Next Article in Journal
Pravastatin Administration Alleviates Kanamycin-Induced Cochlear Injury and Hearing Loss
Next Article in Special Issue
Special Issue: Cholinergic Control of Inflammation
Previous Article in Journal
Genome-Wide Identification, Classification and Expression Analysis of m6A Gene Family in Solanum lycopersicum
Previous Article in Special Issue
The Human-Restricted Isoform of the α7 nAChR, CHRFAM7A: A Double-Edged Sword in Neurological and Inflammatory Disorders
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 9
10.3390/ijms23094523
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Organophosphorus Pesticides as Modulating Substances of Inflammation through the Cholinergic Pathway

by
Milton Rafael Camacho-Pérez
1,
Carlos Eduardo Covantes-Rosales
1,
Gladys Alejandra Toledo-Ibarra
1,
Ulises Mercado-Salgado
1,
María Dolores Ponce-Regalado
2,
Karina Janice Guadalupe Díaz-Resendiz
1,* and
Manuel Iván Girón-Pérez
1,*
1
Laboratorio Nacional de Investigación para la Inocuidad Alimentaria (LANIIA)-Unidad Nayarit, Universidad Autónoma de Nayarit, Tepic 63173, Mexico
2
Centro Universitario de los Altos, Departamento de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 47610, Mexico
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(9), 4523; https://doi.org/10.3390/ijms23094523
Submission received: 31 March 2022 / Revised: 12 April 2022 / Accepted: 14 April 2022 / Published: 20 April 2022
(This article belongs to the Special Issue Cholinergic Control of Inflammation)
Browse Figures
Versions Notes

Abstract

Organophosphorus pesticides (OPs) are widespread insecticides used for pest control in agricultural activities and the control of the vectors of human and animal diseases. However, OPs’ neurotoxic mechanism involves cholinergic components, which, beyond being involved in the transmission of neuronal signals, also influence the activity of cytokines and other pro-inflammatory molecules; thus, acute and chronic exposure to OPs may be related to the development of chronic degenerative pathologies and other inflammatory diseases. The present article reviews and discusses the experimental evidence linking inflammatory process with OP-induced cholinergic dysregulation, emphasizing the molecular mechanisms related to the role of cytokines and cellular alterations in humans and other animal models, and possible therapeutic targets to inhibit inflammation.

Graphical Abstract

1. Organophosphorus Pesticides

In recent years, the application of pesticides has increased, as these substances allow pest and disease control in agriculture and livestock, reducing losses in food production, and allowing better control of vectors of human and veterinary diseases [1]. Currently, the most commonly used pesticides worldwide are organophosphorus pesticides [2,3,4], which are insecticides derived from phosphoric or phosphorothioic acid. In 2019, approximately 2 million tons of pesticides were applied globally; in 2020, pesticides reached up to 3.5 million tons, of which approximately one-third consisted of organophosphorus pesticides [5,6].
Organophosphorus pesticides (OPs) are widely used as insecticides, and the use of OPs has replaced organochlorine pesticides, as OPs have limited environmental persistence [1,7]; however, the incorrect handling of these substances during storage, transport, application and the disposal of residues may cause toxic effects on non-target organisms, such as aquatic organisms, domestic and wild fauna, and even humans [8]. Worldwide, more than 3 million acute intoxications and up to 250,000 deaths caused by pesticides are reported annually [9]; OPs reach organisms via inhalation, dermal and oral exposure, the most common being the last one [10]; once inside the organism, these substances are biotransformed (Figure 1a) to highly toxic metabolites (oxon) by the metabolic activation of cytochrome P450 [11], through the elimination of sulfur bound to phosphorus and the insertion of an oxygen atom (oxidative desulfurization). Oxons are detoxified through dearylation and hydrolysis to produce dialkyl phosphates (DAP) or dialkyl thiophosphates, respectively [12], finally by conjugative reactions; these metabolites are excreted out of the body through urine.

Mechanism of Action of OPs and Toxicity

OPs are designed to inhibit acetylcholinesterase (AChE) activity (Figure 1b) by phosphorylating the hydroxyl group of the serine present in the active site AChE. This interrupts the physiological action of AChE, which degrades the neurotransmitter acetylcholine (ACh), causing its accumulation in the nerve synapses [13], leading to the overstimulation of the muscarinic (mAChR) and nicotinic (nAChR) receptors, and consequently uncontrolled nerve impulses and thus the death of insects [13,14,15,16,17,18,19,20,21]. However, the toxic effects of OPs do not only affect pests; in fact, all organisms that possess cholinergic components can potentially be affected (Table 1) [22,23,24,25,26,27,28,29]. In this sense, humans have a neuronal cholinergic system and—when accidentally or occupationally exposed to these substances—can suffer both acute and chronic effects; the acute effects usually occur minutes or hours after exposure to Ops, and are manifested by clinical signs such as headaches, miosis, diarrhea, muscle weakness, and salivation [30,31], whereas chronic exposure is associated with long-term effects that are complex to attribute to the action of pesticides exclusively. Nevertheless, scientific evidence is growing that these substances induce mutations, epigenetic modifications, tumors, and several types of cancer, as well as cognitive and functional alterations in several physiological systems such as the renal, circulatory, respiratory, endocrine and immune systems [32,33,34,35,36,37]. Currently, several non-neuronal cells, such as pancreatic alpha cells, endothelial cells, placental cells, thrombocytes, and lymphocytes express cholinergic components, which make those cells a target for OPs [38,39,40,41,42,43].
Therefore, several studies have reported that the alteration of the cholinergic system induced by OPs can trigger an inflammatory response and, consequently, pathophysiological alterations [19,44,45,46,47]. Thus, acute OP intoxication has been reported to stimulate an instantaneous and premature robust inflammatory response, whereas chronic exposure to low concentrations of OPs increases inflammatory mediators in a slow but sustained manner [44], or that it could be related to the development of inflammatory diseases such as organophosphate-induced delayed neuropathy (OPIDN) [19], rheumatoid arthritis [45,46], and neuroinflammation [47]. Further studies have shown that exposure to OPs leads to processes of cellular hyperreactivity, synergism with allergens, and the dysregulation of lung physiology, thus promoting susceptibility to asthma development [48,49]. In addition, recent research indicates that exposure to OPs may promote the development of early-stage diabetes mellitus [50].
In the present review, an overview of the experimental evidence linking inflammation to OP-induced cholinergic dysfunction is provided, and the molecular mechanisms through which OPs may induce inflammatory responses are discussed.

2. Cholinergic System

The cholinergic system consists of the biochemical and molecular machinery required to synthesize de novo acetylcholine (ACh), a neurotransmitter that has been conserved throughout evolution [51]. This machinery (Figure 2) consists of synthesis enzymes such as choline acetyltransferase (ChAT, E.C. 2.3.1.6.), storage and transport elements such as ACh vesicles (VaCh), the vesicular ACh transporter (VAChT), the choline transporter (CHT), the muscarinic and nicotinic ACh receptors (mAChR and nAChR, respectively), degradation enzymes such as acetylcholinesterase (AChE, E. C. 3.1.1.7), and non-specific choline esterases such as butyrylcholinesterase (BChE, E.C. 3.1.1.8.) [51]. This set of elements has a fundamental role in the nervous system; however, it is not exclusive to neuronal cells [52,53], as its presence has been demonstrated in other cells such as epithelial (respiratory tract, intestine, skin, urothelium, vagina, placenta, and cornea), endothelial and immune system cells (lymphocytes, macrophages, mast cells, eosinophils, and neutrophils) [54,55], which have been called the “non-neuronal cholinergic system” or “extra-neuronal cholinergic system”; this system is independent of neuronal innervation [39] and has been localized in a wide variety of organisms such as humans and other mammals (rats), as well as lower invertebrates (sponges, corals, ascidians, sea urchins, turbellaria), protozoa, plants, fungi and even bacteria [54].
As previously mentioned, epithelial, endothelial, and immune system cells (macrophages, mast cells, eosinophils, neutrophils, and lymphocytes) are the targets of OPs [43]. In this regard, Kawashima and Fujii [55] documented that mammalian lymphocytes express muscarinic and nicotinic acetylcholine receptors on the cell membrane, and also possess an autonomous cholinergic system, i.e., a non-neuronal cholinergic system through which they produce acetylcholine and degrade it via the enzyme AChE. Other cholinergic components, such as choline acetyltransferase (ChAT), a high-affinity choline transporter, are also expressed in lymphocytes [56]. At present, several studies report the effects of OPs on the vertebrate immune system [1,57,58,59,60,61,62,63,64]; nonetheless, the immunotoxic mechanisms of these substances are not completely elucidated, as OPs could exert a direct cytotoxic effect on lymphocytes, or indirectly, by altering the cholinergic system present in these cells [43,65]. In this way, the lymphocyte cholinergic system could be targeted by OPs in the immunotoxicity phenomenon, which could lead to systemic inflammatory manifestations that manifest as neurological, cardiovascular, and autoimmune diseases [66].

3. Immunotoxicity of OPs through the Cholinergic System

In vertebrates, the modulation of the immune response by cholinergic pathways is well established [21,67,68,69]. Processes like the development, proliferation, differentiation and activation of immune cells have been linked to AChRs [70]. The stimulation of mAChRs increases intracellular Ca2+ influx, upregulates c-Fos expression, and affects cell proliferation [42]. In addition, mAChRs are related to immune defense, as they modulate inflammatory processes and antibody isotype switching [21,67]. Moreover, antigenic stimuli induce the expression of cholinergic components in leukocytes [71]. Among regulatory processes of inflammation, the cholinergic anti-inflammatory pathway (CAP) plays a prominent role, where the neurotransmitter ACh activates nicotinic receptors of inflammatory cells, with the homopentameric receptor nAChR-a7 being one of the most important participants, leading to a decrease in the synthesis of proinflammatory cytokines and LPS-induced TNF and HMGB1 release [72,73]. Hence, the regulation of cholinergic pathways through specific agonists and antagonists may represent a neuro-immune target in chronic inflammatory diseases.
Immune cell function is highly regulated by classical soluble molecules, such as cytokines, hormones, neurotransmitters, and by cell-to-cell interactions, and it can be directly or indirectly affected by several factors, such as toxic lifestyle, iatrogenic, biotoxic, environmental/occupational, and psychosocial/socioeconomic conditions [74]. However, epidemiological and toxicological evidence suggests that OPs exert immune side effects in both humoral and cell mechanisms (innate or adaptive) [43,75]. Immune response perturbation induced by OPs could be an enhancement (hypersensitivity and autoimmunity) or immunosuppression (susceptibility to infections or neoplastic transformation) [76]. OPs can exert toxic effects through mechanisms unrelated to AChE inhibition, as these compounds can bind to cholinergic receptors [77]. In this regard, both the nerve agents Soman and XV, as well as oxon metabolites of OPs (paraoxon, malaoxon, and diazoxon) can directly interact with cholinergic receptors and modulate the level of receptor expression [78]. The dysregulation of RNA and the protein expression of nAChR (α4 and β2 subunits) after exposure to oxon metabolites was demonstrated in pC12 cells [79]. Likewise, it has been shown that some OPs interact more often with the α4β2 subunits of neuronal nAChRs to inhibit the agonist-induced response [80]. Such a finding suggests that, in addition to AChE inhibition, the inhibition of neuronal nAChRs occurs, thus explaining the massive blocking effect of anti-inflammatory metabolic pathways.
In addition, alterations of the neuronal cholinergic system have been reported in the leukocyte cholinergic system, as it has been reported that exposure to diazinon (DZN) in vivo (3.91 mg/L) causes a decrease in the protein concentration of nAChR and mAChR of the immune cells of Nile tilapia [23]. Similar results were obtained by Charoenying et al. [81], who showed that paraoxon causes cholinergic dysregulation in lymphoma (MOLT-3) and neuroblastoma (SH-SY5Y) cell lines, finding that the lymphocyte extraneuronal cholinergic system has greater susceptibility to OPs than its neuronal counterpart, which could be related to immunotoxicity mechanisms. However, the mechanisms of immunotoxicity induced by OPs such as DZN are not yet fully elucidated, although it has been proposed that the extraneuronal cholinergic system could be related to immunotoxicity [22,81,82].
Furthermore, it has been reported that the overactivation of nAChRs and mAChRs leads to increased calcium influx [24], which in turn induces increased ROS production, as both processes are highly coordinated in these cell types [83]. Increased intracellular calcium generates mitochondrial stress that promotes ROS production in this organelle (Figure 3a) [84]. Furthermore, the overactivation of cholinergic receptors in leukocytes has a direct impact on cellular functions such as phagocytosis, which was demonstrated using selective acetylcholine receptor agonists and antagonists [21,85].
The onset of OP-induced immune disorders will depend on the type of cells affected. The authors of [86] reported that patients exposed to organophosphates showed the impairment of neutrophil functions (phagocytosis, respiratory burst, adhesion) leading to recurrent infections, in addition to increased risk of upper respiratory tract infections (tonsillitis, pharyngitis, and bronchitis). On the other hand, the functional mutilation of natural killer (NK) cells due to OP intoxication may partly elevate the risk of cancer and viral infections [87,88]. Deeper effects were observed in the immune system, when the activities of antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, were inhibited, given that they play a key role in the elimination of infectious agents and the deployment of cell-mediated immunity [44]. The functional impairment of DCs and macrophages induced by OPs occurs through negative regulation of co-stimulatory molecules (CD80 and CD86), effector molecules (human leukocyte antigen), MHC expression, and phenotypic modulation [89,90,91].
Pesticide-induced immunosuppression is evidently a risk factor for the clinical complication of inflammatory diseases, especially in occupationally or environmentally exposed individuals, which occurs in developing countries. In this context, the current knowledge of molecular mechanisms suggests a direct effect of the exposure to OPs on immunity and inflammatory processes; however, new experiments with epidemiological approaches are key to demonstrating the existing correlation of the exposure to toxic substances, such as OPs, with the degree of susceptibility of organisms to inflammatory diseases.

