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 ␦ 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.

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…The exposure to Dieldrin, a neurotoxic pesticide associated with PD etiopathogenesis, was shown to induce histone H3 and H4 hyperacetylation via the timedependent CBP accumulation in dopaminergic neurons [111]. Alternatively, wild-type α-synuclein reduces p300 expression level and HAT activity.…”

Histone Hyperacetylation Up-regulates Protein Kinase Cδ in Dopaminergic Neurons to Induce Cell Death

“…An optimal balance between HAT and HDAC activity is required for cell survival, and disruption of this balance has been implicated in neurodegenerative diseases (40). We previously reported that neurotoxic pesticide exposure induced hyperacetylation of histones H3 and H4, which contributed to cell death in cell culture models of PD (41)(42)(43). Similarly, overexpression of a HAT, Tip60, was found to induce neuronal apoptosis in Drosophila (44).…”

Epigenetic Landscape of Parkinson's Disease: Emerging Role in Disease Mechanisms and Therapeutic Modalities

“…Histone acetylation may represent a key epigenetic modification in dopaminergic neuronal cells due to neurotoxic insults. The exposure of paraquat to N27 dopaminergic cells induced histone H3 acetylation and decreased the total HDAC activity [63,64]. Similarly, dieldrin induced a time-dependent increase in the acetylation of core histones H3 and H4 [63].…”

“…In mouse models, exposure to dieldrin induced histone acetylation in the nigrostriatal system. Anacardic acid, a HAT inhibitor, significantly attenuated dieldrin-induced histone acetylation and dieldrin-associated apoptosis, which was independent of its antioxidant effect [63]. In addition, administration of MPTP in murine and non-human primate models has been associated with decreased striatal presence of H3 histone K4 trimethylation, and chronic administration of the DA precursor L-DOPA has been demonstrated to reverse these changes [65].…”

“…The exposure of paraquat to N27 dopaminergic cells induced histone H3 acetylation and decreased the total HDAC activity [63,64]. Similarly, dieldrin induced a time-dependent increase in the acetylation of core histones H3 and H4 [63]. This hyperacetylation was attributed to dieldrin-induced proteasomal dysfunction, resulting in the accumulation of the critical HAT cAMP response element- binding protein (CBP).…”