Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington's disease.

We hypothesized that expression of mutant Huntingtin (HTT) would modulate the neurotoxicity of the commonly used organophosphate insecticide, chlorpyrifos (CPF), revealing cellular mechanisms underlying neurodegeneration. Using a mouse striatal cell model of HD, we report that mutant HD cells are more susceptible to CPF-induced cytotoxicity as compared to wild-type. This CPF-induced cytotoxicity caused increased production of reactive oxygen species, reduced glutathione levels, decreased superoxide dismutase activity, and increased malondialdehyde levels in mutant HD cells relative to wild-type. Furthermore, we show that co-treatment with antioxidant agents attenuated the CPF-induced ROS levels and cytotoxicity. Co-treatment with a NADPH oxidase (NOX) inhibitor, apocynin, also attenuated the CPF-induced ROS production and neurotoxicity. CPF caused increased NOX activity in mutant HD lines that was ameliorated following co-treatment with apocynin. Finally, CPF-induced neurotoxicity significantly increased the protein expression of nuclear factor erythroid 2-related factor (Nrf2) in mutant HD cells as compared to wild-type. This study is the first report of CPF-induced toxicity in HD pathophysiology and suggests that mutant HTT and CPF exhibit a disease-toxicant interaction wherein expression of mutant HTT enhances CPF-induced neurotoxicity via a NOX-mediated oxidative stress mechanism to cause neuronal loss in the full length HTT expressing striatal cells.

Disease-Toxicant Interactions in Parkinson's Disease Neuropathology.

Human disease commonly manifests as a result of complex genetic and environmental interactions. In the case of neurodegenerative diseases, such as Parkinson's disease (PD), understanding how environmental exposures collude with genetic polymorphisms in the central nervous system to cause dysfunction is critical in order to develop better treatment strategies, therapies, and a more cohesive paradigm for future research. The intersection of genetics and the environment in disease etiology is particularly relevant in the context of their shared pathophysiological mechanisms. This review offers an integrated view of disease-toxicant interactions in PD. Particular attention is dedicated to how mutations in the genes SNCA, parkin, leucine-rich repeat kinase 2 (LRRK2) and DJ-1, as well as dysfunction of the ubiquitin proteasome system, may contribute to PD and how exposure to heavy metals, pesticides and illicit drugs may further the consequences of these mutations to exacerbate PD and PD-like disorders. Although the toxic effects induced by exposure to these environmental factors may not be the primary causes of PD, their mechanisms of action are critical for our current understanding of the neuropathologies driving PD. Elucidating how environment and genetics collude to cause pathogenesis of PD will facilitate the development of more effective treatments for the disease. Additionally, we discuss the neuroprotection exerted by estrogen and other compounds that may prevent PD and provide an overview of current treatment strategies and therapies.