Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility

Gearhart, Debra A.; Sickles, Dale W.; Buccafusco, Jerry J.; Prendergast, Mark A.; Terry, Alvin V.

doi:10.1016/j.taap.2006.10.008

Cited by 66 publications

(39 citation statements)

References 78 publications

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“…These observations could be related to Gearhart's study that showed that chlorpyrifos inhibit kinesin-dependent microtubule motility and Grigoryan's study that showed a tubulin polymerization disruption by chlorpyrifos oxon [22], [23]. As a consequence, proteins synthetized and involved in tight junction formation might be restrained to the cytoplasmic space rather than moving along microtubules to tight junction space.…”

Section: Discussionmentioning

confidence: 72%

Increased Gut Permeability and Bacterial Translocation after Chronic Chlorpyrifos Exposure in Rats

et al. 2014

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The epithelium's barrier function is crucial for maintaining homeostasis and preventing the passage of food antigens and luminal bacteria. This function is essentially subserved by tight junctions (TJs), multiprotein complexes located in the most apical part of the lateral membrane. Some gastrointestinal disease states are associated with elevated intestinal permeability to macromolecules. In a study on rats, we determined the influence of chronic, daily ingestion of chlorpyrifos (CPF, a pesticide that crosses the placental barrier) during pre- and postnatal periods on intestinal permeability and TJ characteristics in the pups. Fluorescein isothiocyanate (FITC)-dextran was used as a marker of paracellular transport and mucosal barrier dysfunction. Pups were gavaged with FITC-dextran solution and blood samples were collected every 30 min for 400 min and analyzed spectrofluorimetrically. At sacrifice, different intestinal segments were resected and prepared for analysis of the transcripts (qPCR) and localization (using immunofluorescence) of ZO-1, occludin and claudins (scaffolding proteins that have a role in the constitution of TJs). In rats that had been exposed to CPF in utero and after birth, we observed a progressive increase in FITC-dextran passage across the epithelial barrier from 210 to 325 min at day 21 after birth (weaning) but not at day 60 (adulthood). At both ages, there were significant changes in intestinal TJ gene expression, with downregulation of ZO-1 and occludin and upregulation of claudins 1 and 4. In some intestinal segments, there were changes in the cellular localization of ZO-1 and claudin 4 immunostaining. Lastly, bacterial translocation to the spleen was also observed. The presence of CPF residues in food may disturb epithelial homeostasis in rats. Changes in TJ protein expression and localization may be involved in gut barrier dysfunction in this model. Uncontrolled passage of macromolecules and bacteria across the intestinal epithelium may be a risk factor for digestive inflammatory diseases.

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Section: Discussionmentioning

confidence: 72%

Increased Gut Permeability and Bacterial Translocation after Chronic Chlorpyrifos Exposure in Rats

et al. 2014

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“…In addition, MRI studies have shown that 14-day exposures to 3 and 18 mg/kg/d CPF reduced brain AChE activity by 60–80% in rats and significantly decreased axonal transport of Mn 2+ , both at the end of the exposure period and after a 30-day washout period (Hernandez et al, 2015). CPF-induced impairments in axonal transport can partially be explained by altered motility of mitochondria and changes in motor proteins like kinesin and microtubules, as well as motor-associated proteins like tubulin (Gearhart et al, 2007; Prendergast et al, 2007; Grigoryan and Lockridge, 2009; Middlemore-Risher et al, 2011). Similar impairments in motor proteins are induced by DFP exposure, which may also impair axonal transport (Gearhart et al, 2007; Gao et al, 2016).…”

Section: Mechanisms Of Chronic Op Neurotoxicitymentioning

confidence: 99%

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

et al. 2017

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Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally.

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“…The dissection protocol described by Gearhart et al (2007) was used to isolate six brain regions-basal forebrain, hippocampus (anterior and posterior), striatum, prefrontal cortex, and cortex-from frozen half brains (collected above). Brain regions were manually homogenized using a polypropylene pestle in a 1.5-ml microcentrifuge tube (Scienceware catalog no.…”

Section: Homogenization Of Brain For Enzyme Assaysmentioning

confidence: 99%

Chronic, Intermittent Exposure to Chlorpyrifos in Rats: Protracted Effects on Axonal Transport, Neurotrophin Receptors, Cholinergic Markers, and Information Processing

Terry

Gearhart²,

Beck³

et al. 2007

J Pharmacol Exp Ther

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Persistent behavioral abnormalities have been commonly associated with acute organophosphate (OP) pesticide poisoning; however, relatively little is known about the consequences of chronic OP exposures that are not associated with acute cholinergic symptoms. In this study, the behavioral and neurochemical effects of chronic, intermittent, and subthreshold exposures to the OP pesticide, chlorpyrifos (CPF), were investigated. Rats were injected with CPF s.c. (dose range, 2.5-18.0 mg/kg) every other day over the course of 30 days and then were given a 2-week CPF-free washout period. In behavioral experiments conducted during the washout period, dosedependent decrements in a water-maze hidden platform task and a prepulse inhibition procedure were observed, without significant effects on open-field activity, Rotorod performance, grip strength, or a spontaneous novel object recognition task.After washout, levels of CPF and its metabolite 3,5,6-trichloro-2-pyridinol were minimal in plasma and brain; however, cholinesterase inhibition was still detectable. Furthermore, the 18.0 mg/kg dose of CPF was associated with (brain region-dependent) decreases in nerve growth factor receptors and cholinergic proteins including the vesicular acetylcholine transporter, the high-affinity choline transporter, and the ␣ 7 -nicotinic acetylcholine receptor. These deficits were accompanied by decreases in anterograde and retrograde axonal transport measured in sciatic nerves ex vivo. Thus, low-level (intermittent) exposure to CPF has persistent effects on neurotrophin receptors and cholinergic proteins, possibly through inhibition of fast axonal transport. Such neurochemical changes may lead to deficits in information processing and cognitive function.

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Chlorpyrifos, chlorpyrifos-oxon, and diisopropylfluorophosphate inhibit kinesin-dependent microtubule motility

Cited by 66 publications

References 78 publications

Increased Gut Permeability and Bacterial Translocation after Chronic Chlorpyrifos Exposure in Rats

Increased Gut Permeability and Bacterial Translocation after Chronic Chlorpyrifos Exposure in Rats

Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

Chronic, Intermittent Exposure to Chlorpyrifos in Rats: Protracted Effects on Axonal Transport, Neurotrophin Receptors, Cholinergic Markers, and Information Processing

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