Chlorpyrifos Induces Delayed Cytotoxicity after Withdrawal in Primary Hippocampal Neurons through Extracellular Signal-Regulated Kinase Inhibition

Abstract

Organophosphorus (OP) pesticides are extensively used for control of insects around the home and in agricultural practice. However, they can pose a threat to public health. OP pesticides are known to cause millions of acute poisoning cases per year around the world.1) Besides acute poisoning, OP pesticide exposure causes chronic neurological consequences, especially those related to poor neuropsychiatric changes or neurobehavioral performances in some cognitive domains or mood domain.2) The chronic neurological consequence is called chronic OP-induced neuropsychiatric disorder (COPIND) or organophosphorus ester-induced chronic neurotoxicity (OPICN), [3][4][5] which can occur not only after acute OP pesticide intoxication but after long-term low-level exposure.The mechanism of acute toxicity of OP pesticide has been fully studied and understood. The symptom after absorption of OP pesticide is acute cholinergic syndrome due to inhibition of acetylcholinersterase (AChE) that degrades acetylcholine (ACh).6) By contrast, the mechanism of chronic neurological consequence or COPIND is not very clear now.COPIND is usually long-lasting. Agricultural workers performed worse on tests of cognitive and psychomotor function in 2 years after OP pesticide intoxication. 2,7) In experimental studies, cognitive deficit was found to last days to months after cessation of OP pesticides exposure. 8,9) The long-lasting neuropsychiatric changes suggest that the central nervous system has been permanently damaged.COPIND is sometimes delayed in occurrence, independent of acute toxicity.10) It was found among sheep dippers that long term (2 months later) neurotoxic effects occurred independent of symptoms arising from acute OP pesticides exposure. Only a slight increase in immediate effects but a significant increase in long-term effects were detected compared to the controls 11); Women greenhouse workers were found to show no abnormal neurological changes during the working season despite their contact with OP pesticides. However, abnormal neurological changes occurred after the working season.12) Song et al. 13) found that neurotoxicity appeared after several days' delay upon termination of OP pesticide exposure to rats; Prendergast et al. 14) found the impairment of working memory after OP pesticide withdrawal. These findings suggest that COPIND may not derive from the direct effect of OP pesticide to some extent. The mechanism of delayed neurotoxicity remains little known.In vitro studies may help elucidate the mechanism of OP pesticide neurotoxicity. In this study, the delayed cytotoxicity of chlorpyrifos (CPF) was probed in cultured rat hippocampal neurons. CPF was chosen since it has been a widely used OP pesticide and confirmed to induce long-term neurotoxicity in vivo 8,15,16) and neurotoxicity in vitro. 17,18) Primary hippocampal neurons were used, for hippocampus was the cognition-related brain region and vulnerable to CPF insult. 16,19,20) In the present study, no detectable cytotoxicity was found in the cultured hippocamp...

Delayed Reduction of Hippocampal Synaptic Transmission and Spines Following Exposure to Repeated Subclinical Doses of Organophosphorus Pesticide in Adult Mice

“…This is accompanied by a drastic decrease in the frequency of mEPSCs, slowing of mEPSC kinetics, and decreased input resistance of CA1 neurons in CPF-treated mice. Although our results are in line with reports of CPF-induced delayed cytotoxicity in vitro (Rush et al, 2010;Tan et al, 2009;Terry et al, 2003), we did not observe any change in neuron number in either the CA3 or CA1 regions with treatment in vivo. However, we did observe a large novel decrease in synaptic spine density across both basilar and apical dendrites of CA1 neurons, indicating that synaptic spine loss rather than neuron loss is responsible for the decrease in basal hippocampal synaptic transmission at 3 months following CPF treatment.…”

Chlorpyrifos developmental neurotoxicity: Interaction with glucocorticoids in PC12 cells

“…The augmented cell loss reflects the fact that the two agents reduce cell number through different mechanisms; chlorpyrifos is directly antimitotic and proapoptotic (Qiao et al, 2001; Rush et al, 2010; Slotkin and Seidler, 2012; Song et al, 1998; Tan et al, 2009), whereas dexamethasone enhances the switch from cell replication to neurodifferentiation (Ebert et al, 1997; Jameson et al, 2006b). Notably, these effects were seen at exposures that are not cytotoxic (Jameson et al, 2006b; Qiao et al, 2001; Song et al, 1998), and indeed, dexamethasone actually promotes cell viability (Jameson et al, 2006b).…”

Organophosphorus Compounds and MAPK Signaling Pathways

“…Treatment with two activators of ERK1/2, such as nerve growth factor (NGF) and carbachol, inhibited the delayed neurotoxicity induced by CPF, which shows the influence of the inhibition of ERK1/2 phosphorylation on the delayed neurotoxicity caused by CPF [40].…”

“…In addition, chronic exposure to OPCs caused delayed neuropsychiatric disorders, and a mechanism underlying the delayed neurotoxicity induced by CPF can be the inhibition of ERK1/2 signaling activation. In this context, it was shown that phosphorylation of ERK1/2 during a 96-h exposure to 10 µM CPF occurred but that withdrawal after 48 h of exposure to this agent caused ERK1/2 signal inhibition, which delayed toxicity of CPF in primary rats hippocampal neurons [40].…”

“…Treatment with two activators of ERK1/2, such as nerve growth factor (NGF) and carbachol, inhibited the delayed neurotoxicity induced by CPF, which shows the influence of the inhibition of ERK1/2 phosphorylation on the delayed neurotoxicity caused by CPF [ 40 ]. Moreover, Caughlan et al [ 41 ] have shown that CPF causes mitochondrial dysfunction and apoptosis in primary cortical neurons that have been cultured since the 17th day of embryonic life or in newborn rats.…”