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    Effects of Continuous Exposure of SH-SY5Y Neuroblastoma Cells to Chlorpyrifos on Neuronal Differentiation: Implications for Neurotoxicity

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    Author
    Todd, Spencer Willis
    0000-0002-6145-1062
    Advisor
    Pereira, Edna F. R.
    Randall, William R., Ph.D.
    Date
    2017
    Type
    dissertation
    
    Metadata
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    Abstract
    The acute toxicity of the organophosphorus insecticide chlorpyrifos (CPF) results from the irreversible inhibition of acetylcholinesterase (AChE). However, developmental exposure to levels of CPF insufficient to inhibit AChE is associated with neurological deficits in children and animal models. This study was designed to test the hypothesis that, acting via AChE-independent mechanisms, CPF disrupts neuronal differentiation, a process that shapes the nervous system structurally and functionally from the earliest stages of embryogenesis through adulthood. To address this hypothesis, SH-SY5Y cells, a neuronal cell line used to study differentiation in vitro, were exposed to CPF for 7-days. CPF concentrations that caused AChE inhibition significantly increased the expression of nestin (a marker of neuronal progenitor cells) and reduced the expression of NeuN (a marker of post-mitotic neurons). In contrast, a lower concentration of CPF that did not inhibit AChE significantly decreased nestin expression and increased NeuN expression. When examined by immunofluorescence, cultures exposed to these lower concentrations of CPF exhibited a lower percentage of NeuN-nestin+ cells and a higher percentage of NeuN+nestin- cells. In cultures that were co-treated with CPF and AM4113, a cannabinoid receptor type 1 antagonist, NeuN and nestin expression levels were comparable to control. CPF increased phosphorylation of a number of mitogen-activated protein kinases, including p38. Active p38 was required for CPF-induced increases in histone modifications, particularly dimethylated histone 3 lysine 4. Inhibition of p38 activity, using SB203580, prevented the drop in nestin expression and percentage of NeuN-Nestin+ cells induced by CPF exposure. This is the first demonstration that CPF, acting via AChE-independent mechanisms, operates, in part, through cannabinoid receptor type 1, p38 activity, and histone modifications, to induce neuronal differentiation. These findings provide a framework for future studies to determine how disruption of neurogenesis contributes to the developmental neurotoxicity of CPF.
    Description
    University of Maryland, Baltimore. Toxicology. Ph.D. 2017
    Keyword
    neuronal differentiation
    neurotoxicology
    Chlorpyrifos
    Organophosphates
    Pesticides
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/7053
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    Theses and Dissertations School of Medicine
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