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
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.).
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.062174.
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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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