PT - JOURNAL ARTICLE AU - Chunjuan Song AU - Arthi Kanthasamy AU - Vellareddy Anantharam AU - Faneng Sun AU - Anumantha G. Kanthasamy TI - Environmental Neurotoxic Pesticide Increases Histone Acetylation to Promote Apoptosis in Dopaminergic Neuronal Cells: Relevance to Epigenetic Mechanisms of Neurodegeneration AID - 10.1124/mol.109.062174 DP - 2010 Jan 01 TA - Molecular Pharmacology PG - mol.109.062174 4099 - http://molpharm.aspetjournals.org/content/early/2010/01/22/mol.109.062174.short 4100 - http://molpharm.aspetjournals.org/content/early/2010/01/22/mol.109.062174.full AB - 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), CREB-Binding Protein (CBP). The novel HAT inhibitor anacardic acid significantly attenuated dieldrin-induced histone acetylation, Protein Kinase C delta (PKCĪ“) proteolytic activation and DNA fragmentation in dopaminergic cells protected against dopaminergic neuronal degeneration in primary mesencephalic neuronal cultures. Furthermore, subchronic exposure of dieldrin in mouse models induced histone hyperacetylation in the striatum and substantia nigra. Collectively, for the first time, our results demonstrate that neurotoxic pesticide dieldrin exposure induces acetylation of core histones due to proteasomal dysfunction and that hyperacetylation plays a key role in dopaminergic neuronal degeneration following exposure of dieldrin.The American Society for Pharmacology and Experimental Therapeutics