Abstract
BackgroundIn previous work, we investigated dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. Dieldrin has been reported to be one of the environmental factors correlated with Parkinson's disease and may selectively destroy dopaminergic neurons.MethodsHere we further investigated dieldrin toxicity in a dopaminergic neuronal cell model of Parkinson's disease, namely N27 cells, using biochemical, immunochemical, and flow cytometric analyses.ResultsIn this study, dieldrin-treated N27 cells underwent a rapid and significant increase in reactive oxygen species followed by cytochrome c release into cytosol. The cytosolic cytochrome c activated caspase-dependent apoptotic pathway and the increased caspase-3 activity was observed following a 3 hr dieldrin exposure in a dose-dependent manner. Furthermore, dieldrin caused the caspase-dependent proteolytic cleavage of protein kinase C delta (PKCδ) into 41 kDa catalytic and 38 kDa regulatory subunits in N27 cells as well as in brain slices. PKCδ plays a critical role in executing the apoptotic process in dieldrin-treated dopaminergic neuronal cells because pretreatment with the PKCδ inhibitor rottlerin, or transfection and over-expression of catalytically inactive PKCδK376R, significantly attenuates dieldrin-induced DNA fragmentation and chromatin condensation.ConclusionTogether, we conclude that caspase-3-dependent proteolytic activation of PKCδ is a critical event in dieldrin-induced apoptotic cell death in dopaminergic neuronal cells.
Highlights
In previous work, we investigated dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells
Dieldrin-induced reactive oxygen species (ROS) Exposure of N27 cells to dieldrin resulted in a rapid, transient increase in generation of Reactive oxygen species (ROS) as measured by flow cytometric analysis of hydroethidium dye oxidation
We demonstrated that the cell death pathway observed in dopaminergic neuronal cells following acute exposure to dieldrin was identical to that observed in PC12 cells, i.e., i) initial and rapid increase in reactive oxygen species (ROS), ii) possible mitochondrial damage and subsequent release of cytochrome c, iii) caspase-3 activation and proteolytic cleavage of PKCδ, and iv) apoptotic cell death as a result of activation of these pro-apoptotic molecules
Summary
We investigated dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. PD-associated factors most often cited include residence in a rural area, use of well water as a drinking water source, and occupational use of pesticides, all of which are linked to pesticide exposures These have been reported in numerous epidemiological studies [6,7,8,9,10,11,12,13,14,15,16,17]. Postmortem studies of PD patients have reported significantly higher brain concentrations of chlorinated hydrocarbons, cyclodiene insecticides [19,20,21], further suggesting a direct link between environmental exposure to neurotoxicants and PD. 3 billion tons of these chemicals have been manufactured and used commercially for insect control to date [29]
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