Toxic Organophosphorus Compounds Research Articles

Simultaneous Hydrolysis and Detection of Organophosphate by Benzimidazole Containing Ligand-Based Zinc(II) Complexes

The agricultural use of organophosphorus pesticides is a widespread practice with significant advantages in crop health and product yield. An undesirable consequence is the contamination of soil and groundwater by these neurotoxins resulting from over application and run-off. Here, we design and synthesize the mononuclear zinc(II) complexes, namely, [Zn(AMB)2Cl](ClO4) 1 and [Zn(AMB)2(OH)](ClO4) 2 (AMB = 2-aminomethylbenzimidazole), as artificial catalysts inspired by phosphotriesterase (PTE) for the hydrolysis of organophosphorus compounds (OPs) and simultaneously detect the organophosphate pesticides such as fenitrothion and parathion. Spectral and DFT (B3LYP/Lanl2DZ) calculations revealed that complexes 1 and 2 have a square-pyramidal environment around zinc(II) centers with coordination chromophores of ZnN4Cl and ZnN4O, respectively. Both 1 and 2 were used as a modifier in the construction of a biomimetic sensor for the determination of toxic OPs, fenitrothion and parathion, in phosphate buffer by square wave voltammetry. The hydrolysis of OPs using 1 or 2 generates p-nitrophenol, which is subsequently oxidized at the surface of the modified carbon past electrode. The catalytic activity of 2 was higher than 1, which is attributed to the higher electronegativity of the former. The oxidation peak potentials of p-nitrophenol were obtained at +0.97 V (vs. Ag/AgCl) using cyclic voltammetry (CV) and +0.88 V (vs. Ag/AgCl) using square wave voltammetry. Several parameters were investigated to evaluate the performance of the biomimetic sensor obtained after the incorporation of zinc(II) complex 1 and 2 on a carbon paste electrode (CPE). The calibration curve showed a linear response ranging between 1.0 μM (0.29 ppm) and 5.5 μM (1.6 ppm) for fenitrothion and 1.0 μM (0.28 ppm) and 0.1 μM (0.028 ppm) for parathion with a limit of detection (LOD) of 0.08 μM (0.022 ppm) and 0.51 μM (0.149 ppm) for fenitrothion and parathion, respectively. The obtained results clearly demonstrated that the CPE modified by 1 and 2 has a remarkable electrocatalytic activity towards the hydrolysis of OPs under optimal conditions.

Efficacy of atropine and scopolamine on airway contractions following exposure to the nerve agent VX

Nerve agents are highly toxic organophosphorus compounds that inhibit acetylcholinesterase resulting in rapid accumulation of the neurotransmitter acetylcholine (ACh) causing a cholinergic syndrome including respiratory failure. In the present study, respiratory responses and antimuscarinic treatment efficacy was evaluated ex vivo using rat precision-cut lung slices (PCLS) exposed to the nerve agent VX. The respiratory effects were evaluated either by adding exogenous ACh directly to the culture medium or by applying electric-field stimulation (EFS) to the PCLS to achieve a release of endogenous ACh from neurons in the lung tissue.The airway contraction induced by both methods was enhanced by VX and resulted in lingering airway recovery, in particular when airways were exposed to a high VX-dose. Both contractions induced by EFS and exogenously added ACh were significantly reduced by administration of the antimuscarinic drugs atropine or scopolamine. Two additions of atropine or scopolamine after maximal ACh-induced airway response was demonstrated effective to reverse the contraction. By adding consecutive doubled doses of antimuscarinics, high efficiency to reduce the cholinergic airway response was observed. However, the airways were not completely recovered by atropine or scopolamine, indicating that non-muscarinic mechanisms were involved in the smooth muscle contractions.In conclusion, it was demonstrated that antimuscarinic treatment reversed airway contraction induced by VX but supplemental pharmacological interventions are needed to fully recover the airways. Further studies should therefore clarify the mechanisms of physiological responses in lung tissue following nerve agent exposures to improve the medical management of poisoned individuals.

