title: Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington's disease.
abstract: 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.
authors.affiliation: Neuroscience Department, Oberlin College, Oberlin, OH, USA.
authors.forename: Gifty A
authors.initials: GA
authors.lastname: Dominah
authors.affiliation: Neuroscience Department, Oberlin College, Oberlin, OH, USA.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: McMinimy
authors.affiliation: Neuroscience Department, Oberlin College, Oberlin, OH, USA.
authors.forename: Sallay
authors.initials: S
authors.lastname: Kallon
authors.affiliation: Neuroscience Department, Oberlin College, Oberlin, OH, USA. Electronic address: Gunnar.Kwakye@oberlin.edu.
authors.forename: Gunnar F
authors.initials: GF
authors.lastname: Kwakye
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D002478:Cells, Cultured; D004390:Chlorpyrifos / Q000633:toxicity*; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology*; D003474:Curcumin / Q000008:administration & dosage; D004195:Disease Models, Animal; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics; D007306:Insecticides / Q000633:toxicity*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000098:Acetophenones; D000975:Antioxidants; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007306:Insecticides; D017382:Reactive Oxygen Species; C056165:acetovanillone; D019255:NADPH Oxidases; D003474:Curcumin; D004390:Chlorpyrifos
keywords: Antioxidants; Chlorpyrifos; Disease-toxicant interaction; Huntington’s disease; NADPH oxidase; Oxidative stress