Environmental neurotoxic pesticide increases histone acetylation to promote apoptosis in dopaminergic neuronal cells: relevance to epigenetic mechanisms of …

C Song, A Kanthasamy, V Anantharam, F Sun… - Molecular …, 2010 - ASPET
C Song, A Kanthasamy, V Anantharam, F Sun, AG Kanthasamy
Molecular pharmacology, 2010ASPET
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 …
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.
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