Reactivation of organophosphate-inhibited serum butyrylcholinesterase by novel substituted phenoxyalkyl pyridinium oximes and traditional oximes

Organophosphorus compounds (OPs) include nerve agents and insecticides that potently inhibit acetylcholinesterase (AChE), an essential enzyme found throughout the nervous system. High exposure levels to OPs lead to seizures, cardiac arrest, and death if left untreated. Oximes are a critical piece to the therapeutic regimen which remove the OP from the inhibited AChE and restore normal cholinergic function. The current oximes 2-PAM, MMB-4, TMB-4, HI-6, and obidoxime (OBD) have two drawbacks: lack of broad spectrum protection against multiple OP structures and poor brain penetration to protect against OP central neurotoxicity. An alternative strategy to enhance therapy is reactivation of serum butyrylcholinesterase (BChE). BChE is stoichiometrically inhibited by OPs with no apparent toxic result. Inhibition of BChE in the serum followed by reactivation could create a pseudo-catalytic scavenger allowing numerous regenerations of BChE to detoxify circulating OP molecules before they can reach target AChE. BChE in serum from rats, guinea pigs or humans was screened for the reactivation potential of our novel substituted phenoxyalkyl pyridinium oximes, plus 2-PAM, MMB-4, TMB-4, HI-6, and OBD (100μM) in vitro after inhibition by highly relevant surrogates of sarin, VX, and cyclosarin, and also DFP, and the insecticidal active metabolites paraoxon, phorate-oxon, and phorate-oxon sulfoxide. Novel oxime 15 demonstrated significant broad spectrum reactivation of OP-inhibited rat serum BChE while novel oxime 20 demonstrated significant broad spectrum reactivation of OP-inhibited human serum BChE. All tested oximes were poor reactivators of OP-inhibited guinea pig serum BChE. The bis-pyridinium oximes were poor BChE reactivators overall. BChE reactivation may be an additional mechanism to attenuate OP toxicity and contribute to therapeutic efficacy.

Organophosphorus Nerve Agents: Types, Toxicity, and Treatments.

Organophosphorus compounds are extensively used worldwide as pesticides which cause great hazards to human health. Nerve agents, a subcategory of the organophosphorus compounds, have been produced and used during wars, and they have also been used in terrorist activities. These compounds possess physiological threats by interacting and inhibiting acetylcholinesterase enzyme which leads to the cholinergic crisis. After a general introduction, this review elucidates the mechanisms underlying cholinergic and noncholinergic effects of organophosphorus compounds. The conceivable treatment strategies for organophosphate poisoning are different types of bioscavengers which include stoichiometric, catalytic, and pseudocatalytic. The current research on the promising treatments specifically the catalytic bioscavengers including several wild-type organophosphate hydrolases such as paraoxonase and phosphotriesterase, phosphotriesterase-like lactonase, methyl parathion hydrolase, organophosphate acid anhydrolase, diisopropyl fluorophosphatase, human triphosphate nucleotidohydrolase, and senescence marker protein has been widely discussed. Organophosphorus compounds are reported to be the nonphysiological substrate for many mammalian organophosphate hydrolysing enzymes; therefore, the efficiency of these enzymes toward these compounds is inadequate. Hence, studies have been conducted to create mutants with an enhanced rate of hydrolysis and high specificity. Several mutants have been created by applying directed molecular evolution and/or targeted mutagenesis, and catalytic efficiency has been characterized. Generally, organophosphorus compounds are chiral in nature. The development of mutant enzymes for providing superior stereoselective degradation of toxic organophosphorus compounds has also been widely accounted for in this review. Existing enzymes have shown limited efficiency; hence, more effective treatment strategies have also been critically analyzed.

Catalytic Degradation of Nerve Agents

Nerve agents (NAs) are a group of highly toxic organophosphorus compounds developed before World War II. They are related to organophosphorus pesticides, although they have much higher human acute toxicity than commonly used pesticides. After the detection of the presence of NAs, the critical step is the fast decontamination of the environment in order to avoid the lethal effect of these organophosphorus compounds on exposed humans. This review collects the catalytic degradation reactions of NAs, in particular focusing our attention on chemical hydrolysis. These reactions are catalyzed by different catalyst categories (metal-based, polymeric, heterogeneous, enzymatic and MOFs), all of them described in this review.

Kinetics of Dimethyl Methylphosphonate Adsorption and Decomposition on Zirconium Hydroxide Using Variable Temperature In Situ Attenuated Total Reflection Infrared Spectroscopy.

