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Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells

Butyrylcholinesterase (BChE) is the evolutionary counterpart to acetylcholinesterase (AChE). Both are expressed early in nervous system development prior to cholinergic synapse formation. The organophosphate pesticide chlorpyrifos (CPF) primarily exerts toxicity through the inhibition of AChE, which...

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Autores principales: Tiethof, Angela K., Richardson, Jason R., Hart, Ronald P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160911/
https://www.ncbi.nlm.nih.gov/pubmed/30200437
http://dx.doi.org/10.3390/toxics6030052
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author Tiethof, Angela K.
Richardson, Jason R.
Hart, Ronald P.
author_facet Tiethof, Angela K.
Richardson, Jason R.
Hart, Ronald P.
author_sort Tiethof, Angela K.
collection PubMed
description Butyrylcholinesterase (BChE) is the evolutionary counterpart to acetylcholinesterase (AChE). Both are expressed early in nervous system development prior to cholinergic synapse formation. The organophosphate pesticide chlorpyrifos (CPF) primarily exerts toxicity through the inhibition of AChE, which results in excess cholinergic stimulation at the synapse. We hypothesized that the inhibition of AChE and BChE by CPF may impair early neurogenesis in neural stem cells (NSCs). To model neurodevelopment in vitro, we used human NSCs derived from induced pluripotent stem cells (iPSCs) with a focus on the initial differentiation mechanisms. Over the six days of NSC differentiation, the BChE activity and mRNA expression significantly increased, while the AChE activity and expression remained unchanged. The CPF treatment (10 μM) caused 82% and 92% inhibition of AChE and BChE, respectively. The CPF exposure had no effect on the cell viability or the expression of the differentiation markers HES5, DCX, or MAP2. However, the shRNA-knockdown of the BChE expression resulted in the decreased or delayed expression of the transcription factors HES5 and HES3. BChE may have a role in the differentiation of NSCs independent of, or in addition to, its enzymatic activity.
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spelling pubmed-61609112018-10-01 Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells Tiethof, Angela K. Richardson, Jason R. Hart, Ronald P. Toxics Article Butyrylcholinesterase (BChE) is the evolutionary counterpart to acetylcholinesterase (AChE). Both are expressed early in nervous system development prior to cholinergic synapse formation. The organophosphate pesticide chlorpyrifos (CPF) primarily exerts toxicity through the inhibition of AChE, which results in excess cholinergic stimulation at the synapse. We hypothesized that the inhibition of AChE and BChE by CPF may impair early neurogenesis in neural stem cells (NSCs). To model neurodevelopment in vitro, we used human NSCs derived from induced pluripotent stem cells (iPSCs) with a focus on the initial differentiation mechanisms. Over the six days of NSC differentiation, the BChE activity and mRNA expression significantly increased, while the AChE activity and expression remained unchanged. The CPF treatment (10 μM) caused 82% and 92% inhibition of AChE and BChE, respectively. The CPF exposure had no effect on the cell viability or the expression of the differentiation markers HES5, DCX, or MAP2. However, the shRNA-knockdown of the BChE expression resulted in the decreased or delayed expression of the transcription factors HES5 and HES3. BChE may have a role in the differentiation of NSCs independent of, or in addition to, its enzymatic activity. MDPI 2018-09-01 /pmc/articles/PMC6160911/ /pubmed/30200437 http://dx.doi.org/10.3390/toxics6030052 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tiethof, Angela K.
Richardson, Jason R.
Hart, Ronald P.
Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells
title Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells
title_full Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells
title_fullStr Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells
title_full_unstemmed Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells
title_short Knockdown of Butyrylcholinesterase but Not Inhibition by Chlorpyrifos Alters Early Differentiation Mechanisms in Human Neural Stem Cells
title_sort knockdown of butyrylcholinesterase but not inhibition by chlorpyrifos alters early differentiation mechanisms in human neural stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160911/
https://www.ncbi.nlm.nih.gov/pubmed/30200437
http://dx.doi.org/10.3390/toxics6030052
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