Induction of microglial reactive oxygen species production by the organochlorinated pesticide dieldrin

Abstract

Exposure to pesticides has been speculated to contribute to the development of sporadic Parkinson's disease (PD) characterized by a progressive degeneration of the nigrostriatal dopaminergic pathway. Activation of brain microglia that produce various neurotoxic factors including cytokines and reactive oxygen species (ROS) has been increasingly associated with dopaminergic neurodegeneration induced by various toxicants. Dieldrin, a highly persistent organochlorinated pesticide found enriched in the substantia nigra of some postmortem PD brains, has been shown to be toxic to dopamine neurons. In this study, we set out to determine the effect of dieldrin on the production of ROS and the underlying mechanism of action in murine microglia. Treatment of microglial cells with 0.1 nM to 1 microM dieldrin for 24 h resulted in a concentration-dependent generation of ROS. The dieldrin-induced microglial ROS generation was time-dependent in that significant ROS production was observed in cells 12-24 h, but not 6 h after dieldrin treatment. Furthermore, the dieldrin-induced microglial ROS generation was significantly reduced by inhibitors of NADPH oxidase, gene transcription and protein synthesis. In addition to immortalized microglial cells, dieldrin induced a concentration-dependent ROS generation in primary microglia, but not in primary astroglia. These results demonstrate that nanomolar concentrations of dieldrin can stimulate microglia to produce ROS that may contribute to the degeneration of dopamine neurons known to be vulnerable to oxidative damage. These findings provide important information on the potential role of microglia in dieldrin-induced neurodegeneration in relevance to the development of idiopathic PD.