The decomposition mechanisms of dimethyl methylphosphonate (DMMP), a widely used simulant for organophosphorus chemical warfare agents (CWAs), are relatively well understood from previous studies. However, there still lacks a quantitative description of DMMP decomposition kinetics under ambient conditions that is relevant for sequestration applications. We investigated adsorption and decomposition kinetics of DMMP on amorphous zirconium hydroxide (ZH) using variable-temperature in situ attenuated total reflection (ATR) infrared spectroscopy. We demonstrate that quantifying DMMP decomposition kinetics using conventional methods, where the integrated absorbance of P-O vibrational modes is monitored, can be inaccurate because these spectra are also convoluted with C-O vibrational modes from transient surface methoxy species that are not proportional to DMMP decomposition due to methanol desorption. Here, we propose to use the ρ(PCH3) modes as an alternative way to track DMMP adsorption and decomposition reactions. On the basis of density functional theory (DFT) simulations and comparisons to relatively unreactive monoclinic zirconia (m-ZrO2), we assign the deconvoluted components of the ρ(PCH3) region and use it to monitor decomposition products over time at various temperatures. Because the PCH3 group is present in many toxic organophosphorus compounds, tracking the PCH3 bands in time-dependent IR spectra is useful for measuring surface kinetics of CWAs and their simulants on various decontamination materials.

Nerve Agents’ Surrogates: Invaluable Tools for Development of Acetylcholinesterase Reactivators

The use of nerve agents as warfare and in terrorist acts has drawn much attention from the governments and societies. Such toxic organophosphorus compounds are listed in Chemical Weapons Convention as Schedule 1 chemicals. The discussion about the chemical identity of the elusive Novichok agents, more potent compounds than best known G- and V-Agents, which have been implicated in recent rumorous assassination plots, clearly demonstrating the importance of the matter. Furthermore, accidents with pesticides or misuse thereof have been a pressing issue in many countries. In this context, the continued development of novel cholinesterase reactivators, antidotes for organophosphorus poisoning, a rather restricted class of pharmaceutical substances, is warranted. Testing of novel candidates may require use of actual nerve agents. Nonetheless, only a few laboratories comply with the requirements for storing, possession and manipulation of such toxic chemicals. To overcome such limitations, nerve agents’ surrogates may be a useful alternative, as they undergo the same reaction with cholinesterases, yielding similar adducts, allowing assays with novel antidote candidates, among other applications.

A Comprehensive Understanding of Enzymatic Degradation of the G-Type Nerve Agent by Phosphotriesterase: Revised Role of Water Molecules and Rate-Limiting Product Release

Nerve agents are highly toxic organophosphorus compounds, and the wild-type phosphotriesterase (PTE) enzyme is capable of hydrolyzing these organophosphates but with a low catalytic efficiency. Her...

Human plasma-derived butyrylcholinesterase is behaviorally safe and effective in cynomolgus macaques (Macaca fascicularis) challenged with soman

Organophosphorus compounds (OP) pose a significant threat. Administration of human butyrylcholinesterase (HuBChE) may reduce or prevent OP toxicity. Thus, we evaluated the safety and efficacy of HuBChE in monkeys using sensitive neurobehavioral tests while concurrently characterizing absorption and elimination in the presence and absence of high-dose soman exposure to predict time course and degree of protection. Eight young adult male cynomolgus macaques were trained on two distinct automated tests of neurobehavioral functioning. HuBChE purified under current Good Manufacturing Practices (CGMP) was injected intramuscularly at 13.1 mg/kg, producing an average peak plasma value (Cmax) of over 27 Units/ml. The apparent time to maximum concentration (Tmax) approximated 7 h, the elimination half-life approximated 102 h, and plasma levels returned to pre-administration (baseline) levels by 14 days. No behavioral disruptions following HuBChE administration were observed on either neurobehavioral test, even in monkeys injected 24 h later with an otherwise lethal dose of soman. Thus, HuBChE provided complete neurobehavioral protection from soman challenge. The present data replicate and extend previous results from our laboratory that had used a different route of administration (intravenous), a different species (rhesus macaque), and a different BChE product (non-CGMP material). The addition of two sensitive neurobehavioral tests coupled with the PK/PD results convincingly demonstrates the neurobehavioral safety of plasma-derived HuBChE at therapeutic levels. Protection against an otherwise-lethal dose of soman by a pre-exposure treatment dose that is devoid of side effects establishes a foundation for additional testing using other exposure routes and treatment times, other challenge agents/routes, or other classes of organophosphate scavengers.

