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Research ArticleArticle

Environmental Neurotoxic Pesticide Increases Histone Acetylation to Promote Apoptosis in Dopaminergic Neuronal Cells: Relevance to Epigenetic Mechanisms of Neurodegeneration

C. Song, A. Kanthasamy, V. Anantharam, F. Sun and A. G. Kanthasamy
Molecular Pharmacology April 2010, 77 (4) 621-632; DOI: https://doi.org/10.1124/mol.109.062174
C. Song
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A. Kanthasamy
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V. Anantharam
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F. Sun
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A. G. Kanthasamy
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Abstract

Pesticide exposure has been implicated in the etiopathogenesis of Parkinson's disease (PD); in particular, the organochlorine insecticide dieldrin is believed to be associated with PD. Emerging evidence indicates that histone modifications play a critical role in cell death. In this study, we examined the effects of dieldrin treatment on histone acetylation and its role in dieldrin-induced apoptotic cell death in dopaminergic neuronal cells. In mesencephalic dopaminergic neuronal cells, dieldrin induced a time-dependent increase in the acetylation of core histones H3 and H4. Histone acetylation occurred within 10 min of dieldrin exposure indicating that acetylation is an early event in dieldrin neurotoxicity. The hyperacetylation was attributed to dieldrin-induced proteasomal dysfunction, resulting in accumulation of a key histone acetyltransferase (HAT), cAMP response element-binding protein. The novel HAT inhibitor anacardic acid significantly attenuated dieldrin-induced histone acetylation, Protein kinase C δ proteolytic activation and DNA fragmentation in dopaminergic cells protected against dopaminergic neuronal degeneration in primary mesencephalic neuronal cultures. Furthermore, 30-day exposure of dieldrin in mouse models induced histone hyperacetylation in the striatum and substantia nigra. For the first time, our results collectively demonstrate that exposure to the neurotoxic pesticide dieldrin induces acetylation of core histones because of proteasomal dysfunction and that hyperacetylation plays a key role in dopaminergic neuronal degeneration after exposure of dieldrin.

Footnotes

    fn-2
  • This work was supported by National Institutes of Health National Institute of Environmental Health Sciences [Grant ES10586]; the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS38644, NS45133]; and The W. Eugene and Linda Lloyd Endowed Chair (to A.G.K.).

  • fn-3
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.062174.

  • fn-4
  • ABBREVIATIONS:

    PD
    Parkinson's disease
    PKCδ
    protein kinase C δ
    HDAC
    histone deacetylase
    HAT
    histone acetyltransferase
    AFC
    7-amino-4-methylcoumarin
    Ac-DEVD-AFC
    acetyl-Asp-Glu-Val-Asp-AFC
    ELISA
    enzyme-linked immunosorbent assay
    CBP
    CREB-binding protein
    CREB
    cAMP response element-binding protein
    HBSS
    Hanks' balanced salt solution
    PBS
    phosphate-buffered saline
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate
    ROS
    reactive oxygen species
    DA
    dopamine
    siRNA
    small interfering RNA
    TH
    tyrosine hydroxylase
    PCAF
    P300/CBP-associated factor
    ANOVA
    analysis of variance
    MG-132
    N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal.

    • Received November 11, 2009.
    • Accepted January 19, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Environmental Neurotoxic Pesticide Increases Histone Acetylation to Promote Apoptosis in Dopaminergic Neuronal Cells: Relevance to Epigenetic Mechanisms of Neurodegeneration

C. Song, A. Kanthasamy, V. Anantharam, F. Sun and A. G. Kanthasamy
Molecular Pharmacology April 1, 2010, 77 (4) 621-632; DOI: https://doi.org/10.1124/mol.109.062174

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Research ArticleArticle

Environmental Neurotoxic Pesticide Increases Histone Acetylation to Promote Apoptosis in Dopaminergic Neuronal Cells: Relevance to Epigenetic Mechanisms of Neurodegeneration

C. Song, A. Kanthasamy, V. Anantharam, F. Sun and A. G. Kanthasamy
Molecular Pharmacology April 1, 2010, 77 (4) 621-632; DOI: https://doi.org/10.1124/mol.109.062174
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