title: Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of neurodegeneration.
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 delta 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.
authors.affiliation: Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA.
authors.forename: C
authors.initials: C
authors.lastname: Song
authors.forename: A
authors.initials: A
authors.lastname: Kanthasamy
authors.forename: V
authors.initials: V
authors.lastname: Anantharam
authors.forename: F
authors.initials: F
authors.lastname: Sun
authors.forename: A G
authors.initials: AG
authors.lastname: Kanthasamy
mesh_terms: D000107:Acetylation; D048729:Anacardic Acids / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D050882:CREB-Binding Protein / Q000032:analysis; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004026:Dieldrin / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism*; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000139:chemically induced*; D018696:Neuroprotective Agents / Q000494:pharmacology; D061988:Proteasome Inhibitors; D051745:Protein Kinase C-delta / Q000378:metabolism; D051381:Rats
chemical_list: D048729:Anacardic Acids; D000975:Antioxidants; D004785:Environmental Pollutants; D006657:Histones; D007306:Insecticides; D018696:Neuroprotective Agents; D061988:Proteasome Inhibitors; C088115:anacardic acid; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; C497260:Prkcd protein, rat; D051745:Protein Kinase C-delta; D053148:Caspase 3; D004026:Dieldrin