The Experimental Oxime K027-A Promising Protector From Organophosphate Pesticide Poisoning. A Review Comparing K027, K048, Pralidoxime, and Obidoxime.

Poisoning with organophosphorus compounds (OPCs) is a major problem worldwide. Standard therapy with atropine and established oxime-type enzyme reactivators (pralidoxime, obidoxime) is unsatisfactory. In search of more efficacious broad-spectrum oximes, new bispyridinium (K-) oximes have been synthesized, with K027 being among the most promising. This review summarizes pharmacokinetic characteristics of K027, its toxicity and in vivo efficacy to protect from OPC toxicity and compares this oxime with another experimental bisquaternary asymmetric pyridinium aldoxime (K048) and two established oximes (pralidoxime, obidoxime). After intramuscular (i.m.) injection, K027 reaches maximum plasma concentration within ∼30 min; only ∼2% enter the brain. Its intrinsic cholinesterase inhibitory activity is low, making it relatively non-toxic. In vitro reactivation potency is high for ethyl-paraoxon-, methyl-paraoxon-, dichlorvos-, diisopropylfluorophosphate (DFP)- and tabun-inhibited cholinesterase. When administered in vivo after exposure to the same OPCs, K027 is comparable or more efficacious than pralidoxime and obidoxime. When given as a pretreatment before exposure to ethyl-paraoxon, methyl-paraoxon, DFP, or azinphos-methyl, it is superior to the Food and Drug Administration-approved compound pyridostigmine and comparable to physostigmine, which because of its entry into the brain may cause unwanted behavioral effects. Because of its low toxicity, K027 can be given in high dosages, making it a very efficacious oxime not only for postexposure treatment but also for prophylactic administration, especially when brain penetration is undesirable.

Evaluation of a robust engineered enzyme towards organophosphorus insecticide bioremediation using planarians as biosensors

Organophosphorus compounds (OPs) are neurotoxic molecules developed as insecticides and chemical warfare nerve agents (CWNAs). They are covalent inhibitors of acetylcholinesterase (AChE), a key enzyme in central and peripheral nervous systems and are responsible for numerous poisonings worldwide. Many animal models have been studied over the years but finding a suitable in vivo model to account for both acute toxicity and long-term exposure remains a topical issue. Recently, an emerging aquatic animal model harboring a mammalian-like cholinergic nervous system, the freshwater planarian from Platyhelminthes, has been used to investigate neurotoxicity and developmental disruption.Given the tremendous toxicity of OPs, various bioremediation strategies have been considered over the years to counter their poisonous effects. Among these, enzymes have been particularly highlighted as they can degrade OPs in a fast, non toxic and environmentally friendly manner. In this article we investigated the biotechnological potential for decontaminating OPs of the previously reported variant SsoPox-αsD6 from the hyperstable enzyme SsoPox, isolated from the archaea Sulfolobus solfataricus. The capacity to hydrolyze 4 new substrates (methyl-pirimiphos, quinalphos, triazophos and dibrom) was demonstrated and the degradation products generated by enzymatic hydrolysis were characterized. We further evaluated the capacity of SsoPox-αsD6 for in vivo protection of freshwater planarians Schmidtea mediterranea (Smed). The use of SsoPox-αsD6 drastically decreased mortality and enhanced mobility of planarians. Then, an enzyme-based filtration device was developed by immobilizing intact Escherichia coli cells expressing SsoPox-αsD6 into alginate beads. The efficacy of the device was demonstrated using planarians as biosensors.

An Organophosphorus(III)-Selective Chemodosimeter for the Ratiometric Electrochemical Detection of Phosphines

The high toxicity of phosphine and the use of organophosphines as nerve agent precursors has provoked the requirement for a rapid and reliable detection methodology for their detection. Herein, we demonstrate that a ferrocene-derived molecular probe, armed with an azidobenzene trigger, delivers a ratiometric electrochemical signal selectively in response to organophosphorus(III) compounds and can be accurately measured with an inexpensive, handheld potentiostat. Through an intensive assay optimization process, conditions were found that could determine the presence of a model organophosphine(III) nerve agent precursor within minutes and achieved a limit of detection for triphenylphosphine of just 13 ppm. Due to the portability of the detection system and the excellent stability of the probe in solution, we envisaged that this proof-of-concept of work could easily be taken into the field to enable potentially toxic organophosphorus(III) compounds to be detected at the point-of-need.

Molecular recognition of organophosphorus compounds in water and inhibition of their toxicity to acetylcholinesterase.

Molecular tubes with hydrogen bonding donors in their deep hydrophobic cavities are able to selectively bind organophosphorus compounds in water through hydrogen bonding and the hydrophobic effect. They can also be used as a fluorescent sensor for nerve agent simulants and as an inhibitor to reduce the toxicity of paraoxon to acetylcholinesterase.

Determination of the Structure of Alkyl Radicals in a Series of Highly Toxic Organophosphorus Compounds Using Mass Spectrometry Databases and Library Search

We propose an approach to the identification of alkyl radicals attached to the ester oxygen atom in a series of highly toxic organophosphorus compounds, based on the revealed regularities in the formation of mass spectra of monofunctional RX compounds (R is alkyl radical and X is functional group). The method includes the extraction of the hydrocarbon subspectrum from the mass spectrum of the analyte and its comparison with the hydrocarbon subspectra of the known monofunctional compounds. Alkyl radicals are identified using simple metrics that characterize the coincidence of hydrocarbon subspectra. The results of the identification of alkyl (cycloalkyl) radicals in a series of O-alkyl (cycloalkyl) alkylphosphonofluoridates, and O-alkyl (cycloalkyl) N,N-dialkylphosphoramidocyanidates show that ≥95% of the structures of the radicals of these compounds are within 10 positions of the search result list.

Assessment of exogenous melatonin action on mouse liver cells after exposure to soman

Melatonin is a hormone with many different biological activities and therefore seems to be an important factor reducing the harmful effects caused by toxic organophosphorus compounds. In this study, we attempted to evaluate the protective effect of melatonin on liver cells of mice challenged with chemical warfare agent-soman. The study was conducted at the level of ultrastructural and biochemical changes (analysis of the activity of model lysosomal enzymes and assessment of the level of lipid peroxidation). Significant biochemical and ultrastructural changes were found in the studied mouse hepatocytes after administration of soman alone, and soman in combination with melatonin, and the scope of the disclosed changes was dependent on the time of action of the examined factors. Melatonin has shown protective action, shielding liver cells from toxic effects of soman, which may result from its antioxidant properties and stimulation of the lysosomal compartment, the system coordinating the isolation and removal of cell-threatening processes.

Sensitive biosensing of organophosphate pesticides using enzyme mimics of magnetic ZIF-8.

Development of a sensitive detection method for the reliable screening of widely used organophosphorus (OP) toxins is a crucial request to control their side-effects. Herein, a novel fluorometric assay based on the acetylcholinesterase (AChE) inhibited enzymatic activity and the new peroxidase-like Fe3O4 nanoparticles@ZIF-8 composite (Fe3O4 NPs@ZIF-8) was developed for the determination of OPs. Magnetic Fe3O4 NPs were encapsulated into ZIF-8 and the high mimetic activity of produced composite was assessed on the oxidation of substrates. This observation was applied to the rapid detection of diazinon as a model OP compound. The sensing tool contains AChE and choline oxidase (CHO) enzymes, peroxidase colorimetric or fluorometric substrate, and Fe3O4 NPs@ZIF-8 as the catalyst. In the presence of mimic Fe3O4 NPs@ZIF-8, the generated H2O2 from the enzymatic reactions of acetylcholine is decomposed to hydroxyl radicals. The radicals oxidize the peroxidase substrates to generate a detectable signal. However, due to the inhibition effect of OPs on the enzymatic activity of AChE, lower H2O2 amounts are produced in the presence of diazinon. Using the fluorometric detection system, the generated signal is decreased proportionally by increasing diazinon concentration in the range of 0.5-500 nM. The limit of detection was obtained 0.2 nM. Consequently, the usage of high performance peroxidase-mimic Fe3O4 NPs@ZIF-8 provided a sensitive bio-assay with a potential to be applied as screening tool for toxic OP compounds. The developed assay was successfully applied for the determination of diazinon in water and fruit juices.

Interactions between acetylcholinesterase, toxic organophosphorus compounds and a short series of structurally related non-oxime reactivators: Analysis of reactivation and inhibition kinetics in vitro

Poisoning by organophosphorus compounds (OP) is characterized by inhibition of the key enzyme acetylcholinesterase (AChE) and potentially fatal outcomes in humans. Insufficient efficacy of the standard therapy with atropine and AChE reactivators (oximes) against certain OP initiated synthesis of novel non-oxime reactivators basing on the common structure 4-amino-2-((diethylamino)methyl)phenol (ADOC). Recently, we reported of a pyrrolidine-bearing ADOC analogue (3 l) with a remarkable ability to reactivate OP-inhibited AChE. This in vitro study was undertaken to determine reactivity, affinity and overall reactivation constants of 3 l, the reference compound ADOC and two structural analogues with human AChE inhibited by paraoxon, sarin, cyclosarin and VX. The data showed a 10 to 34-fold reactivating potency of 3 l compared to ADOC mainly due to improved affinity. Additionally, various interactions between non-oximes, human or guinea pig (GP) AChE and structurally different OP were investigated: OP-inhibited guinea pig AChE was less amenable to reactivation by ADOC and 3 l than human AChE. Compound 3 l was considered as potential pretreatment to prevent AChE from irreversible inhibition by OP: In the presence of 10 μM 3 l inhibition of native human AChE was attenuated resulting in protective indices (PI) ranging from about 2.7 to 6.0. A combination of 3 l and the bispyridinium oxime HI-6 was tested to reactivate OP-inhibited AChE: The superior reactivator of the respective OP-AChE combination dominated the reactivation process and a synergistic effect could not be observed.In conclusion, novel non-oxime reactivators like 3 l may be considered as promising templates for the design of more potent therapeutics against poisoning by highly toxic OP.

Organophosphorus poisoning in animals and enzymatic antidotes.

Organophosphorus compounds (OPs) are neurotoxic molecules developed as pesticides and chemical warfare nerve agents (CWNAs). Most of them are covalent inhibitors of acetylcholinesterase (AChE), a key enzyme in nervous systems, and are therefore responsible for numerous poisonings around the world. Many animal models have been studied over the years in order to decipher the toxicity of OPs and to provide insights for therapeutic and decontamination purposes. Environmental impact on wild animal species has been analyzed to understand the consequences of OP uses in agriculture. In complement, various laboratory models, from invertebrates to aquatic organisms, rodents and primates, have been chosen to study chronic and acute toxicity as well as neurobehavioral impact, immune response, developmental disruption, and other pathological signs. Several decontamination approaches were developed to counteract the poisoning effects of OPs. Among these, enzyme-based strategies are particularly attractive as they allow efficient external decontamination without toxicity or environmental impact and may be of interest for treatment. Approaches using bioscavengers for prophylaxis, treatment, and external decontamination are emphasized and their potential is discussed in the light of toxicological observations from various animal models. The relevance of animal models, regarding their cholinergic system and the abundance of naturally protecting enzymes, is also discussed for better extrapolation of results to human.

Electro-behavioral phenotype and cell injury following exposure to paraoxon-ethyl in mice: Effect of the genetic background

Organophosphorus compounds (OP) are irreversible inhibitors of both central and peripheral cholinesterases (ChE). They still represent a major health issue in some countries as well as a terrorist and military threat. In order to design appropriate medical counter-measures, a better understanding of the pathophysiology of the poisoning is needed. Little to nothing is known regarding the impact of the genetic background on OP-induced seizures and seizure-related cell injury. Using two different mouse strains, Swiss and C57BL/6J, exposed to a convulsing dose of the OP pesticide paraoxon-ethyl (POX), our study focused on seizure susceptibility, especially the occurrence of SE and related mortality. We also evaluated the initial neuropathological response and SE-induced cell injury.Following the administration of 2.4 mg/kg POX, more Swiss mice experienced SE than C57BL/6J (55.6% versus 17.2%) but the duration of their SE, based on EEG recordings, was shorter (64.3 ± 19.5 min versus 180.8 ± 36.8 min). No significant difference was observed between strains regarding mortality (33% versus 14%). In both strains limited cell injury was observed in the medial temporal cortex, the dentate gyrus and the CA3 field without inter-strain differences (Fluorojade C-positive cells/mm2). Conversely, only C57BL/6J mice showed cell injury in the CA1 field. There was no obvious correlation between the number of Fluorojade C-positive cells and the duration of the EEG discharges.Our work suggests some differences between Swiss and C57BL/6J mice and lay ground to further studies on the impact of strains in the development of central nervous system toxicity of OP.

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication.

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways.