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.