Repeated exposure to chlorpyrifos leads to prolonged impairments of axonal transport in the living rodent brain

Hernandez, Caterina M.; Beck, Wayne D.; Naughton, Sean X.; Poddar, Indrani; Adam, Bao Ling; Yanasak, N. E.; Middleton, Chris; Terry, Alvin V.

doi:10.1016/j.neuro.2015.01.002

Cited by 57 publications

(45 citation statements)

References 64 publications

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“…The changes occurred at concentrations of CPF and CPF-oxon that did not inhibit AChE activity, they were not blocked by cholinergic receptor antagonists, and they did not appear to be associated with direct (OP-related) effects on mitochondrial viability or function (i.e., mitochondrial membrane potential or ATP production). Most recently, we observed (using a magnetic resonance imaging technique) that repeated exposures to doses of CPF that were below the threshold for acute toxicity led to prolonged impairments of axonal transport in the brains of living rodents (Hernandez et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

Gao

Naughton

Wulff

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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The extensive use of organophosphates (OPs) is an ongoing environmental health concern due to multiple reports of OPrelated neurologic abnormalities. The mechanism of the acute toxicity of OPs has been attributed to inhibition of acetylcholinesterase (AChE), but there is growing evidence that this may not account for all the long-term neurotoxic effects of OPs. In previous experiments (using ex vivo and in vitro model systems) we observed that the insecticide OP chlorpyrifos impaired the movements of vesicles and mitochondria in axons. Here, using a time-lapse imaging technique, we evaluated the OP-nerve agent diisopropylfluorophosphate (DFP) across a wide range of concentrations (subnanomolar to micromolar) for effects on fast axonal transport of membrane-bound organelles (MBOs) that contain the amyloid precursor protein (APP) tagged with the fluorescent marker Dendra2 (APPDendra2). Both 1 and 24 hours of exposure to DFP and a positive control compound, colchicine, resulted in a decrease in the velocity of anterograde and retrograde movements of MBOs and an increase in the number of stationary MBOs. These effects occurred at picomolar (100 pM) to low nanomolar (0.1 nM) concentrations that were not associated with compromised cell viability or cytoskeletal damage. Moreover, the effects of DFP on axonal transport occurred at concentrations that did not inhibit AChE activity, and they were not blocked by cholinergic receptor antagonists. Given the fundamental importance of axonal transport to neuronal function, these observations may explain some of the long-term neurologic deficits that have been observed in humans who have been exposed to OPs.

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Section: Introductionmentioning

confidence: 99%

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

Gao

Naughton

Wulff

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…Hyperphosphorylation following OP treatment has been reported for neurofilaments (49), Tau protein (50), calcium/cAMP-response element-binding protein (13), tubulin and microtubule-associated protein 2 (51). Studies in cell-free systems and in animals provide evidence for impaired axonal transport and decreased neuron synaptic spine density as consequences of treatment with OP (14, 52, 53). Our results from the current work suggest that chronic neurotoxicity from OP exposure could be initiated by OP-adduct formation followed by isopeptide bond formation and protein aggregation.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in cultured cells and laboratory rodents exposed to low levels of OP have provided evidence that multiple pathways are potentially affected by low doses of chlorpyrifos (CPS) and its active metabolite, chlorpyrifos oxon (CPO). These include altered receptor levels, adenylyl cyclase activity, and signal transduction activity, increased phosphorylation of Ca 2+ /cAMP-response element-binding protein, and impaired axonal transport (12–14). These studies did not identify molecular targets for CPS or CPO and did not propose a mechanism for neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Chlorpyrifos oxon promotes tubulin aggregation via isopeptide cross-linking between diethoxyphospho-Lys and Glu or Asp: Implications for neurotoxicity

Schopfer

Lockridge

2018

Journal of Biological Chemistry

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Exposure to organophosphorus toxicants (OP) can have chronic adverse effects that are not explained by inhibition of acetylcholinesterase, the cause of acute OP toxicity. We therefore hypothesized that OP-induced chronic illness is initiated by the formation of organophosphorus adducts on lysine residues in proteins, followed by protein cross-linking and aggregation. Here, Western blots revealed that exposure to the OP chlorpyrifos oxon converted porcine tubulin from its original 55-kDa mass to high-molecular-weight aggregates. Liquid chromatography–tandem MS analysis of trypsin-digested samples identified several diethoxyphospho-lysine residues in the OP-treated tubulin. Using a search approach based on the Batch Tag program, we identified cross-linked peptides and found that these chemically activated lysines reacted with acidic amino acid residues creating γ-glutamyl-ϵ-lysine or aspartyl-ϵ-lysine isopeptide bonds between β- and α-tubulin. Of note, these cross-linked tubulin molecules accounted for the high-molecular-weight aggregates. To the best of our knowledge, this is the first report indicating that chlorpyrifos oxon–exposed tubulin protein forms intermolecular cross-links with other tubulin molecules, resulting in high-molecular-weight protein aggregates. It is tempting to speculate that chronic illness from OP exposure may be explained by a mechanism that starts with OP adduct formation on protein lysines followed by protein cross-linking. We further speculate that OP-modified or cross-linked tubulin can impair axonal transport, reduce neuron connections, and result in neurotoxicity.

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“…CPF is able to cause developmental toxicity, immunological abnormalities, and neurotoxicity (Ki et al, 2013). Moreover, OP occupational exposure has been related in human epidemiological studies with neurological and neuro-behavioral deficits including impairments of cognition (Hernandez et al, 2015;Rohlman et al, 2011). In this regard, CPF has been shown to produce learning deficits in rats after acute and repeated administration similar to those induced in Alzheimer's disease (AD) (Lopez-Granero et al, 2013b;Middlemore-Risher et al, 2010;Moser et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…However, human studies of occupational exposures to OPs often fail to find a significant correlation between blood cholinesterase activity and neuro-behavioral deficits (Hernandez et al, 2015;Rohlman et al, 2011). Otherwise, it has been suggested that OP could lead to deficits in axonal transport and mitochondrial dynamics (Middlemore-Risher et al, 2010;Terry et al, 2007Terry et al, , 2003 similar to those that have been proposed to be involved in the pathogenesis of AD (Baltazar et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Acute and long-term exposure to chlorpyrifos induces cell death of basal forebrain cholinergic neurons through AChE variants alteration

et al. 2015

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Repeated exposure to chlorpyrifos leads to prolonged impairments of axonal transport in the living rodent brain

Cited by 57 publications

References 64 publications

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

Diisopropylfluorophosphate Impairs the Transport of Membrane-Bound Organelles in Rat Cortical Axons

Chlorpyrifos oxon promotes tubulin aggregation via isopeptide cross-linking between diethoxyphospho-Lys and Glu or Asp: Implications for neurotoxicity

Acute and long-term exposure to chlorpyrifos induces cell death of basal forebrain cholinergic neurons through AChE variants alteration

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