4. Cytokine-Mediated Modulation of the Inflammatory Process by OP Exposure

The consequences of chronic or early-life exposure to pesticides may be extended beyond innate immune dysfunction to the increased risk of late-life chronic inflammatory-based diseases. Immune cells can release a variety of inflammation mediators, activating pro- and anti-inflammatory processes and regulating intracellular pathways [92].
It is essential to understand the ways in which OPs affect immune cell activities and, consequently, the function of the immune system, as these substances can induce alterations in the humoral/cellular mechanisms causing a direct impact on lymphoid tissues and immune cell function [93]. While previous studies reported that OPs could affect immunity through different mechanisms [76,94], immune suppression/dysregulation is a major mechanism by which pesticides exert their immunomodulatory activity, affect immunocompetence, and consequently increase the host’s susceptibility to diseases and an array of immune disorders. OPs can affect immunity by interfering with cell signaling pathways, which could result in changes in cytokine production, surface marker expression, and cell activation (Table 2) [76,90,93,95,96,97,98,99,100,101,102,103]. Thus, pro-inflammatory cytokines induce the initiation of inflammation through interaction with Toll-Like Receptors (TLR), IL-1 receptor (IL-1R), IL-6 receptor (IL-6R), and TNF receptor (TNFR). Receptor activation modulates intracellular signaling pathways, including those controlled by the Mitogen-Activated Protein Kinase (MAPK), Nuclear Factor kappa-B (NF-κB), Janus Kinase (JAK)-Signal Transducer, and the Activator of Transcription (STAT). These transcription factors promote cytokine expression, modulating a large number of inflammatory genes, such as IL-1, TNF-α, IL-6, interferons, Transforming Growth Factor (TGF), and chemokines [104].
In this context, it has been shown that exposure to OPs induces the activation of calcium-mediated p38-MAPK and ERK signaling (Figure 3b), promoting an inflammatory stage through NF-KB activation and increased levels of pro-inflammatory cytokines such as TNF-alpha IL-6 [105,106,107]. Lasram et al. [95] reported that malathion induces the release of pro-inflammatory cytokines such as IL-1β, IL-6, and INF-γ. These cytokines are responsible for the activation of nuclear transcription factors such as NF-κB, and are involved in inflammation and the apoptosis of damaged cells. El-Sayed et al. [96] reported that chlorpyrifos can upregulate the expression of some pro-inflammatory markers such as TNF-α and IL-1β, besides the activation of NF-κB, which is an important transcription factor that can be found in the cytoplasm in the form of a dimer of p65 and p50 subunits. Under normal conditions, NF-κB was found to be bound to the inhibitory protein IκB. However, upon exposure to stressful conditions (such as environmental contaminants such as OPs), IκB is phosphorylated, and is separated from the p65 subunit of NF-κB. Consequently, NF-κB is translocated into the nucleus to activate the transcription of pro-inflammatory cytokines like TNF-α and interleukins to instigate inflammatory responses, and consequently to activate the apoptotic pathway (Figure 3b) [96,97], supporting a critical role for NF-κB in transducing diverse environmental stimuli to upregulate cytokine expression in inflammatory cells.
Moreover, it has been shown that exposure to OPs causes phospholipase C inhibition, as well as decreased CREB phosphorylation and decreased levels of cAMP (Figure 3c) and mAChR mRNA (M1, M2, M3) [108,109]. CREB phosphorylation is a focal point for multiple signaling cascades, and is recognized to play a critical role in neuronal development, synaptic plasticity, memory function, regeneration, and cell survival in response to diverse types of stress [110]. The reduced phosphorylation of CREB by exposure to OPs may contribute to neurobehavioral deficits, and may also affect the transcription of genes associated with learning, memory, and synaptic plasticity. It has recently been suggested that the persistence of long-term memories may depend on the activation of the cAMP/MAPK/CREB transcriptional pathway in the hippocampus [111,112]. CREB also plays many different roles in immune function by promoting anti-inflammatory immune responses, such as the inhibition of NF-κB activity, the induction of IL-10, and the generation of T-regs [113]. However, reduced CREB phosphorylation induced by OP exposure promotes NF-κB activation causing a cascade of signaling events that ultimately lead to the degradation of IκB (Figure 3c), which allows NF-κB release and facilitates NF-κB nuclear translocation, where it promotes the transcription of genes involved in pro-inflammatory immune responses [113,114,115].
Macrophages also play an important role in OP-induced inflammation [103]. Ogasawara et al. [102] showed that OPs not only enhance the production of pro-inflammatory markers such as IL-6 and TNF-α but also the number of macrophages, and increase the expression of cyclooxygenase (COX)-2 and inducible nitric oxide synthase enzymes as a major source of ROS. In this way, oxidative stress can stimulate the expression of inflammatory transcription factors, which are crucial regulatory components in the induction of inflammatory responses [96].
Nevertheless, in the cells, there are a plethora of negative regulators of inflammatory signaling pathways that operate in a negative feedback fashion (i.e., those pathways which are inducible by inflammatory signals). These include the suppressor of cytokine signaling (SOCS) proteins, negative regulators of Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling, and A20, a negative regulator of nuclear factor-kB (NF-kB) signaling [116]. However, this plethora of negative regulators of inflammatory signaling pathways can also be modulated by OP exposure [117,118,119,120,121]. Esquivel-Sentíes et al. [117] proposed that the alteration of the function and components of the immune system may be related to the sequence and intensity of the phosphorylation and dephosphorylation of protein kinases, an essential mechanism that controls the function of the immune system. SOCS3 (suppressor of cytokine signaling 3) is a critical molecule in this process, as it functions as a negative regulator of cytokine signaling. SOCS3 regulates STAT by inhibiting the phosphorylation of STAT5 affecting cell proliferation [118,119].
Recent reports have shown that metabolites (dialkyl phosphates) generated by the biotransformation of OPs as diethyl thiophosphate (DETP) and diethyl dithiophosphate (DEDTP) modify the phosphorylation status of STAT5 (Figure 3d) proteins, and thus produce several immunomodulatory effects, for instance, the reduction of CD25 and CD4 expression, the reduced secretion of IL2, and the altered signalization of IL-2R [117,120]. Esquivel-Sentíes et al. [117] reported that DEDTP treatment in human T lymphocytes increases SOCS3 phosphorylation and decreases STAT5 phosphorylation, resulting in the arrest of T cell proliferation (Figure 3d). On the other hand, Lima et al. [121] reported that DEDTP can trigger SOCS3-mediated cell cycle arrest that initiates a feedback mechanism associated with the expression of p21 and p53. DEDTP also induced the phosphorylation of ERK, JNK, and p38 [117], which results in the assembly of AP1, ELK,1, and NFAT, which are the main transcription factors involved in the autocrine IL-2 pathway (Figure 3e) [117,121,122].
Regarding the cholinergic system, acute OP poisoning induces the overstimulation of cholinergic receptors due to the accumulation of ACh at immunological synapse, evoking intracellular Ca2+ signaling, the upregulation of c-fos expression (Figure 3b), and IL-2-induced signal transduction in T cells and B cells, as well as triggering inflammatory responses in macrophages [44,55,76]. In contrast, chronic OP poisoning through the down-regulation of cholinergic receptors may trigger cholinergic anti-inflammatory pathways, which result in the suppression of T-cell activity, predisposition to cancer, and certain infections [44,76,82,83].

5. Therapeutic Strategies to Mitigate the Long-Term Inflammatory Effects of Acute OP Intoxication

The canonical mechanism of the neurotoxicity of OPs is AChE inhibition [123]; thus, acute AChE inhibition (>60 to 80%) can induce a clinical condition termed cholinergic crisis [47], which is characterized by peripheral parasympathetic symptoms, the depression of central breathing control, seizures that can quickly progress to status epilepticus (SE), and the death of the intoxicated individual [124,125]. The conventional treatment to control OP-induced cholinergic seizures is based on the use of drugs such as atropine (a peripheral muscarinic receptor antagonist) [47], pralidoxime (a reactivator of AChE activity) [126] and benzodiazepine (which reduces seizure activity) [124,127]; however, in severe cases of OP poisoning, these agents are not effective. Furthermore, OP intoxication can result in long-term alterations, which are manifested by cognitive dysfunction, affective disorders, or spontaneous recurrent seizures (SRS) [30,128,129,130,131,132], which are linked to neuroinflammatory processes [128].
In the neuroinflammatory disorder induced by OPs, microglia cells play a central role in regulating the production of pro-inflammatory cytokines that eventually damage neurons and exacerbate the course of neurodegenerative alterations [133]. Therefore, new pharmacological therapies should focus urgently on the inactivation of microglia and the inhibition of the inflammatory response. In this regard, it has been shown that blocking intracellular Ca2+ release, inhibiting NLRP3-inflammasome (NF-κB and MAPK blockers), and controlling ROS production (NADPH oxidase inhibitors -Nox1, Nox2, and Nox4) may be important therapeutic targets to counteract the neuronal damage caused by OPs [47,66,134,135,136,137,138,139].

