Differential epigenetic effects of chlorpyrifos and arsenic in proliferating and differentiating human neural progenitor cells

Kim, Hee Yeon; Wegner, Susanna; Ness, Kirk P. Van; Park, Julie Juyoung; Pacheco, Sara; Workman, Tomomi; Hong, Sungchul; Griffith, William C.; Faustman, Elaine M.

doi:10.1016/j.reprotox.2016.08.005

Cited by 23 publications

(12 citation statements)

References 87 publications

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“…Collectively, these data suggest the testable hypothesis that early life exposures to OPs elicit lasting changes in the morphology of airway nerves, thereby altering functional patterns of neuronal connectivity to increase the susceptibility of the lung to AHR. A second possibility for how developmental OP exposures might cause persistent asthma derives from literature demonstrating that OPs can cause epigenetic changes (133,188,254,255).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of organophosphorus pesticide toxicity in the context of airway hyperreactivity and asthma

Shaffo

Grodzki

Fryer

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

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Numerous epidemiologic studies have identified an association between occupational exposures to organophosphorus pesticides (OPs) and asthma or asthmatic symptoms in adults. Emerging epidemiologic data suggest that environmentally relevant levels of OPs may also be linked to respiratory dysfunction in the general population and that in utero and/or early life exposures to environmental OPs may increase risk for childhood asthma. In support of a causal link between OPs and asthma, experimental evidence demonstrates that occupationally and environmentally relevant OP exposures induce bronchospasm and airway hyperreactivity in preclinical models. Mechanistic studies have identified blockade of autoinhibitory M2 muscarinic receptors on parasympathetic nerves that innervate airway smooth muscle as one mechanism by which OPs induce airway hyperreactivity, but significant questions remain regarding the mechanism(s) by which OPs cause neuronal M2 receptor dysfunction and, more generally, how OPs cause persistent asthma, especially after developmental exposures. The goals of this review are to 1) summarize current understanding of OPs in asthma; 2) discuss mechanisms of OP neurotoxicity and immunotoxicity that warrant consideration in the context of OP-induced airway hyperreactivity and asthma, specifically, inflammatory responses, oxidative stress, neural plasticity, and neurogenic inflammation; and 3) identify critical data gaps that need to be addressed in order to better protect adults and children against the harmful respiratory effects of low-level OP exposures.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of organophosphorus pesticide toxicity in the context of airway hyperreactivity and asthma

Shaffo

Grodzki

Fryer

et al. 2018

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…In a study using NSCs derived from human umbilical cord blood to model DNT, minimal toxicity was observed at 10 µM CPF, although the cells differentiated more towards an astrocytic phenotype and showed a partial decrease in viability [ 41 ]. Another recent study used a commercial, immortalized human cell line to test the epigenetic effects of CPF in both proliferating and differentiating NSCs, and the toxic effects were not detected at concentrations below 57 µM [ 42 ]. Neither study quantified the cholinesterase activity.…”

Section: Discussionmentioning

confidence: 99%

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

Tiethof

Richardson

Hart³

2018

Toxics

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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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“…In a study using NSCs derived from human umbilical cord blood to model DNT, minimal toxicity was observed at 10 µM CPF, although cells differentiated more towards an astrocytic phenotype and showed partial decrease in viability [42]. Another recent study used a commercial, immortalized human cell line to test epigenetic effects of CPF in both proliferating and differentiating NSCs, and toxic effects were not detected at concentrations below 57 µM [43]. Neither study quantified cholinesterase activity.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of butyrylcholinesterase but not inhibition by chlorpyrifos alters early differentiation mechanisms in human neural stem cells

Teithof

Richardson

Hart³

2018

Preprint

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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 inhibition of AChE, which results in excess cholinergic stimulation at the synapse. We hypothesized that 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 initial differentiation mechanisms. Over six days of NSC differentiation, BChE activity and mRNA expression significantly increased, while AChE activity and expression remained unchanged. CPF treatment (10 μM) caused 82% and 92% inhibition of AChE and BChE, respectively. CPF exposure had no effect on cell viability or the expression of differentiation markers HES5, DCX or MAP2. However, shRNA-knockdown of BChE expression resulted in decreased or delayed expression of transcription factors HES5 and HES3. BChE may have a role in the differentiation of NSCs independent of, or in addition to, its enzymatic activity.

show abstract

Differential epigenetic effects of chlorpyrifos and arsenic in proliferating and differentiating human neural progenitor cells

Cited by 23 publications

References 87 publications

Mechanisms of organophosphorus pesticide toxicity in the context of airway hyperreactivity and asthma

Mechanisms of organophosphorus pesticide toxicity in the context of airway hyperreactivity and asthma

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

Knockdown of butyrylcholinesterase but not inhibition by chlorpyrifos alters early differentiation mechanisms in human neural stem cells

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