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

Title:
Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington’s disease
Authors:
Dominah, Gifty A.; McMinimy, Rachael A.; Kallon, Sallay; Kwakye, Gunnar F.
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.
Citation:
Dominah, Gifty A., Rachael A. McMinimy, Sallay Kallon, and Gunnar F. Kwakye. 2017. "Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington’s disease." NeuroToxicology 60: 54-69.
Publisher:
Elsevier
DATE ISSUED:
2017-05
Department:
Neuroscience
Type:
Article
PUBLISHED VERSION:
10.1016/j.neuro.2017.03.004
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0161813X17300499
PERMANENT LINK:
http://hdl.handle.net/11282/620512

Full metadata record

DC FieldValue Language
dc.contributor.authorDominah, Gifty A.en
dc.contributor.authorMcMinimy, Rachael A.en
dc.contributor.authorKallon, Sallayen
dc.contributor.authorKwakye, Gunnar F.en
dc.date.accessioned2017-09-13T17:50:20Z-
dc.date.available2017-09-13T17:50:20Z-
dc.date.issued2017-05-
dc.identifier.citationDominah, Gifty A., Rachael A. McMinimy, Sallay Kallon, and Gunnar F. Kwakye. 2017. "Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington’s disease." NeuroToxicology 60: 54-69.en
dc.identifier.issn0161-813X-
dc.identifier.urihttp://hdl.handle.net/11282/620512-
dc.description.abstractWe 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.en
dc.language.isoen_USen
dc.publisherElsevieren
dc.identifier.doi10.1016/j.neuro.2017.03.004-
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0161813X17300499en
dc.subject.departmentNeuroscienceen_US
dc.titleAcute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington’s diseaseen_US
dc.typeArticleen
dc.identifier.journalNeuroToxicologyen
dc.subject.keywordChlorpyrifosen_US
dc.subject.keywordOxidative stressen_US
dc.subject.keywordHuntington's diseaseen_US
dc.subject.keywordDisease-toxicant interactionen_US
dc.subject.keywordAntioxidantsen_US
dc.subject.keywordNADPH oxidaseen_US
dc.identifier.volume60en_US
dc.identifier.startpage54en_US
dc.rightsArchived with thanks to NeuroToxicologyen
All Items in The Five Colleges of Ohio Digital Repository are protected by copyright, with all rights reserved, unless otherwise indicated.