6. Lower Vertebrates as a Biomedical Model

Lower vertebrates have become relevant in the field of biomedical research, given that such vertebrates offer advantages over different study models (e.g., mice). An example of these are fish, which belong to the phylogenetically oldest group of vertebrates, including more than half of the vertebrates on the planet; the vast majority of fishes are teleosts (teleosts, possessing a bony skeleton), and some are highlighted for both their ecological and economic significance, while other species are widely used as biological models for genomic studies and developmental biology [65,140]. Furthermore, as these organisms are the first to present adaptive immune mechanisms, the study of the immune system in these organisms is of great relevance, as it provides information on the evolution of the immune system in vertebrates, thus supporting the knowledge of basic aspects of immunology, and thus the possible treatment of emerging diseases in humans and other animals. Wilson [141] proposed that teleost fishes can be a good model for translational research because they possess mechanisms of innate and adaptive immunity (TLR toll-like receptors, cytokines, complement molecules, B cells, T cells, and immunological memory) which are very similar to those of higher mammals.
Furthermore, teleost fish have also been used as bioindicators of pollution, as they can respond to environmental pollution through alterations in physiology or through the storage of pollutants [142,143]. The use of fish as bioindicators is of great importance for several reasons, due to their sensitivity to environmental stressors, wide geographic distribution, presence in the food chain, and ease of adaptation to captivity, which permits the evaluation of the effect of environmental stressors under controlled conditions [144]. Given this background, our research group has used Nile tilapia (Oreochromis niloticus) and guppy fish (Poecilia reticulata) as bioindicator organisms and biomedical study models, to elucidate the mechanism of immunotoxicity by OPs (Table 3).
Initial studies demonstrated that OPs (chlorpyrifos and diazinon) cause immunotoxic effects by altering the physiological parameters of leukocytes, such as decreased phagocytic capacity [145,146,147], increased respiratory burst [61], and the dysregulation of IgM concentration and lysozyme activity [61,148], in addition to oxidative damage in liver and gill proteins [149]. Subsequently—derived from Kawashima and Fujii [55], who reported that mammalian lymphocytes possessed all of the biochemical and molecular machinery necessary to synthesize ACh de novo—we were prompted to search for this cholinergic system in the mononuclear cells of Nile tilapia, demonstrating not only the presence of the extraneuronal cholinergic system in these cells but also that when the organisms were exposed to DZN, the activity of AChE was inhibited and the concentration of ACh increased [23], suggesting that the lymphocyte cholinergic system could be targeted by OPs in the immunotoxicity phenomenon [43]. Later, in order to elucidate a possible mechanism of immunotoxicity by OPS, the effect of DZN and its metabolite oxon (diazoxon) on intracellular Ca2+ flux and pERK1/2, parameters that play a fundamental role in cell signaling were assessed, in addition to mitochondrial membrane potential (ΔΨm), ROS, NETs, senescence, and apoptosis, which were determined in Nile tilapia leukocytes, demonstrating that DZN and its metabolite oxon alter intracellular Ca2+ and pERK1/2 signaling, leading to the depolarization of the mitochondrial membrane by increased ROS, leading cells to NETosis, senescence and/or death by apoptosis [107,147,150,151]. Likewise, it was demonstrated that tilapia leukocytes express mAChR (M2, M3, M4, M5A) [152], and that after exposure to diazoxon, the expression of muscarinic receptors (M3, M4, M5) and nAChR-β2 decreases [152].
On the other hand, guppy fish (P. reticulata) have also been used by our research group as a model organism to study the toxic effects of these substances used by the Mexican Ministry of Health to control vectors that transmit viral diseases such as dengue, chikungunya, and Zika. The results of these investigations indicate that exposure (7 and 21 days) in vivo to temephos (0.5 mg/L), an OP, causes cholinergic alterations (the inhibition of AChE and the accumulation of the neurotransmitter ACh) in muscle tissue [153]. In addition, it causes a decrease in phagocytic capacity [154] and a decrease in leukocyte viability, inducing apoptosis and necrosis. The data even reveal that temephos induces apoptosis up to 35 days post-exposure, indicating recovery up to 70 days [155].
At present, our research group is working on the effect of diazinon and its metabolite oxon on key molecules involved in cell signaling, aiming to elucidate a possible mechanism of immunotoxicity by these substances. In this sense, we are focusing on the effects of OPs on the expression of cytokines (anti-inflammatory and pro-inflammatory) and master transcription factors (T-bet, GATA-3, RORγt, and FOXP3), as well as on the phosphorylation of JAK/STAT, and levels of cAMP, DAG, and IP3.
Table 3. Effect of OPs on the molecular and cellular parameters of fishes leukocytes as a study model.
Table 3. Effect of OPs on the molecular and cellular parameters of fishes leukocytes as a study model.
OPsDoseExposure TimeEffectsTissue/Cell LineOrganism ModelReferences
DiazinonLC50-7.830 ppm, ½ LC50-3.915 ppm96 h↓ AChE activity
↑ ACh levels		Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[22].
Diazinon0.97, 1.95 and 3.91 mg/L6, 12 and 24 h↓ AChE activity ↓mAChR, nAChR concentration and ↑ ACh levels.Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[23].
Diazoxon1 nm, 1 µM, and 10 µM24 h↓ (M3, M4, M5)
receptors and nAChR-β2 expression.		Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[24].
Diazinon1.96 mg/L96 h↑ Respiratory burst and IgM concentrationSpleen
mononuclear cells		Nile tilapia
(O. niloticus)		[61].
Diazinon0.97, 1.95 and 3.91 mg/L6 and 24 hAlterations in Ca2+ flux and pERK 1/2.
↑ Cellular senescence
↓ mitchondrial membrane. potential
↑ apoptotic cells.		Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[107].
Chlorpyrifos0.422 and 0.211 mg/L)96 h↓ Phagocytic
Capacity.		Peripheral bloodNile tilapia
(O. niloticus)		[145].
DiazinonLC50-7.830 ppm96 h↓ Phagocytic capacity and cellular proliferation.Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[146].
Diazinon0.97, 1.95 and 3.91 mg/L6 and 24 h↑ Reactive oxygen species
↓ Phagocytic activity		Peripheral blood
mononuclear cells		Nile tilapia
(O. niloticus)		[147].
Chlorpyrifos0.051 mg/L96 h↓ IgM levels and
deregulation in
lysozyme activity.		Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[148].
Diazinon0.97, 1.95 and 3.91 mg/L12 and 24 h↑ Protein oxidative damage.Liver
and gills		Nile tilapia
(O. niloticus)		[149].
Diazinon0.97, 1.95 and 3.91 mg/L6 and 24 h↑ Neutrophil
extracellular traps (NETs) induction.		Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[150].
Diazoxon 1   nm ,   1   µ M ,   and   10   µ M1 h and 2 h↓ Ca2+ flux against PMA and ionomycin
stimulation.
↓ ERK1/2
phosphorylation.
↓ Mitochondrial membrane potential.
↑Apoptotic and cellular senescence.		Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[151].
Temephos10 mg/L7 and 21 daysAChE inhibition
↑ ACh levels		Smooth muscleGuppy fish (Poecilia reticulata)[153].
Temephos10 mg/L7 days↓ Phagocytic capacitySpleen
mononuclear cells		Guppy fish (P. reticulata)[154].
Temephos10 mg/L7, 14, and 21 days↑ Leucocytes deathSpleen
mononuclear cells		Guppy fish (P. reticulata)[155].
↑ increase ↓ decrease; ACh: acetylcholine; AChE: acetylcholinesterase; mAChR: muscarinic acetylcholine receptor; nAChR: nicotinic acetylcholine receptor; ROS: reactive oxygen species; NETs: neutrophil extracellular traps. IgM: immunoglobulin M; ERK: extracellular signal-regulated kinase.

7. Conclusions

In conclusion, the present review clearly shows that OPs are substances that, despite being designed for insect control, affect the physiology of non-target organisms, including humans. Due to the mechanism of action of OPs, these substances alter the activity of the cholinergic system, which significantly influences the transcription, synthesis, and release of inflammatory mediators such as cytokines. Consequently, acute and chronic exposure to OPs may be related to the development of chronic degenerative pathologies, as well as allergies or immunosuppression phenomena, alterations in which inflammatory components play a central role.

Author Contributions

M.R.C.-P.: writing of the manuscript; C.E.C.-R.: writing of the manuscript and editing; G.A.T.-I.: comments on the final version of the paper; U.M.-S.: writing of the manuscript; M.D.P.-R.: comments on the final version of the paper; K.J.G.D.-R.: conceptualization, coordination, and writing of the manuscript; M.I.G.-P.: conceptualization and comments on the final version of the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This research received funding from CONACyT-Mexico (Project number CB-A1-S-53561-2017–2018).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Camacho-Pérez M.R. is a Masters student from the program at the Universidad Autónoma de Nayarit en Ciencias Biologico-Agropecuarias.

Conflicts of Interest

The authors report no conflict of interest.

