Chronic dietary exposure to chlorpyrifos causes behavioral impairments, low activity of brain membrane-bound acetylcholinesterase, and increased brain acetylcholinesterase-R mRNA

López-Granero, Caridad; Cardona, Diana M.; Giménez, Estela; Lozano, Rafael; Barril, J.; Sánchez-Santed, Fernando; Cañadas, Fernando

doi:10.1016/j.tox.2013.03.009

Cited by 29 publications

(16 citation statements)

References 53 publications

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“…While exposure to CPF results in higher levels of ChE inhibition than APH inhibition in the early periods following exposure, the inhibition of APH is much more persistent than is that of AChE (Quistad et al, 2005; Cardona et al, 2013; Lopez-Granero et al, 2013a). However, subsequent long term behavioral studies involving either a high dose acute exposure or a chronic feeding exposure to CPF did not find any association between APH activity and cognitive deficits observed (Lopez-Granero et al, 2013b; 2014). While APH has greater sensitivity to inhibition by certain OP compounds, its role in the long term effects of OP exposure is not clear.…”

Section: Discussionmentioning

confidence: 85%

Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition

et al. 2014

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The prevailing dogma is that chlorpyrifos (CPF) mediates its toxicity through inhibition of cholinesterase (ChE). However, in recent years, the toxicological effects of developmental CPF exposure have been attributed to an unknown non-cholinergic mechanism of action. We hypothesize that the endocannabinoid system may be an important target because of its vital role in nervous system development. We have previously reported that repeated exposure to CPF results in greater inhibition of fatty acid amide hydrolase (FAAH), the enzyme that metabolizes the endocannabinoid anandamide (AEA), than inhibition of either forebrain ChE or monoacylglycerol lipase (MAGL), the enzyme that metabolizes the endocannabinoid 2-arachidonylglycerol (2-AG). This exposure resulted in the accumulation of 2-AG and AEA in the forebrain of juvenile rats; however, even at the lowest dosage level used (1.0 mg/kg), forebrain ChE inhibition was still present. Thus, it is not clear if FAAH activity would be inhibited at dosage levels that do not inhibit ChE. To determine this, 10 day old rat pups were exposed daily for 7 days to either corn oil or 0.5 mg/kg CPF by oral gavage. At 4 and 12 h post-exposure on the last day of administration, the activities of serum ChE and carboxylesterase (CES) and forebrain ChE, MAGL, and FAAH were determined as well as the forebrain AEA and 2-AG levels. Significant inhibition of serum ChE and CES was present at both 4 and 12 h. There was no significant inhibition of the activities of forebrain ChE or MAGL and no significant change in the amount of 2-AG at either time point. On the other hand, while no statistically significant effects were observed at 4 h, FAAH activity was significantly inhibited at 12 h resulting in a significant accumulation of AEA. Although it is not clear if this level of accumulation impacts brain maturation, this study demonstrates that developmental CPF exposure at a level that does not inhibit brain ChE can alter components of endocannabinoid signaling.

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Section: Discussionmentioning

confidence: 85%

Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition

et al. 2014

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“…Furthermore, Lopez-Granero et al (2013b) reported that chronic dietary exposure in rats produced cognitive and emotional disorders related with changes in AChE isoforms. Otherwise, AChE-S overexpression has been reported to induce basal forebrain cholinergic cell death (Del Pino et al 2014.…”

Section: Discussionmentioning

confidence: 99%

“…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). Moreover, Lopez-Granero et al (2013b) reported that chronic CPF dietary exposure in rats produced cognitive and emotional disorders related to changes in AChE forms specifically due to a high inhibition of the particulate form and a modification of alternative splicing of mRNA.…”

Section: Introductionmentioning

confidence: 86%

“…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). However, the complete mechanisms through which CPF induces these cognitive alterations are unknown.…”

Section: Introductionmentioning

confidence: 99%

“…AChE-S overexpression has been also linked to intensification of neuro-deterioration (Birikh et al, 2003), programmed cell death (Greenberg et al, 2010;Toiber et al, 2009) and cell death of basal forebrain cholinergic neurons (Del Pino et al, 2014. Moreover, a selective loss of the tetrameric AChE form as observed after CPF exposure (Lopez-Granero et al, 2013b) has been related with neurodegenerative disorders, such as AD (Saez-Valero et al, 1999). According to all the above, the cognitive disorders could be mediated by induction of septal cholinergic neuronal loss through alteration of the AChE splice variants expression.…”

Section: Introductionmentioning

confidence: 99%

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Different toxins, including chemicals and natural, can be entered from various routes and influence human health. Herbal medicines and their active components can attenuate the toxicity of agents via multiple mechanisms. For example, kaempferol, as a flavonoid, can be found in fruits and vegetables, and has an essential role in improving disorders such as cardiovascular disorders, neurological diseases, cancer, pain, and inflammation situations. The beneficial effects of kaempferol may be related to the inhibition of oxidative stress, attenuation of inflammatory factors such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2) and nuclear factor ĸB (NF-ĸB) as well as the modulation of apoptosis and mitogen-activated protein kinase (MAPK) signaling pathways. This flavonoid boasts a wide spectrum of toxin targeting effects in tissue fibrosis, inflammation, and oxidative stress thus

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Chronic dietary exposure to chlorpyrifos causes behavioral impairments, low activity of brain membrane-bound acetylcholinesterase, and increased brain acetylcholinesterase-R mRNA

Cited by 29 publications

References 53 publications

Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition

Low level chlorpyrifos exposure increases anandamide accumulation in juvenile rat brain in the absence of brain cholinesterase inhibition

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

A comprehensive and mechanistic review on protective effects of kaempferol against natural and chemical toxins: Role of NF‐κB inhibition and Nrf2 activation

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