for the Neurotoxic Effect of the Polychlorinated Biphenyl Mixture Aroclor 1254 in Neuroblastoma SH-SY5Y Cells

Luigi Formisano, Natascia Guida, Stefania Cocco, Agnese Secondo, Rossana Sirabella, Luca Ulianich, Flora Paturzo, Gianfranco Di Renzo and Lorella M. T. Canzoniero
Journal of Pharmacology and Experimental Therapeutics September 1, 2011, 338 (3) 997-1003; DOI: https://doi.org/10.1124/jpet.111.181289

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Research ArticleToxicology

The Repressor Element 1-Silencing Transcription Factor Is a Novel Molecular Target for the Neurotoxic Effect of the Polychlorinated Biphenyl Mixture Aroclor 1254 in Neuroblastoma SH-SY5Y Cells

Luigi Formisano, Natascia Guida, Stefania Cocco, Agnese Secondo, Rossana Sirabella, Luca Ulianich, Flora Paturzo, Gianfranco Di Renzo and Lorella M. T. Canzoniero
Journal of Pharmacology and Experimental Therapeutics September 1, 2011, 338 (3) 997-1003; DOI: https://doi.org/10.1124/jpet.111.181289
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