References

  1. Al-Ghanim, K.A. Acute toxicity and effects of sub-lethal malathion exposure on biochemical and haematological parameters of Oreochromis niloticus. Sci. Res. Essays 2012, 7, 1674–1680. [Google Scholar] [CrossRef]
  2. Sidhu, G.K.; Singh, S.; Kumar, V.; Dhanjal, D.S.; Datta, S.; Singh, J. Toxicity, monitoring and biodegradation of organophosphate pesticides: A review. Crit. Rev. Environ. Sci. Technol. 2019, 49, 1135–1187. [Google Scholar] [CrossRef]
  3. International Code of Conduct on the Distribution and Use of Pesticides. Available online: http://apps.who.int/iris/bitstream/handle/10665/70602/WHO_HTM_NTD_WHOPES_2010.7_spa.pdf;jsessionid=6BF8CBB80C94FB71C65499FC33ACB281?sequence=1 (accessed on 28 February 2022).
  4. Cancer Clusters. Available online: https://www.cdc.gov/nceh/clusters/fallon/organophosfaq.htm#:~:text=Organophosphates%20are%20the%20most%20widely,in%20the%20body%20called%20acetylcholinesterase (accessed on 28 February 2022).
  5. Sharma, A.; Kumar, V.; Shahzad, B.; Tanveer, M.; Sidhu, G.P.S.; Handa, N.; Kohli, S.K.; Yadav, P.; Bali, A.S.; Parihar, R.D.; et al. Worldwide pesticide usage and its impacts on ecosystem. SN Appl. Sci. 2019, 1, 1446. [Google Scholar] [CrossRef]
  6. Tudi, M.; Ruan, H.D.; Wang, L.; Lyu, J.; Sadler, R.; Connell, D.; Chu, C.; Phung, D. Agriculture Development, Pesticide Application and Its Impact on the Environment. Int. J. Environ. Res. Public Health 2021, 18, 1112. [Google Scholar] [CrossRef]
  7. Torres-Palma, R.; Serna-Galvis, E. Sonolysis; Academic Press: Cambridge, MA, USA, 2018; pp. 177–213. [Google Scholar] [CrossRef]
  8. Fernández, A.; Mancipe, L.; Fernández, A. Intoxicación por organofosforados. Rev. Med. 2010, 18, 84–92. [Google Scholar] [CrossRef]
  9. Chowdhary, S.; Bhattacharyya, R.; Banerjee, D. Acute organophosphorus poisoning. Clin. Chim. Acta 2014, 431, 66–76. [Google Scholar] [CrossRef]
  10. Nkinsa, P.N.; Muckle, G.; Ayotte, P.; Lanphear, B.P.; Arbuckle, T.E.; Fraser, W.D.; Bouchard, M.F. Organophosphate pesticides exposure during fetal development and IQ scores in 3 and 4-year old Canadian children. Environ. Res. 2020, 190, 110023. [Google Scholar] [CrossRef]
  11. Abbas, R.; Leister, C.; El-Gaaloul, M.; Chalon, S.; Sonnichsen, D. Ascending Single-Dose Study of the Safety Profile, Tolerability, and Pharmacokinetics of Bosutinib Coadministered with Ketoconazole to Healthy Adult Subjects. Clin. Therap. 2012, 34, 2011–2019. [Google Scholar] [CrossRef]
  12. Kaur, K.; Besnier, F.; Glover, K.A.; Nilsen, F.; Aspehaug, V.T.; Fjørtoft, H.B.; Horsberg, T.E. The mechanism (Phe362Tyr mutation) behind resistance in Lepeophtheirus salmonis pre-dates organophosphate use in salmon farming. Sci. Rep. 2017, 7, 12349. [Google Scholar] [CrossRef]
  13. Oruc, E.; Usta, D. Evaluation of oxidative stress responses and neurotoxicity potential of diazinon in different tissues of Cyprinus carpio. Environ. Toxicol. Pharmacol. 2007, 23, 48–55. [Google Scholar] [CrossRef]
  14. Fulton, M.H.; Key, P.B. Acetylcholinesterase inhibition in estuarine fish and invertebrates as an indicator of organophosphorus insecticide exposure and effects. Environ. Toxicol. Chem. 2001, 20, 37–45. [Google Scholar] [CrossRef] [PubMed]
  15. Profile for Diazinon. Available online: https://www.atsdr.cdc.gov/toxprofiles/tp86.pdf (accessed on 28 February 2022).
  16. Elersek, T.; Filipič, M. Organophosphorous Pestidices Mechanism of Their Toxicity Pesticides—The Impact of Pesticides Expusure; Intech: Rijeka, Croatia, 2011. [Google Scholar] [CrossRef]
  17. Robb, E.L.; Baker, M.B. Organophosphathe Toxicity. In StatPearls; StatPearls Publishing: Treasure Island, FL, USA, 2021; PMID: 29261901. [Google Scholar]
  18. Vásquez, M.O. Intoxicación por organofosforados. Rev. Med. Sinerg. 2020, 5, e558. [Google Scholar] [CrossRef]
  19. King, A.M.; Aaron, C.K. Organophosphate and Carbamate Poisoning. Emerg. Med. Clin. N. Am. 2015, 33, 133–151. [Google Scholar] [CrossRef] [PubMed]
  20. Mileson, B.E.; Chambers, J.E.; Chen, W.L.; Dettbarn, W.; Ehrich, M.; Eldefrawi, A.T.; Gaylor, D.W.; Hamernik, K.; Hodgson, E.; Karczmar, A.G.; et al. Common Mechanism of Toxicity: A Case Study of Organophosphorus Pesticides. Toxicol. Sci. 1998, 41, 8–20. [Google Scholar] [CrossRef]
  21. Kawashima, K.; Fujii, T.; Moriwaki, Y.; Misawa, H.; Horiguchi, K. Reconciling neuronally and nonneuronally derived acetylcholine in the regulation of immune function. Life Sci. 2012, 1261, 1027–1032. [Google Scholar] [CrossRef]
  22. Girón-Pérez, M.I.; Zaitseva, G.; Casas-Solis, J.; Santerre, A. Effects of diazinon and diazoxon on the lymphoproliferation rate of splenocytes from Nile tilapia (Oreochromis niloticus): The immunosuppresive effect could involve an increase in acetylcholine levels. Fish Shellfish Immunol. 2008, 25, 517–521. [Google Scholar] [CrossRef] [PubMed]
  23. Toledo-Ibarra, G.; Díaz-Resendiz, K.; Pavón-Romero, L.; Rojas-García, A.; Medina-Díaz, I.; Girón-Pérez, M. Effects of diazinon on the lymphocytic cholinergic system of Nile tilapia fish (Oreochromis niloticus). Vet. Immunol. Immunopathol. 2016, 176, 58–63. [Google Scholar] [CrossRef]
  24. Toledo-Ibarra, G.; Girón-Pérez, M.; Covantes-Rosales, C.; Ventura-Ramón, G.; Pérez-Sánchez, G.; López-Torres, A.; Diaz-Resendiz, K.; Becerril-Villanueva, E.; Pavón, L. Alterations in the non-neuronal cholinergic system induced by in-vitro exposure to diazoxon in spleen mononuclear cells of Nile tilapia (O. niloticus). Fish Shellfish Immunol. 2021, 108, 134–141. [Google Scholar] [CrossRef]
  25. Proskocil, B.; Bruun, D.A.; Thompson, C.M.; Fryer, A.; Lein, P.J. Organophosphorus Pesticides Decrease M2 Muscarinic Receptor Function in Guinea Pig Airway Nerves via Indirect Mechanisms. PLoS ONE 2010, 5, e10562. [Google Scholar] [CrossRef]
  26. Poojary, A.; Basha, P.M. Cold stress interaction on organophosphate insecticide poisoning: Age-related assessment in rat cerebral cortex. Indian J. Exp. Biol. 2012, 50, 110–116. [Google Scholar]
  27. Basaure, P.; Guardia-Escote, L.; Cabré, M.; Peris-Sampedro, F.; Sánchez-Santed, F.; Domingo, J.L.; Colomina, M.T. Postnatal chlorpyrifos exposure and apolipoprotein E (APOE) genotype differentially affect cholinergic expression and developmental parameters in transgenic mice. Food Chem. Toxicol. 2018, 118, 42–52. [Google Scholar] [CrossRef] [PubMed]
  28. Zhang, X.; Li, S.; Wang, C.; Tian, H.; Wang, W.; Ru, S. Effects of monocrotophos pesticide on cholinergic and dopaminergic neurotransmitter systems during early development in the sea urchin Hemicentrotus pulcherrimus. Toxicol. Appl. Pharmacol. 2017, 328, 46–53. [Google Scholar] [CrossRef] [PubMed]
  29. Xu, C.; Zhang, X.-G.; Yang, X.; He, Y.-Z. The diagnostic value of butyrylcholinesterase in acute organophosphorus pesticide poisoning. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue= Chin. Crit. Care Med. = Zhongguo Weizhongbing Jijiuyixue 2010, 22, 193–196. [Google Scholar]
  30. Figueiredo, T.H.; Apland, J.P.; Braga, M.F.M.; Marini, A.M. Acute and long-term consequences of exposure to organophosphate nerve agents in humans. Epilepsia 2018, 59, 92–99. [Google Scholar] [CrossRef]
  31. Bayrami, M.; Hashemi, T.; Malekirad, A.A.; Ashayeri, H.; Faraji, F.; Abdollahi, M. Electroencephalogram, cognitive state, psychological disorders, clinical symptom, and oxidative stress in horticulture farmers exposed to organophosphate pesticides. Toxicol. Ind. Health 2012, 28, 90–96. [Google Scholar] [CrossRef]
  32. Perry, J.; Cotton, J.; Rahman, M.; Brumby, S. Organophosphate exposure and the chronic effects on farmers: A narrative review. Rural Remote Health 2020, 20, 4508. [Google Scholar] [CrossRef]
  33. De Silva, H.J.; Samarawickrema, N.A.; Wickremasinghe, A.R. Toxicity due to organophosphorus compounds: What about chronic exposure? Trans. R. Soc. Trop. Med. Hyg. 2006, 100, 803–806. [Google Scholar] [CrossRef]
  34. Thrasher, J.D.; Heuser, G.; Broughton, A. Immunological Abnormalities in Humans Chronically Exposed to Chlorpyrifos. Arch. Environ. Health Int. J. 2002, 57, 181–187. [Google Scholar] [CrossRef]
  35. Zafar, R.; Munawar, K.; Nasrullah, A.; Haq, S.; Ghazanfar, H.; Sheikh, A.B.; Khan, A.Y. Acute Renal Failure due to Organophosphate Poisoning: A Case Report. Cureus 2017, 9, e1523. [Google Scholar] [CrossRef]
  36. Cavari, Y.; Landau, D.; Sofer, S.; Leibson, T.; Lazar, I. Organophosphate Poisoning-Induced Acute Renal Failure. Pediatr. Emerg. Care 2013, 29, 646–647. [Google Scholar] [CrossRef]
  37. Ortega-Miller, J.G.; Yezioro-Rubinsky, S.; Benavides-Pinto, B.C.; Báez-Quintero, L.C. Efectos teratogénicos de insecticidas organofosforados en la etiología de labio y paladar hendido: Revisión de literatura. Rev. Nac. De Odontol. 2017, 13, 13. [Google Scholar] [CrossRef][Green Version]
  38. Rodriguez-Diaz, R.; Dando, R.; Jacques-Silva, M.C.; Fachado, A.; Molina, J.; Abdulreda, M.H.; Ricordi, C.; Roper, S.D.; Berggren, P.-O.; Caicedo, A. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat. Med. 2011, 17, 888–892. [Google Scholar] [CrossRef] [PubMed]
  39. Wessler, I.; Kirkpatrick, C.J.; Racké, K. Non-neuronal acetylcholine, a locally acting molecule, widely distributed in biological systems: Expression and function in humans. Pharmacol. Ther. 1998, 77, 59–79. [Google Scholar] [CrossRef]
  40. Bhuiyan, M.; Murad, F.; Fant, M. The placental cholinergic system: Localization to the cytotrophoblast and modulation of nitric oxide. Cell Commun. Signal. 2006, 4, 4–7. [Google Scholar] [CrossRef]
  41. Lev-Lehman, E.; Deutsch, V.; Eldor, A.; Soreq, H. Immature Human Megakaryocytes Produce Nuclear-Associated Acetylcholinesterase. Blood 1997, 89, 3644–3653. [Google Scholar] [CrossRef]
  42. Kawashima, K.; Fujii, T. The lymphocytic cholinergic system and its biological function. Life Sci. 2003, 72, 2101–2109. [Google Scholar] [CrossRef]
  43. Resendiz, K.J.G.D.; Toledo-Ibarra, G.A.; Girón-Pérez, M.I. Modulation of Immune Response by Organophosphorus Pesticides: Fishes as a Potential Model in Immunotoxicology. J. Immunol. Res. 2015, 2015, 213836. [Google Scholar] [CrossRef]
  44. Banks, C.N.; Lein, P.J. A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation. NeuroToxicology 2012, 33, 575–584. [Google Scholar] [CrossRef]
  45. Koureas, M.; Rachiotis, G.; Tsakalof, A.; Hadjichristodoulou, C. Increased Frequency of Rheumatoid Arthritis and Allergic Rhinitis among Pesticide Sprayers and Associations with Pesticide Use. Int. J. Environ. Res. Public Health 2017, 14, 865. [Google Scholar] [CrossRef]
  46. Meyer, A.; Sandler, D.P.; Freeman, L.E.B.; Hofmann, J.; Parks, C.G. Pesticide Exposure and Risk of Rheumatoid Arthritis among Licensed Male Pesticide Applicators in the Agricultural Health Study. Environ. Health Perspect. 2017, 125, 077010. [Google Scholar] [CrossRef]
  47. Andrew, P.M.; Lein, P.J. Neuroinflammation as a Therapeutic Target for Mitigating the Long-Term Consequences of Acute Organophosphate Intoxication. Front. Pharmacol. 2021, 12, 12. [Google Scholar] [CrossRef] [PubMed]
  48. Hernández, A.F.; Parrón, T.; Alarcón, R. Pesticides and asthma. Curr. Opin. Allergy Clin. Immunol. 2011, 11, 90–96. [Google Scholar] [CrossRef] [PubMed]
  49. Benka-Coker, W.; Loftus, C.; Karr, C.; Magzamen, S. Association of Organophosphate Pesticide Exposure and a Marker of Asthma Morbidity in an Agricultural Community. J. Agromed. 2020, 25, 106–114. [Google Scholar] [CrossRef] [PubMed]
  50. Chung, Y.-L.; Hou, Y.-C.; Wang, I.-K.; Lu, K.-C.; Yen, T.-H. Organophosphate pesticides and new-onset diabetes mellitus: From molecular mechanisms to a possible therapeutic perspective. World J. Diabetes 2021, 12, 1818–1831. [Google Scholar] [CrossRef]
  51. Wessler, I.K.; Kirkpatrick, C.J. The Non-neuronal Cholinergic System: An Emerging Drug Target in the Airways. Pulm. Pharmacol. Ther. 2001, 14, 423–434. [Google Scholar] [CrossRef]
  52. Abreu-Villaça, Y.; Filgueiras, C.; Manhães, A.C. Developmental aspects of the cholinergic system. Behav. Brain Res. 2011, 221, 367–378. [Google Scholar] [CrossRef]
  53. Nizri, E.; Brenner, T. Modulation of inflammatory pathways by the immune cholinergic system. Amino Acids 2011, 45, 73–85. [Google Scholar] [CrossRef]
  54. Wessler, I.; Kirkpatrick, C.J. Acetylcholine beyond neurons: The non-neuronal cholinergic system in humans. J. Cereb. Blood Flow Metab. 2008, 154, 1558–1571. [Google Scholar] [CrossRef]
  55. Kawashima, K.; Fujii, T. Extraneuronal cholinergic system in lymphocytes. Pharmacol. Ther. 2000, 86, 29–48. [Google Scholar] [CrossRef]
  56. Mokarizadeh, A.; Faryabi, M.R.; Rezvanfar, M.A.; Abdollahi, M. A comprehensive review of pesticides and the immune dysregulation: Mechanisms, evidence and consequences. Toxicol. Mech. Methods 2015, 25, 258–278. [Google Scholar] [CrossRef]
  57. Wang, X.; Yang, Z.; Xue, B.; Shi, H. Activation of the Cholinergic Antiinflammatory Pathway Ameliorates Obesity-Induced Inflammation and Insulin Resistance. Endocrinology 2011, 152, 836–846. [Google Scholar] [CrossRef] [PubMed]
  58. El-Bouhy, Z.; El-Hakim, Y.A.; Mohamed, E. Chronic Effect of Chlorpyrifos on Biochemical, Immunological Changes and DNA Damage in Juvenile Nile Tilapia (Oreochromis niloticus). Zagazig Vet. J. 2018, 46, 51–59. [Google Scholar] [CrossRef][Green Version]
  59. Ahmadi, K.; Mirvaghefei, A.R.; Banaee, M.; Vosoghei, A.R. Effects of long-term diazinon exposure on some immunological and haematological parameters in rainbow trout Oncorhynchus mykiss (Walbaum, 1792). Toxicol. Environ. Health Sci. 2014, 6, 1–7. [Google Scholar] [CrossRef]
  60. Castillo-Sosa, Y.; Sierra-Fonseca, A.; Martínez-Martínez, A.; Plenge-Tellechea, F. Efecto del diazinón sobre el cultivo de linfocitos de sangre periférica de human. Tecnoscience 2009, 3, 97–106. Available online: https://vocero.uach.mx/index.php/tecnociencia/article/view/734 (accessed on 2 March 2022).
  61. Girón-Pérez, M.; Velázquez-Fernández, J.B.; Díaz-Resendiz, K.J.G.; Díaz-Salas, F.; Canto-Montero, C.; Medina-Díaz, I.; Robledo-Marenco, M.; Rojas-García, A.; Zaitseva, G. Immunologic parameters evaluations in Nile tilapia (Oreochromis niloticus) exposed to sublethal concentrations of diazinon. Fish Shellfish Immunol. 2009, 27, 383–385. [Google Scholar] [CrossRef]
  62. Banaee, M.; Sureda, A.; Mirvaghefi, A.; Ahmadi, K. Effects of diazinon on biochemical parameters of blood in rainbow trout (Oncorhynchus mykiss). Pestic. Biochem. Physiol. 2011, 99, 1–6. [Google Scholar] [CrossRef]
  63. Alluwaimi, A.M.; Hussein, Y. Diazinon immunotoxicity in mice: Modulation of cytokines level and their gene expression. Toxicology 2007, 236, 123–131. [Google Scholar] [CrossRef]
  64. Khoshbavar-Rostami, H.; Soltani, M.; Hassan, H. Immune response of great sturgeon (Huso huso) subjected to long-term exposure to sublethal concentration of the organophosphate, diazinon. Aquaculture 2006, 256, 88–94. [Google Scholar] [CrossRef]
  65. Toledo-Ibarra, G.A.; Rojas-Mayorquín, A.E.; Girón-Pérez, M.I. Influence of the Cholinergic System on the Immune Response of Teleost Fishes: Potential Model in Biomedical Research. Clin. Dev. Immunol. 2013, 2013, 536534. [Google Scholar] [CrossRef]
  66. Naughton, S.X.; Terry, A.V. Neurotoxicity in acute and repeated organophosphate exposure. Toxicology 2018, 408, 101–112. [Google Scholar] [CrossRef]
  67. Pavlov, V.A.; Wang, H.; Czura, C.J.; Friedman, S.G.; Tracey, K.J. The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation. Mol. Med. 2003, 9, 125–134. [Google Scholar] [CrossRef] [PubMed]
  68. Fujii, T.; Mashimo, M.; Moriwaki, Y.; Misawa, H.; Ono, S.; Horiguchi, K.; Kawashima, K. Expression and Function of the Cholinergic System in Immune Cells. Front. Immunol. 2017, 8, 1085. [Google Scholar] [CrossRef] [PubMed]
  69. Torrealba, D.; Balasch, J.C.; Criado, M.; Tort, L.; Mackenzie, S.; Roher, N. Functional evidence for the inflammatory reflex in teleosts: A novel α7 nicotinic acetylcholine receptor modulates the macrophage response to dsRNA. Dev. Comp. Immunol. 2018, 84, 279–291. [Google Scholar] [CrossRef] [PubMed]
  70. de la Torre, E.; Davel, L.; Jasnis, M.A.; Gotoh, T.; de Lustig, E.S.; Sales, M.E. Muscarinic receptors participation in angiogenic response induced by macrophages from mammary adenocarcinoma-bearing mice. Breast Cancer Res. 2005, 7, R345–R352. [Google Scholar] [CrossRef]
  71. Kawashima, K. Expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function. Front. Biosci. 2004, 9, 2063–2085. [Google Scholar] [CrossRef]
  72. Pavlov, V.A.; Ochani, M.; Yang, L.-H.; Gallowitsch-Puerta, M.; Ochani, K.; Lin, X.; Levi, J.; Parrish, W.R.; Rosas-Ballina, M.; Czura, C.J.; et al. Selective α7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit. Care Med. 2007, 35, 1139–1144. [Google Scholar] [CrossRef]
  73. Wang, H.; Yu, M.; Ochani, M.; Amella, C.A.; Tanovic, M.; Susarla, S.; Li, J.H.; Wang, H.; Yang, H.; Ulloa, L.; et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 2003, 421, 384–388. [Google Scholar] [CrossRef]
  74. Kostoff, R.N.; Briggs, M.B.; Porter, A.L.; Hernández, A.F.; Abdollahi, M.; Aschner, M.; Tsatsakis, A. The under-reported role of toxic substance exposures in the COVID-19 pandemic. Food Chem. Toxicol. 2020, 145, 111687. [Google Scholar] [CrossRef]
  75. Galloway, T.; Handy, R. Immunotoxicity of Organophosphorous Pesticides. Ecotoxicology 2003, 12, 345–363. [Google Scholar] [CrossRef]
  76. Mitra, A.; Sarkar, M.; Chatterjee, C. Modulation of immune response by organophosphate pesticides: Mammals as potential model. Proc. Zoologic. Soc. 2019, 72, 13–24. [Google Scholar] [CrossRef]
  77. Bakry, N.M.S.; El-Rashidy, A.H.; Eldefrawi, A.T.; Eldefrawi, M.E. Direct actions of organophosphate anticholinesterases on nicotinic and muscarinic acetylcholine receptors. J. Biochem. Toxicol. 1988, 3, 235–259. [Google Scholar] [CrossRef] [PubMed]
  78. Trailović, S.M.; Marjanović, D.S.; Uzelac, T.V.; Milovanović, M.; Trailović, J.N. Two opposite dose-dependent effects of diazinon on the motor activity of the rat ileum. Res. Vet. Sci. 2017, 112, 18–25. [Google Scholar] [CrossRef] [PubMed]
  79. Mehrani, H.; Golmanesh, L. Changes in mRNA and protein levels of nicotinic acetylcholine receptors in Diazoxon exposed pC12 cells. Toxicol. In Vitro 2008, 22, 1257–1263. [Google Scholar] [CrossRef] [PubMed]
  80. Smulders, C.J.G.M.; Bueters, T.J.H.; Vailati, S.; Van Kleef, R.G.D.M.; Vijverberg, H.P.M. Block of Neuronal Nicotinic Acetylcholine Receptors by Organophosphate Insecticides. Toxicol. Sci. 2004, 82, 545–554. [Google Scholar] [CrossRef] [PubMed]
  81. Charoenying, T.; Suriyo, T.; Thiantanawat, A.; Chaiyaroj, S.C.; Parkpian, P.; Satayavivad, J. Effects of paraoxon on neuronal and lymphocytic cholinergic systems. Environ. Toxicol. Pharmacol. 2011, 31, 119–128. [Google Scholar] [CrossRef]
  82. Tarkowski, M.S.; Lutz, W.; Birindelli, S. The lymphocytic cholinergic system and its modulation by organophosphorus pesticides. Int. J. Occup. Med. Environ. Health 2004, 17, 325–337. [Google Scholar]
  83. Görlach, A.; Bertram, K.; Hudecova, S.; Krizanova, O. Calcium and ROS: A mutual interplay. Redox Biol. 2015, 6, 260–271. [Google Scholar] [CrossRef]
  84. Adam-Vizi, V.; Starkov, A.A. Calcium and Mitochondrial Reactive Oxygen Species Generation: How to Read the Facts. J. Alzheimer’s Dis. 2010, 20, S413–S426. [Google Scholar] [CrossRef]
  85. Buccafusco, J.J.; Beach, J.W.; Terry, A. Desensitization of Nicotinic Acetylcholine Receptors as a Strategy for Drug Development. J. Pharmacol. Exp. Ther. 2008, 328, 364–370. [Google Scholar] [CrossRef]
  86. Wang, C.; Wu, C.; Tsan, Y.; Hsu, J.; Hung, D.-Z.; Wang, C.-H. Early onset pneumonia in patients with cholinesterase inhibitor poisoning. Respirology 2010, 15, 961–968. [Google Scholar] [CrossRef]
  87. Faustini, A.; Settimi, L.; Pacifici, R.; Fano, V.; Zuccaro, P.; Forastiere, F. Immunological changes among farmers exposed to phenoxy herbicides: Preliminary observations. Occup. Environ. Med. 1996, 53, 583–585. [Google Scholar] [CrossRef] [PubMed]
  88. Luebke, B. Pesticide-Induced Immunotoxicity: Are Humans at Risk? Hum. Ecol. Risk Assess. Int. J. 2002, 8, 293–303. [Google Scholar] [CrossRef]
  89. Dietert, R.R. Developmental immunotoxicology (DIT): Windows of vulnerability, immune dysfunction and safety assessment. J. Immunotoxicol. 2008, 5, 401–412. [Google Scholar] [CrossRef] [PubMed]
  90. Schäfer, M.; Koppe, F.; Stenger, B.; Brochhausen, C.; Schmidt, A.; Steinritz, D.; Thiermann, H.; Kirkpatrick, C.J.; Pohl, C. Influence of organophosphate poisoning on human dendritic cells. Chem. Interact. 2013, 206, 472–478. [Google Scholar] [CrossRef] [PubMed]
  91. Xia, C.; Wang, M.; Liang, Q.; Yun, L.; Kang, H.; Fan, L.; Wang, D.; Zhang, G. Changes in monoclonal HLA-DR antigen expression in acute organophosphorus pesticide-poisoned patients. Exp. Ther. Med. 2014, 7, 137–140. [Google Scholar] [CrossRef]
  92. Costa, C.; Briguglio, G.; Catanoso, R.; Giambò, F.; Polito, I.; Teodoro, M.; Fenga, C. New perspectives on cytokine pathways modulation by pesticide exposure. Curr. Opin. Toxicol. 2020, 19, 99–104. [Google Scholar] [CrossRef]
  93. Helali, I.; Ferchichi, S.; Maaouia, A.; Aouni, M.; Harizi, H. Modulation of macrophage functionality induced in vitro by chlorpyrifos and carbendazim pesticides. J. Immunotoxicol. 2016, 13, 745–750. [Google Scholar] [CrossRef]
  94. Li, Q.; Kobayashi, M.; Kawada, T. Organophosphorus pesticides induce apoptosis in human NK cells. Toxicology 2007, 239, 89–95. [Google Scholar] [CrossRef]
  95. Lasram, M.M.; Lamine, A.J.; Dhouib, I.B.; Bouzid, K.; Annabi, A.; Belhadjhmida, N.; Ben Ahmed, M.; El Fazaa, S.; Abdelmoula, J.; Gharbi, N. Antioxidant and anti-inflammatory effects of N-acetylcysteine against malathion-induced liver damages and immunotoxicity in rats. Life Sci. 2014, 107, 50–58. [Google Scholar] [CrossRef]
  96. El-Sayed, N.M.; Ahmed, A.A.M.; Selim, M.A.A. Cytotoxic effect of chlorpyrifos is associated with activation of Nrf-2/HO-1 system and inflammatory response in tongue of male Wistar rats. Environ. Sci. Pollut. Res. 2018, 25, 12072–12082. [Google Scholar] [CrossRef] [PubMed]
  97. Proskocil, B.J.; Grodzki, A.C.G.; Jacoby, D.B.; Lein, P.J.; Fryer, A.D. Organophosphorus Pesticides Induce Cytokine Release from Differentiated Human THP1 Cells. Am. J. Respir. Cell Mol. Biol. 2019, 61, 620–630. [Google Scholar] [CrossRef] [PubMed]
  98. Kianpour, F.; Mohseni, M.; Beigmohamadi, M.; Yazdinezhad, A.; Ramazani, A.; Hosseini, M.-J.; Sharafi, A. The protective effects of Ziziphora tenuior L. against chlorpyrifos induced toxicity: Involvement of inflammatory and cell death signaling pathways. J. Ethnopharmacol. 2021, 272, 113959. [Google Scholar] [CrossRef]
  99. Liu, X.; Zhao, X.; Wang, Y.; Hong, J.; Shi, M.; Pfaff, D.; Guo, L.; Tang, H. Triphenyl phosphate permeates the blood brain barrier and induces neurotoxicity in mouse brain. Chemosphere 2020, 252, 126470. [Google Scholar] [CrossRef] [PubMed]
  100. Ince, S.; Arslan-Acaroz, D.; Demirel, H.H.; Varol, N.; Ozyurek, H.A.; Zemheri, F.; Kucukkurt, I. Taurine alleviates malathion induced lipid peroxidation, oxidative stress, and proinflammatory cytokine gene expressions in rats. Biomed. Pharmacother. 2017, 96, 263–268. [Google Scholar] [CrossRef] [PubMed]
  101. Weis, G.C.C.; Assmann, C.E.; Mostardeiro, V.B.; Alves, A.D.O.; da Rosa, J.R.; Pillat, M.M.; de Andrade, C.M.; Schetinger, M.R.C.; Morsch, V.M.M.; da Cruz, I.B.M.; et al. Chlorpyrifos pesticide promotes oxidative stress and increases inflammatory states in BV-2 microglial cells: A role in neuroinflammation. Chemosphere 2021, 278, 130417. [Google Scholar] [CrossRef] [PubMed]
  102. Ogasawara, N.; Matsushima, M.; Kawamura, N.; Atsumi, K.; Yamaguchi, T.; Ochi, H.; Kusatsugu, Y.; Oyabu, S.; Hashimoto, N.; Hasegawa, Y.; et al. Modulation of immunological activity on macrophages induced by diazinon. Toxicology 2017, 379, 22–30. [Google Scholar] [CrossRef]
  103. Tigges, J.; Worek, F.; Thiermann, H.; Wille, T. Organophosphorus pesticides exhibit compound specific effects in rat precision-cut lung slices (PCLS): Mechanisms involved in airway response, cytotoxicity, inflammatory activation and antioxidative defense. Arch. Toxicol. 2021, 96, 321–334. [Google Scholar] [CrossRef]
  104. Fioranelli, M.; Roccia, M.; Flavin, D.; Cota, L. Regulation of Inflammatory Reaction in Health and Disease. Int. J. Mol. Sci. 2021, 22, 5277. [Google Scholar] [CrossRef]
  105. Farkhondeh, T.; Mehrpour, O.; Buhrmann, C.; Pourbagher-Shahri, A.M.; Shakibaei, M.; Samarghandian, S. Organophosphorus Compounds and MAPK Signaling Pathways. Int. J. Mol. Sci. 2020, 21, 4258. [Google Scholar] [CrossRef]
  106. Mostafalou, S.; Eghbal, M.A.; Nili-Ahmadabadi, A.; Baeeri, M.; Abdollahi, M. Biochemical evidence on the potential role of organophosphates in hepatic glucose metabolism toward insulin resistance through inflammatory signaling and free radical pathways. Toxicol. Ind. Health 2012, 28, 840–851. [Google Scholar] [CrossRef]
  107. Díaz-Resendiz, K.J.G.; Ortiz-Lazareno, P.; Rosales, C.E.C.; Trujillo-Lepe, A.; Toledo-Ibarra, G.; Ventura, H.; Girón-Pérez, M. Effect of diazinon, an organophosphate pesticide, on signal transduction and death induction in mononuclear cells of Nile tilapia fish (Oreochromis niloticus). Fish Shellfish Immunol. 2019, 89, 12–17. [Google Scholar] [CrossRef] [PubMed]
  108. Verma, S.K.; Raheja, G.; Gill, K.D. Role of muscarinic signal transduction and CREB phosphorylation in dichlorvos-induced memory deficits in rats: An acetylcholine independent mechanism. Toxicology 2009, 256, 175–182. [Google Scholar] [CrossRef]
  109. Falkenburger, B.H.; Jensen, J.B.; Hille, B. Kinetics of M1 muscarinic receptor and G protein signaling to phospholipase C in living cells. J. Gen. Physiol. 2010, 135, 81–97. [Google Scholar] [CrossRef] [PubMed]
  110. Lonze, B.; Ginty, D.D. Function and Regulation of CREB Family Transcription Factors in the Nervous System. Neuron 2002, 35, 605–623. [Google Scholar] [CrossRef]
  111. Eckel-Mahan, K.; Phan, T.; Han, S.; Wang, H.; Chan, G.C.-K.; Scheiner, Z.S.; Storm, D.R. Circadian oscillation of hippocampal MAPK activity and cAMP: Implications for memory persistence. Nat. Neurosci. 2008, 11, 1074–1082. [Google Scholar] [CrossRef] [PubMed]
  112. Caughlan, A.; Newhouse, K.; Namgung, U.; Xia, Z. Chlorpyrifos Induces Apoptosis in Rat Cortical Neurons that is Regulated by a Balance Between p38 and ERK/JNK MAP Kinases. Toxicol. Sci. 2004, 78, 125–134. [Google Scholar] [CrossRef] [PubMed]
  113. Wen, A.Y.; Sakamoto, K.M.; Miller, L.S. The Role of the Transcription Factor CREB in Immune Function. J. Immunol. 2010, 185, 6413–6419. [Google Scholar] [CrossRef] [PubMed]
  114. Ghosh, S.; Hayden, M. New regulators of NF-κB in inflammation. Nat. Rev. Immunol. 2008, 8, 837–848. [Google Scholar] [CrossRef]
  115. Medzhitov, R.; Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 2009, 9, 692–703. [Google Scholar] [CrossRef]
  116. Medzhitov, R. The spectrum of inflammatory responses. Science 2021, 374, 1070–1075. [Google Scholar] [CrossRef]
  117. Esquivel-Sentíes, M.; Barrera, I.; Ortega, A.; Vega, L. Organophosphorous pesticide metabolite (DEDTP) induces changes in the activation status of human lymphocytes by modulating the interleukin 2 receptor signal transduction pathway. Toxicol. Appl. Pharmacol. 2010, 248, 122–133. [Google Scholar] [CrossRef] [PubMed]
  118. Dimitriou, I.D.; Clemenza, L.; Scotter, A.J.; Chen, G.; Guerra, F.M.; Rottapel, R. Putting out the fire: Coordinated suppression of the innate and adaptive immune systems by SOCS1 and SOCS3 proteins. Immunol. Rev. 2008, 224, 265–283. [Google Scholar] [CrossRef] [PubMed]
  119. Cohney, S.J.; Sanden, D.; Cacalano, N.A.; Yoshimura, A.; Mui, A.; Migone, T.S.; Johnston, J.A. SOCS-3 Is Tyrosine Phosphorylated in Response to Interleukin-2 and Suppresses STAT5 Phosphorylation and Lymphocyte Proliferation. Mol. Cell. Biol. 1999, 19, 4980–4988. [Google Scholar] [CrossRef] [PubMed]
  120. Magnarelli, G.; Fonovich, T. Protein phosphorylation pathways disruption by pesticides. Adv. Biol. Chem. 2013, 03, 460–474. [Google Scholar] [CrossRef][Green Version]
  121. Lima, A.; Vega, L. Methyl-parathion and organophosphorous pesticide metabolites modify the activation status and interleukin-2 secretion of human peripheral blood mononuclear cells. Toxicol. Lett. 2005, 158, 30–38. [Google Scholar] [CrossRef]
  122. Malek, T.R. The Biology of Interleukin-2. Annu. Rev. Immunol. 2008, 26, 453–479. [Google Scholar] [CrossRef]
  123. Costa, L.G. Organophosphorus Compounds at 80: Some Old and New Issues. Toxicol. Sci. 2018, 162, 24–35. [Google Scholar] [CrossRef]
  124. Eddleston, M.; Buckley, N.; Eyer, P.; Dawson, A. Management of acute organophosphorus pesticide poisoning. Lancet 2008, 371, 597–607. [Google Scholar] [CrossRef]
  125. Hulse, E.J.; Davies, J.; Simpson, A.J.; Sciuto, A.M.; Eddleston, M. Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care. Am. J. Respir. Crit. Care Med. 2014, 190, 1342–1354. [Google Scholar] [CrossRef]
  126. Kaushal, J.; Khatri, M.; Arya, S.K. A treatise on Organophosphate pesticide pollution: Current strategies and advancements in their environmental degradation and elimination. Ecotoxicol. Environ. Saf. 2021, 207, 111483. [Google Scholar] [CrossRef]
  127. Bird, S.B.; Gaspari, R.; Dickson, E.W. Early Death Due to Severe Organophosphate Poisoning Is a Centrally Mediated Process. Acad. Emerg. Med. 2003, 10, 295–298. [Google Scholar] [CrossRef] [PubMed]
  128. Roldan-Tapia, M.; Nieto-Escamez, F.A.; del Águila, E.; Laynez, F.; Parron, T.; Sanchez-Santed, F. Neuropsychological sequelae from acute poisoning and long-term exposure to carbamate and organophosphate pesticides. Neurotoxicol. Teratol. 2006, 28, 694–703. [Google Scholar] [CrossRef] [PubMed]
  129. Dassanayake, T.; Weerasinghe, V.; Dangahadeniya, U.; Kularatne, K.; Dawson, A.; Karalliedde, L.; Senanayake, N. Cognitive processing of visual stimuli in patients with organophosphate insecticide poisoning. Neurology 2007, 68, 2027–2030. [Google Scholar] [CrossRef] [PubMed]
  130. Chen, Y. Organophosphate-induced brain damage: Mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies. NeuroToxicology 2012, 33, 391–400. [Google Scholar] [CrossRef] [PubMed]
  131. Furtado, M.D.A.; Rossetti, F.; Chanda, S.; Yourick, D. Exposure to nerve agents: From status epilepticus to neuroinflammation, brain damage, neurogenesis and epilepsy. NeuroToxicology 2012, 33, 1476–1490. [Google Scholar] [CrossRef]
  132. Pereira, E.F.R.; Aracava, Y.; DeTolla, L.J.; Beecham, E.J.; Basinger, G.W.; Wakayama, E.J.; Albuquerque, E.X. Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds. J. Pharmacol. Exp. Ther. 2014, 350, 313–321. [Google Scholar] [CrossRef]
  133. Xanthos, D.N.; Sandkühler, J. Neurogenic neuroinflammation: Inflammatory CNS reactions in response to neuronal activity. Nat. Rev. Neurosci. 2014, 15, 43–53. [Google Scholar] [CrossRef]
  134. Olas, B.; Wachowicz, B. Resveratrol and vitamin C as antioxidants in blood platelets. Thromb. Res. 2002, 106, 143–148. [Google Scholar] [CrossRef]
  135. Zaidi, S.R.; Banu, N. Antioxidant potential of vitamins A, E and C in modulating oxidative stress in rat brain. Clin. Chim. Acta 2004, 340, 229–233. [Google Scholar] [CrossRef]
  136. Ojha, A.; Srivastava, N. Redox imbalance in rat tissues exposed with organophosphate pesticides and therapeutic potential of antioxidant vitamins. Ecotoxicol. Environ. Saf. 2012, 75, 230–241. [Google Scholar] [CrossRef]
  137. Deshpande, L.; Blair, R.E.; Huang, B.A.; Phillips, K.F.; DeLorenzo, R.J. Pharmacological blockade of the calcium plateau provides neuroprotection following organophosphate paraoxon induced status epilepticus in rats. Neurotoxicol. Teratol. 2016, 56, 81–86. [Google Scholar] [CrossRef] [PubMed]
  138. El-Ebiary, A.A.; Elsharkawy, R.E.; Soliman, N.A.; Soliman, M.A.; Hashem, A.A. N-acetylcysteine in Acute Organophosphorus Pesticide Poisoning: A Randomized, Clinical Trial. Basic Clin. Pharmacol. Toxicol. 2016, 119, 222–227. [Google Scholar] [CrossRef] [PubMed]
  139. Fang, J.; She, J.; Lin, F.; Wu, J.-C.; Han, R.; Sheng, R.; Wang, G.; Qin, Z.-H. RRx-001 Exerts Neuroprotection Against LPS-Induced Microglia Activation and Neuroinflammation Through Disturbing the TLR4 Pathway. Front. Pharmacol. 2022, 13, 1219. [Google Scholar] [CrossRef]
  140. Lin, C.-Y.; Chiang, C.-Y.; Tsai, H.-J. Zebrafish and Medaka: New model organisms for modern biomedical research. J. Biomed. Sci. 2016, 23, 19. [Google Scholar] [CrossRef]
  141. Wilson, A.B. MHC and adaptive immunity in teleost fishes. Immunogenetics 2017, 69, 521–528. [Google Scholar] [CrossRef]
  142. Saha, A.; Ghosh, R.K.; Jesna, P.-K.; Choudhury, P.P. Bioindicators of Pesticide Contaminations. Sustain. Agric. Rev. 2021, 48, 185–231. [Google Scholar] [CrossRef]
  143. Medina-Garza, H. Uso de Biomarcadores en Peces Como Herramienta Para Evaluar la Exposición y Efecto de Contaminantes Ambientales en Cuerpos de Agua. Master’s Thesis, Universidad Autonoma de San Luis Potosí, México, December 2012. [Google Scholar]
  144. Gonçalves, C.; Marins, A.T.; Amaral, A.M.B.D.; Nunes, M.E.M.; Müller, T.E.; Severo, E.; Feijó, A.; Rodrigues, C.C.; Zanella, R.; Prestes, O.D.; et al. Ecological impacts of pesticides on Astyanax jacuhiensis (Characiformes: Characidae) from the Uruguay river, Brazil. Ecotoxicol. Environ. Saf. 2020, 205, 111314. [Google Scholar] [CrossRef]
  145. Girón-Pérez, M.I.; Barcelós-García, R.; Vidal-Chavez, Z.G.; Romero-Bañuelos, C.A.; Robledo-Marenco, M.L. Effect of Chlorpyrifos on the Hematology and Phagocytic Activity of Nile Tilapia Cells (Oreochromis niloticus). Toxicol. Mech. Methods 2006, 16, 495–499. [Google Scholar] [CrossRef]
  146. Girón-Pérez, M.I.; Santerre, A.; Gonzalez-Jaime, F.; Casas-Solis, J.; Hernández-Coronado, M.; Peregrina-Sandoval, J.; Takemura, A.; Zaitseva, G. Immunotoxicity and hepatic function evaluation in Nile tilapia (Oreochromis niloticus) exposed to diazinon. Fish Shellfish Immunol. 2007, 23, 760–769. [Google Scholar] [CrossRef]
  147. Covantes-Rosales, C.E.; Trujillo-Lepe, A.; Díaz-Resendiz, K.J.G.; Toledo-Ibarra, G.; Ventura, H.; Ortiz-Lazareno, P.; Girón-Pérez, M. Phagocytosis and ROS production as biomarkers in Nile tilapia (Oreochromis niloticus) leukocytes by exposure to organophosphorus pesticides. Fish Shellfish Immunol. 2019, 84, 189–195. [Google Scholar] [CrossRef]
  148. Díaz-Resendiz, K.G.J.; Girón-Pérez, M.I. Effect of chlorpyrifos on the immune response of Nile tilapia (Oreochromis niloticus). Rev. BioCiencias. 2014, 3, 59–64. [Google Scholar] [CrossRef]
  149. Toledo-Ibarra, G.A.; Díaz-Resendiz, K.J.G.; Ventura-Ramón, G.H.; González-Jaime, F.; Vega-López, A.; Becerril-Villanueva, E.; Pavón, L.; Girón-Pérez, M.I. Oxidative damage in gills and liver in Nile tilapia (Oreochromis niloticus) exposed to diazinon. Comp. Biochem. Physiol. Part A Mol. Integr. Physiol. 2016, 200, 3–8. [Google Scholar] [CrossRef] [PubMed]
  150. Covantes-Rosales, C.E.; Toledo-Ibarra, G.A.; González-Navarro, I.; Agraz-Cibrian, J.M.; Girón-Pérez, D.A.; Ventura-Ramon, G.H.; Diaz-Resendiz, K.J.G.; Bueno-Durán, A.Y.; Ponce-Regalado, M.D.; Girón-Pérez, M.I. Diazinon acute exposure induces neutrophil extracellular traps in Nile tilapia (Oreochromis niloticus). Food Agric. Immunol. 2020, 31, 1004–1013. [Google Scholar] [CrossRef]
  151. Díaz-Resendiz, K.J.G.; Bernal-Ortega, J.; Covantes-Rosales, C.E.; Ortiz-Lazareno, P.C.; Toledo-Ibarra, G.A.; Ventura-Ramon, G.H.; Girón-Pérez, M.I. In-vitro effect of diazoxon, a metabolite of diazinon, on proliferation, signal transduction, and death induction in mononuclear cells of Nile tilapia fish (Oreochromis niloticus). Fish Shellfish Immunol. 2020, 105, 8–15. [Google Scholar] [CrossRef] [PubMed]
  152. Covantes-Rosales, C.; Toledo-Ibarra, G.; Díaz-Resendíz, K.; Ventura-Ramón, G.; Girón-Pérez, M. Muscarinic acetylcholine receptor expression in brain and immune cells of Oreochromis niloticus. J. Neuroimmunol. 2019, 328, 105–107. [Google Scholar] [CrossRef]
  153. Toledo-Ibarra, G.A.; Rodríguez-Sánchez, E.J.; Ventura-Ramón, H.G.; Resendiz, K.J.G.D.; Giron, M.I. Cholinergic alterations by exposure to pesticides used in control vector: Guppies fish (Poecilia reticulta) as biological model. Int. J. Environ. Health Res. 2017, 28, 79–89. [Google Scholar] [CrossRef]
  154. Girón-Pérez, D.A.; Hermosillo-Escobedo, A.T.; Macias-Garrigos, K.; Díaz-Resendiz, K.J.G.; Toledo-Ibarra, G.A.; Ventura-Ramón, G.H.; Girón-Pérez, M.I. Altered phagocytic capacity due to acute exposure and long-term post-exposure to pesticides used for vector-borne disease as dengue. Int. J. Environ. Health Res. 2020, 32, 455–462. [Google Scholar] [CrossRef]
  155. Díaz-Resendiz, K.J.G.; Hermosillo-Escobedo, A.T.; Ventura-Ramón, G.H.; Toledo-Ibarra, G.A.; Girón-Pérez, D.A.; Bueno-Durán, A.Y.; Girón-Pérez, M.I. Death of guppy fish (Poecilia reticulata) leukocytes induced by in vivo exposure to temephos and spinosad. Int. J. Environ. Health Res. 2020, 32, 701–711. [Google Scholar] [CrossRef]
Ijms 23 04523 g001
Figure 1. General metabolic pathway of organophosphate pesticides with the neurotoxic mechanism of action. (a) The parent organophosphorothionates bioactivated to highly toxic oxon forms by cytochrome P450 through the removal of sulfur attached to phosphorus and insertion of the oxygen atom (oxidative desulphuration) using the reactive and electrophilic iron–oxo intermediate, detoxified by dearylation to form dialkyl thiophosphates (inactive metabolites) or further hydrolyzed to dialkyl phosphates (inactive metabolites) by paraoxonase-1 (PON1) and carboxylesterase (CE) in phase I. Furthermore, phase II involves conjugative reactions carried out by glutathione transferases (GSTs); N-acetyltransferases (NATs); UDP-glucuronosyltransferase (UGTs); and sulphotransferases (SULTs), UDP-glucuronyltransferases (UGT), sulphotransferases (SULT), N-acetyltransferases (NAT), glutathione S-transferases (GST); and is excreted out through urine in a nontoxic form. (b) The oxon metabolite phosphorylates the hydroxyl group of the serine present in the active site of the enzyme acetylcholinesterase (AChE) causing ACh accumulation in the nerve synapsis [12].
Figure 1. General metabolic pathway of organophosphate pesticides with the neurotoxic mechanism of action. (a) The parent organophosphorothionates bioactivated to highly toxic oxon forms by cytochrome P450 through the removal of sulfur attached to phosphorus and insertion of the oxygen atom (oxidative desulphuration) using the reactive and electrophilic iron–oxo intermediate, detoxified by dearylation to form dialkyl thiophosphates (inactive metabolites) or further hydrolyzed to dialkyl phosphates (inactive metabolites) by paraoxonase-1 (PON1) and carboxylesterase (CE) in phase I. Furthermore, phase II involves conjugative reactions carried out by glutathione transferases (GSTs); N-acetyltransferases (NATs); UDP-glucuronosyltransferase (UGTs); and sulphotransferases (SULTs), UDP-glucuronyltransferases (UGT), sulphotransferases (SULT), N-acetyltransferases (NAT), glutathione S-transferases (GST); and is excreted out through urine in a nontoxic form. (b) The oxon metabolite phosphorylates the hydroxyl group of the serine present in the active site of the enzyme acetylcholinesterase (AChE) causing ACh accumulation in the nerve synapsis [12].
Ijms 23 04523 g001
Ijms 23 04523 g002
Figure 2. Neuronal cholinergic system. Ch: Choline; A: acetate; ACh: acetylcholine; AChE: acetylcholinesterase; ChAT: choline acetyltransferase; VaCh: ACh vesicles; mAChR: muscarinic ACh receptor; nAChR: nicotinic ACh receptor.
Figure 2. Neuronal cholinergic system. Ch: Choline; A: acetate; ACh: acetylcholine; AChE: acetylcholinesterase; ChAT: choline acetyltransferase; VaCh: ACh vesicles; mAChR: muscarinic ACh receptor; nAChR: nicotinic ACh receptor.
Ijms 23 04523 g002
Ijms 23 04523 g003
Figure 3. Modulation of signal transduction through the cholinergic system by OP exposure. Exposure to OPs induces AChE inhibition and ACh accumulation, leading to AChR overstimulation. (a) The overactivation of nAChRs and mAChRs leads to increased Ca2+ influx, which in turn induces increased ROS in mitochondria. (b) Increased intracellular Ca2+ induces activation of p38-MAPK and ERK signaling promoting an inflammatory stage through NF-KB the activation and increased levels of pro-inflammatory cytokines (TNF-alpha and IL-6). In addition, intracellular Ca2+ signaling evokes the up-regulation of c-fos expression and IL-2-induced signal transduction in T and B cells, triggering inflammatory responses. (c) OPs cause the inhibition of phospholipase C and decreased CREB phosphorylation and cAMP levels. Reduced CREB phosphorylation promotes NF-κB activation and leads to the degradation of IκB, which allows the release of NF-κB and facilitates its nuclear translocation, where it promotes the transcription of genes involved in pro-inflammatory immune responses. (d) The OP metabolite (DEDTP) promotes the phosphorylation of SOCS3 and the dephosphorylation of STAT5 protein, and leads to the activation of p21, resulting in T-cell arrest. (e) DEDTP also induced the phosphorylation of ERK, JNK, and p38, resulting in the assembly of AP1, ELK,1, and NFAT, which are the major transcription factors involved in the IL-2 autocrine pathway.
Figure 3. Modulation of signal transduction through the cholinergic system by OP exposure. Exposure to OPs induces AChE inhibition and ACh accumulation, leading to AChR overstimulation. (a) The overactivation of nAChRs and mAChRs leads to increased Ca2+ influx, which in turn induces increased ROS in mitochondria. (b) Increased intracellular Ca2+ induces activation of p38-MAPK and ERK signaling promoting an inflammatory stage through NF-KB the activation and increased levels of pro-inflammatory cytokines (TNF-alpha and IL-6). In addition, intracellular Ca2+ signaling evokes the up-regulation of c-fos expression and IL-2-induced signal transduction in T and B cells, triggering inflammatory responses. (c) OPs cause the inhibition of phospholipase C and decreased CREB phosphorylation and cAMP levels. Reduced CREB phosphorylation promotes NF-κB activation and leads to the degradation of IκB, which allows the release of NF-κB and facilitates its nuclear translocation, where it promotes the transcription of genes involved in pro-inflammatory immune responses. (d) The OP metabolite (DEDTP) promotes the phosphorylation of SOCS3 and the dephosphorylation of STAT5 protein, and leads to the activation of p21, resulting in T-cell arrest. (e) DEDTP also induced the phosphorylation of ERK, JNK, and p38, resulting in the assembly of AP1, ELK,1, and NFAT, which are the major transcription factors involved in the IL-2 autocrine pathway.
Ijms 23 04523 g003
Table 1. Effects on cholinergic systems by OP exposure.
Table 1. Effects on cholinergic systems by OP exposure.
OPsDoseExposure TimeCholinergic
Effects		Tissue/Cell LineOrganism ModelReferences
DiazinonLC50-7.830 ppm, ½ LC50-3.915 ppm96 h↓ AChE activity
↑ ACh levels		Spleen
mononuclear cells		Nile tilapia
(Oreochromis niloticus)		[22].
Diazinon0.97, 1.95 and 3.91 mg/L6, 12, and 24 h↓ AChE activity ↓ mAChR, nAChR concentration and ↑ ACh levels.Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[23].
Diazoxon1 nm, 1 µM, and 10 µM24 h↓ (M3, M4, M5)
receptors and nAChR β2 expression.		Spleen
mononuclear cells		Nile tilapia
(O. niloticus)		[24].
Paraoxon1 mg/kg6 and 24 h↓ mAChR M2
function
↑ ACh levels.
↑ mAChR M3
stimulation		Peripheral bloodGuinea Pig[25].
ChlorpyrifosLD50
1/3 LD50		48 h↓ ChAT activity
↓ AChE activity		Cerebral cortexMale Rat[26].
Chlorpyrifos1 mg/Kg1 h and 6 h↓ ChAT activity, nAChR α4, and α7 expression
↓ VAChT expression		Forebrain
Peripheral blood		Human apoE-TR mice[27].
Monocrotophos0.01, 0.10, or 1.00 mg/LN/A↓ ChAT activity
↓ AChE activity		EmbryosSea urchin (Hemicentrotus pulcherrimus)[28].
OPsAcute
exposure		N/A↓ BuChE activityPeripheral bloodHuman[29].
↑ increase ↓ decrease; ACh: acetylcholine; AChE: acetylcholinesterase; mAChR: muscarinic ACh receptor; nAChR: nicotinic ACh receptor; ChAT: choline acetyltransferase; VAChT: vesicular ACh transporter; BuChE: butyrylcholinesterase.
Table 2. Reports of the modulation of the inflammatory process mediated by cytokines due to exposure to OPs.
Table 2. Reports of the modulation of the inflammatory process mediated by cytokines due to exposure to OPs.
OPsDoseExposure TimeEffects of
Cytokines		Inflammation
Results		Organism ModelReferences
Chlorpyrifos, dimethoate0–1000 μM24 hIL-10 was significantly downregulated↓ DC-specific cell surface markers (i.e., CD83 and CD209). Inhibition of Akt familyDC, differentiated from the monocyte cell line THP-1[90].
Chlorpyrifos0, 001, 10 μM24 h↓ Expression of IL-1β and TNF-αBiphasic responses of lysosomal enzyme activity. inhibition NO releaseMacrophages from mouse peritoneum[93].
Malathion200 mg/kg b.w./day28 days↑ Expression of IL-1β, IL-6 and IFN-γ↑ Activities of hepatocellular enzymes in plasma, lipid peroxidation index, CD3+/CD4+ and CD3+/CD4+ percentAdult male Wistar rats[95].
chlorpyrifos3.375–13.5 mg/kg28 days↑ Expression of IL-1β and TNF-α↑ Activation of NF-kB, cleaved caspase 3 and HO-1 and Nrf-2 pathway
Cellular damage in organs		Male
Wistar rats		[96].
Parathion, chlorpyrifos, and diazinon1–100 μM24 h↑ Expression of TNF-α, IL-1β PDGF (platelet-derived growth factor) and TGF-β (transforming growth factor-β).
the of TNF-α protein.		↑ NF-κB activation and ↓AChE activityTHP1 cells differentiated into macrophages[97].
Chlorpyrifos6.75 mg/kg8 weeks↑ Expression of IL-6, TLR-2, IL-1β, TNF-α, and NLPR3↑ Expression of apoptotic genes (Caspase 3, Caspase 9, Caspase 8 and Bax)Male rats[98].
Triphenyl phosphate0, 50, or 150 mg/kg30 days↑ Expression of IL-6 and TNF-α↑ Inflammation in the thalamus and hippocampus. MAPK signaling pathways were significantly affected.Male mice (C57/BL6)[99].
Malathion27 mg/kg (1/50 of LD50)30 days↑ Expression of IF-γ, IL1-β, TNF-α, and NFĸB↓AChE levels in serum (30%) and liver (25%) compared to the control group. Lipid peroxidation.Rats[100].
Chlorpyrifos0.3–300 μM24 h↑ Expression of IL-1β and NLRP3↑ Oxidative stress production (NO, MDA, and O2∙)BV-2
microglial cells.		[101].
Diazinon10–100 μM24 hInduce expression of TNF-α and IL-6↑ ROS generation. Induced expressions of COX-2, iNOS, and cell-surface molecules CD40, CD86, and MHC class II.
↓phagocytic activity		RAW264.7 cells[102].
Parathion,
Malathion,
paraoxon and malaoxon		100–2000 µmol/L24 h↑ Expression of IL-6, GM-CSF and MIP-1α↓Viability, intracellular GSH and phosphorylation of STAT3.
↑Phosphorylated p38MAPK		Rat
precision-cut lung slices		[103].
↑ increase ↓ decrease; IL-6: Interleukin 6; IL-2: Interleukin 2; IL-1β: Interleukin 1 beta; TLR-2: Toll-like receptor; TNF- α: Tumor necrosis factor alpha; NLPR3: NLR family pyrin domain containing 3; IFN-γ: Interferon gamma; GM-CSF: Granulocyte-macrophage colony-stimulating factor; MIP-1α: Macrophage inflammatory protein; IL-10: Interleukin 10.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Camacho-Pérez, M.R.; Covantes-Rosales, C.E.; Toledo-Ibarra, G.A.; Mercado-Salgado, U.; Ponce-Regalado, M.D.; Díaz-Resendiz, K.J.G.; Girón-Pérez, M.I. Organophosphorus Pesticides as Modulating Substances of Inflammation through the Cholinergic Pathway. Int. J. Mol. Sci. 2022, 23, 4523. https://doi.org/10.3390/ijms23094523

AMA Style

Camacho-Pérez MR, Covantes-Rosales CE, Toledo-Ibarra GA, Mercado-Salgado U, Ponce-Regalado MD, Díaz-Resendiz KJG, Girón-Pérez MI. Organophosphorus Pesticides as Modulating Substances of Inflammation through the Cholinergic Pathway. International Journal of Molecular Sciences. 2022; 23(9):4523. https://doi.org/10.3390/ijms23094523

Chicago/Turabian Style

Camacho-Pérez, Milton Rafael, Carlos Eduardo Covantes-Rosales, Gladys Alejandra Toledo-Ibarra, Ulises Mercado-Salgado, María Dolores Ponce-Regalado, Karina Janice Guadalupe Díaz-Resendiz, and Manuel Iván Girón-Pérez. 2022. "Organophosphorus Pesticides as Modulating Substances of Inflammation through the Cholinergic Pathway" International Journal of Molecular Sciences 23, no. 9: 4523. https://doi.org/10.3390/ijms23094523

APA Style

Camacho-Pérez, M. R., Covantes-Rosales, C. E., Toledo-Ibarra, G. A., Mercado-Salgado, U., Ponce-Regalado, M. D., Díaz-Resendiz, K. J. G., & Girón-Pérez, M. I. (2022). Organophosphorus Pesticides as Modulating Substances of Inflammation through the Cholinergic Pathway. International Journal of Molecular Sciences, 23(9), 4523. https://doi.org/10.3390/ijms23094523

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop