Organophosphorus Research Articles

Supercharged Phosphotriesterase for improved Paraoxon activity.

Phosphotriesterases (PTEs) represent a class of enzymes capable of efficient neutralization of organophosphates (OPs), a dangerous class of neurotoxic chemicals. PTEs suffer from low catalytic activity, particularly at higher temperatures, due to low thermostability and low solubility. Supercharging, a protein engineering approach via selective mutation of surface residues to charged residues, has been successfully employed to generate proteins with increased solubility and thermostability by promoting charge-charge repulsion between proteins. We set out to overcome the challenges in improving PTE activity against OPs by employing a computational protein supercharging algorithm in Rosetta. Here, we discover two supercharged PTE variants, one negatively supercharged (with -14 net charge) and one positively supercharged (with +12 net charge) and characterize them for their thermodynamic stability and catalytic activity. We find that positively supercharged PTE possesses slight but significant losses in thermostability, which correlates to losses in catalytic efficiency at all temperatures, whereas negatively supercharged PTE possesses increased catalytic activity across 25°C-55°C while offering similar thermostability characteristic to the parent PTE. The impact of supercharging on catalytic efficiency will inform the design of shelf-stable PTE and criteria for enzyme engineering.

Comparison of the presence of high production volume chemicals in farmed and wild fish highly consumed in catalonia and their risk assessment

The decline in fish populations and the depletion of marine resources have sparked concerns about sustainable fish production, driving the innovation of new aquaculture methods. While some argue that wild fish are healthier than farmed fish due to less exposure to contaminants and pathogens, wild fish can accumulate contaminants from more contaminated water sources. The slower growth of wild fish and their longer exposure to the environment may contribute to higher pollutant levels in fish tissues. In this study, we focus on 25 contaminants considered as high production volume chemicals (HPVCs), such as organophosphate esters (OPEs), benzothiazoles (BTs), benzosulfonamides (BSAs) and phthalates (PAEs). The compounds were extracted from the edible part of the fish using the QuEChERS method and analysed by gas chromatography-tandem mass spectrometry.A total of 74 samples were analysed from three of the most commonly consumed species in Catalonia, Spain (turbot, sea bass and sea bream). Two samples of each species were collected each month, one form farmed and one from wild origin. In general, the compounds were found in all the samples in a wide concentrations range, although no significant differences were observed between the mean concentration of wild and farmed samples. Although similar mean concentrations for the OPEs, BTs and BSAs were found between farmed and wild origin samples, PAEs were more frequently detected in farmed samples. Di-n-octyl phthalate and diethyl phthalate showed the highest concentrations in all fish samples, with values up to 19505 and 17605 ng g−1 (d.w.), in sea bass and sea bream, respectively. Di-(2-ethylexyl)-adipate proved to be the most relevant carcinogenic compound, with no associated health risk. Despite the detection of the studied HPVCs, no health risk was associated with the consumption of these three fish species.

Comprehensive Clinical Assessment of Patients With Acute Organophosphorus Poisoning in a Tertiary Care Hospital.

Background The use of organophosphorus (OP) compounds as pesticides is widespread, particularly in developing nations such as India. These substances are easily accessible and often linked to suicide poisoning incidents, especially among distressed farmers. In India, OP poisoning remains a significant cause of emergency hospital admissions. This study aims to analyze the clinical profile of patients admitted with OP poisoning, focusing on the various clinically significant characteristics and aspects associated with these cases. Methods Throughout the course of two years (from June 2022 to May 2024), five hospitals with critical care units participated in this prospective observational study. These hospitals referred patients to the Prathima Institute of Medical Sciences, which served as the central facility for the study. The study focused on individuals who arrived at the emergency room within 24 hours of acute exposure to organophosphate pesticides. A total of 150 patients meeting the inclusion criteria were enrolled. Data collection included a comprehensive clinical examination, detailed patient history, and monitoring of the response to intravenous atropine. The severity of the poisoning was evaluated using the Peradeniya Organophosphorus Poisoning (POP) scale, adapted for this study. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23 (Released 2015; IBM Corp., Armonk, New York), with descriptive statistics used to summarize the categorical and continuous variables. Results The results of the study demonstrated a notable relationship between the arrival time at the health facility and mortality rates among patients with OPpoisoning. Patients who arrived within three hours had a mortality rate of 13.2% (five out of 38 cases), while those arriving between three and six hours had a slightly higher rate of 14.3% (10 out of 70 cases). The mortality rate sharply increased to 28.6% (12 out of 42 cases) for patients who arrived after six hours. Among the OP compounds, monocrotophos showed the highest mortality rate at 80% (eight out of 10 cases), followed by dimethoate with 42.9% (12 out of 28 cases) and dichlorvos with 62.5% (five out of eight cases). The overall mortality rate in the study was 22.7% (34 out of 150 cases). Conclusions Poisoning with OP has primarily impacted young, productive men. Considerable mortality results from a disease condition that is more severe at presentation. It is advised to selectively outlaw the riskier substances that account for a larger percentage of fatalities.

HI-6-Loaded Vehicle of Liposomes Mediated by an Amphiphilic Pillar[5]arene against Paraoxon Poisoning.

Organophosphate (OP) intoxication has become a severe common health matter all over the world. For the treatment of acute OP poisoning, the effective intracerebral delivery of acetylcholinesterase reactivators is crucial. Here, an amphiphilic hydrazide-pillar[5]arene (HP5A-6C), which could be readily integrated into liposomal bilayers' zwitterionic disaturated phosphatidylcholine (DSPC), was synthesized. A T7 peptide-containing guest (G) was attached on the surface via a noncovalent interaction to make mixed liposomes a particularly appealing candidate for brain-targeting delivery. Such coassembly could remain stable at room temperature for up to 6 weeks, and safety evaluations initially verified its fine biological compatibility. The hydrophilic interiors of T7/HP5A-6C@DSPC could further load HI-6 with 89.70% encapsulation efficiency. Support for brain-targeting potency came from imaging results. Notably, intravenous injection of HI-6-loaded vesicles exhibited a remarkable therapeutic effect on paraoxon (POX)-poisoned mice, effectively alleviating seizures and brain damage and significantly increasing the improving survival rate to 60% over the course of 7 days.

Occupational Exposure of On-Shift Ottawa Firefighters to Flame Retardants and Polycyclic Aromatic Hydrocarbons.

Firefighters can be exposed to complex mixtures of airborne substances, including hazardous substances released during structural fires. This study employed silicone wristbands (SWBs) as passive samplers to investigate potential exposure to polycyclic aromatic hydrocarbons (PAHs) and flame retardants (FRs). SWBs were deployed at different areas of four fire stations, in four truck cabins, and at an office control location; they were also donned outside the jackets of 18 firefighters who responded to fire calls. Overall, office areas had significantly lower PAHs than fire station areas. Vehicle bays and truck cabins had significantly higher concentrations of low molecular weight (LMW) PAHs than sleeping and living room areas. For organophosphate ester flame retardants (OPFRs), tri-n-butyl phosphate (TnBP) and tris(1-chloro-2-propyl) phosphate (TCPP) were detected in all the samples; 2-ethylhexyl diphenyl phosphate (EHDPP) was more frequently detected in the fire station areas. Triphenyl phosphate (TPP) concentrations were highest in the truck cabin and office areas, and tris(1,3-dichloro-2-propyl)phosphate (TDCPP) was highest in truck cabins. Thirteen of 16 PAHs and nine of 36 OPFRs were detected in all the SWBs worn by firefighters, and tris (2-butoxyethyl) phosphate (TBEP) was the predominant OPFR. Levels of LMW PAHs were significantly lower when firefighters did not enter the fire. LMW PAHs, HMW (high molecular weight) PAHs, and EHDPP were significantly elevated when heavy smoke was reported. This work highlights the potential for occupational exposure to PAHs and flame retardants in some fire station areas; moreover, factors that may influence exposure during fire suppression. Whilst firefighters' occupational exposure to PAHs is likely related to fire suppression and exposure to contaminated gear and trucks, exposure to OPFRs may be more related to their presence in truck interiors and electronics.

Identification and biophysical characterization of potential phytochemical inhibitors of carboxyl/choline esterase from Helicoverpa armigera for advancing integrated pest management strategies

In the realm of disease vectors and agricultural pest management, insecticides play a crucial role in preserving global health and ensuring food security. The pervasive use, particularly of organophosphates (OPs), has given rise to a substantial challenge in the form of insecticide resistance. Carboxylesterases emerge as key contributors to OP resistance, owing to their ability to sequester or hydrolyze these chemicals. Consequently, carboxylesterase enzymes become attractive targets for the development of novel insecticides. Inhibiting these enzymes holds the potential to restore the efficacy of OPs against which resistance has developed. This study aimed to screen the FooDB library to identify potent inhibitory compounds targeting carboxylesterase, Ha006a from the agricultural pest Helicoverpa armigera. The ultimate objective is to develop effective interventions for pest control. The compounds with the highest scores underwent evaluation through docking studies and pharmacophore analysis. Among them, four phytochemicals—donepezil, protopine, 3′,4′,5,7-tetramethoxyflavone, and piperine—demonstrated favorable binding affinity. The Ha006a-ligand complexes were subsequently validated through molecular dynamics simulations. Biochemical analysis, encompassing determination of IC50 values, complemented by analysis of thermostability through Differential Scanning Calorimetry and interaction kinetics through Isothermal Titration Calorimetry was conducted. This study comprehensively characterizes Ha006a-ligand complexes through bioinformatics, biochemical, and biophysical methods. This investigation highlights 3′,4′,5,7-tetramethoxyflavone as the most effective inhibitor, suggesting its potential for synergistic testing with OPs. Consequently, these inhibitors offer a promising solution to OP resistance and address environmental concerns associated with excessive insecticide usage, enabling a significant reduction in their overuse.

Decontamination of Organophosphates: Efficacy of Oxime Incorporated Palm Oil based Liquid Soaps for Methyl Parathion Neutralization

Organophosphates (OPs) are a group of poisonous chemicals that are commonly used as pesticides and at times as chemical weapons. Decontamination of these compounds from the contaminated surfaces is an important step in their poisoning incident management but techniques that are commonly used currently, washings with soap solutions are not effective as the contaminants are still active in the waste solutions. Addition of an active ingredient such as an oxime which acts as a nucleophile in the soap solutions will enhance the ability of the washing liquids to hydrolyse OPs to convert them into innocuous compounds. This article describes a procedure to synthesize and characterize oxime-incorporated palm oil-based liquid soaps with an oxime concentration in the range of 0.05–1% and the results of their evaluation for their decontamination efficacy to degrade the OPs into non-toxic compounds. The soaps were formulated from palm oil and stable with the pH of 11.0, which is within the pH range for decontamination purposes. Upon mixing the soap solutions with Methyl Parathion (MP), the MP degrades slowly with the formation of p-nitrophenol (p-NP) after 24h which appears at peaks 400nm of the UV-Visible spectrum. However, in the presence of 2-pyridine aldoxime methiodide (2-PAM) with concentrations of 0.05% to 1.0%, the degradation is immediately observed involving the 2-PAM/MP complexation, in addition to the formation of p-NP after 24h. Furthermore, with the concentration of 2-PAM of 0.5% to 1.0%, the degradation does not produce p-NP but dimethylthiophosphate (DMPT) suggesting that the oxime content in the soap is sufficient to neutralise the MP. Based on the above findings, it can be concluded that the addition of the 2-PAM at the right concentration into the soaps significantly enhances their ability to efficiently decontaminate MP.

Correlation of Pseudocholinesterase Level with Clinical, Biochemical Parameters Including Cardiac Profile and the Outcome in Organophosphorus Poisoning.

Poisoning is a significant health hazard and a leading cause of morbidity and mortality worldwide. India, being a predominantly agrarian country, routinely employs organophosphate (OP) pesticides in farming, and they are readily available "over the counter." OPs exert their toxicity by interfering with the normal function of acetylcholine, an essential neurotransmitter throughout the autonomic and central nervous systems. Due to the limited availability of facilities and resources in health-care systems, and economically restraining patients, it is necessary to rely more on clinical features to assess the severity of poisoning and manage the condition properly. It was a hospital-based prospective observational study that included patients aged >13 years in a tertiary care hospital. All patients were clinically evaluated based on their history and examination. The diagnosis was made based on characteristic clinical manifestations or evidence of exposure to organophosphorus compounds (corroborative evidence such as empty containers and the odor of gastric aspirates). Clinical severity was assessed and categorized according to the Peradeniya Organophosphorus Poisoning Scale (POP scale). A score of 0-3 is considered mild poisoning, 4-7 as moderate poisoning, and 8-11 as severe poisoning. Out of the 50 patients enrolled in the study, 17 (34.00%) were aged <20 years, 19 (38%) were in the 20-30 years age group, and 14 (28%) were aged >30 years. Ingestion is the only mode of exposure to poisoning. None of the patients had history of contact or inhalational exposure. Of the 50 cases, 12 (24.0%) were in the mild category, 26 (52.0%) in the moderate category, and 12 (24%) in the severe category on the POP grading. A comparison of the mean serum pseudocholinesterase, troponin-T, and pro-BNP levels with severity was performed. In mild OP poisoning, the mean serum PChE level was 2766.58 ± 1120.44; in moderate, it was 1969.35 ± 1330.07, and in severe, it was 701.83 ± 961.17. Pseudocholinesterase levels decreased progressively with increasing clinical severity from mild-to-severe cases, and this association was statistically significant (P < 0.001). Two-dimensional echocardiography screening done in all patients did not show any significant abnormalities. This study shows that serum PCE is reduced in OP poisoning and correlates with the clinical severity grading done by the POP scale and is also associated with an increase in the duration of intensive care unit stay. No significant evidence of direct cardiac injury was observed in this study. A low Glasgow Coma Scale score and an increased respiratory rate at presentation are associated with poor outcomes.

Development and child health in a world of synthetic chemicals.

Chemical pollution is one of today's most significant threats to the developmental potential of children worldwide. Maternal exposure to toxicants can perturb sensitive windows of fetal development, indirectly through promoting antenatal disorders, abnormal placental adaptation, or directly through maternal-fetal transport. Current evidence clearly shows that persistent organic chemicals promote hypertensive disorders of pregnancy, placental abnormalities, and fetal growth restriction, whereas findings are less consistent for phthalates and bisphenols. Prospective birth cohorts strongly support a link between adverse neurodevelopmental outcomes and prenatal exposure to flame retardants and organophosphate pesticides. Emerging evidence reveals a potential association between in utero exposure to bisphenols and childhood behavioral disorders, while childhood metabolic health is more consistently associated with postnatal exposure to phthalates and bisphenols. IMPACT: Synthesizes emerging evidence linking modern forms of chemical pollution to antenatal disorders, fetal growth restriction and childhood disorders. Highlights potential developmental impacts of emerging pollutants of concern now ubiquitous in our environment but without regulatory restrictions.

Recognition of organophosphate and carbamate pesticides by cholinesterase sensor arrays on the basis of enzymes from different organisms

Herein, we developed a multisensor array utilizing multiple cholinesterase (ChE) and indoxyl acetate (IDA) sensors for the detection and differentiation of trichlorfon (Tri), profenofos (Pro), methomyl (Met), carbofuran (Car), phoxim (Pho), and pyridaphenthion (Pyr). The detection mechanism involves the inactivation of ChE by organophosphates (OPs) and carbamates (CMs), leading to a reduction in the production of indoxyl groups through IDA hydrolysis. We observed distinct and varied inhibition rates of the three enzymes in response to Tri, Pro, Met, Car, Pho, and Pyr. Linear discriminant analysis (LDA) and hierarchical cluster analysis (HCA) plots illustrated the effectiveness of the system in accurately distinguishing both individual and mixed pesticides. Additionally, the platform showed the sensor array’s ability to identify pesticide mixtures and resist interference. Furthermore, the successful classification and determination of celery samples highlighted its practical applicability. This approach holds promise for developing a straightforward sensor array for detecting and discriminating pesticides in complex samples.

Migration patterns of organophosphate esters from plastic food packaging simulants to foods: Donors, behaviours, and influencing factors

In recent years, organophosphate esters (OPEs) have been widely produced and used as flame retardants and plasticizer additives, posing significant ecological and health risks. Dietary intake is considered to be the primary route of human exposure to OPEs. Plastic food packaging materials are considered a crucial source for contamination of OPEs in food. However, the migration behaviour of OPEs from plastic food packaging materials into foods has received limited attention. In this study, we employed a novel method to prepare migration donors containing 13 kinds of OPEs. The migration behaviours of OPEs from food packaging simulants (polypropylene) to foods (full-fat milk powder) were simulated, and factors influencing the migration of OPEs were examined, including the properties of the target compounds, migration temperature, fat content of the migration receptors, and mass transfer mode. The results indicated that OPEs exhibited a significant migration tendency. Low molecular weight OPEs (< 300 Da) had faster migration efficiency compared to high molecular weight OPEs. The mean migration efficiencies of various OPEs showed a significant negative correlation with their molecular weights (p < 0.01) and a significant positive correlation with temperature (p < 0.01). Except for resorcinol bis(diphenyl phosphate) (RDP), which showed almost no migration, the mean migration efficiencies of other OPEs at 25 °C, 40 °C, and 60 °C were 3.1–37.5 %, 9.0–60.0 %, and 23.9–80.4 %, respectively. Most of the OPEs demonstrated higher migration efficiency in high-fat content food than low-fat content food. The migration of OPEs from food packaging simulants to foods primarily occurred through contact rather than gas-phase mass transfer. Overall, this study uncovers the migration behaviours of OPEs from food packaging simulants to foods and scrutinized the relevant factors influencing the migration. It is expected that the research in terms of the contamination control of OPEs in food will benefit from this work.

Comprehensive monitoring and prioritizing for contaminants of emerging concern in the Upper Yangtze River, China: An integrated approach

Contaminants of emerging concern (CECs) in aquatic environments can adversely impact ecosystems and human health even at low concentrations. This study assessed the risk of 162 CECs, including neonicotinoid pesticides, triazine pesticides, carbamate pesticides, psychoactive substances, organophosphate esters, antidepressants, per- and polyfluoroalkyl substances, and antibiotics in 10 drinking water sources and two tributaries (Jialing and Wujiang Rivers) of the Upper Yangtze River in Chongqing, China. Target screening detected 156 CECs at 0.01–2218.2 ng/L, while suspect screening via LC-QTOF-MS identified 64 CECs, with 13 pesticides, 29 pharmaceuticals and personal care products, and 2 industrial chemicals reported for the first time in the Yangtze River Basin. Risk quotient-based ecological risk assessment revealed that 48 CECs posed medium to high risks (RQ > 0.1) to aquatic life, with antibiotics (n = 20) as the main contributors. Non-carcinogenic risks were below negligible levels, but carcinogenic risks from neonicotinoids, triazines, antidepressants, and antibiotics were concerning. A multi-criteria prioritization approach integrating occurrence, physico-chemical properties, and toxicological data ranked 26 CECs as high priority. This study underscores the importance of comprehensive CEC screening in rivers and provides insights for future monitoring and management strategies.

Development of a scintillation proximity assay for [3H]epibatidine binding sites of Tetronarce californica muscle-type nicotinic acetylcholine receptor

The therapy of intoxication with distinct organophosphorus (OP) compounds is still limited today. Especially chemical warfare agents like tabun and soman as well as novichok intoxications are difficult to address using established oxime therapeutics. These neurotoxins inhibit acetylcholinesterase (AChE), a pivotal enzyme in the synaptic cleft. The following accumulation of acetylcholine in the synaptic cleft leads to a dysfunctional, desensitized state of nicotinic acetylcholine receptors (nAChR). Without adequate treatment, the resulting cholinergic crisis leads to death by respiratory arrest. Consequently, the research approach for new therapeutic options needs to be expanded. A promising option would be substances interacting directly with nAChRs. Therefore, screening methods for new drug candidates are needed, with affinity assays playing an important role. In the present work, a saturation and competition scintillation proximity assay (SPA) for binding studies at [3H]epibatidine binding sites, conventionally classified as orthosteric binding sites of the muscle type nAChR was developed. This method offers several advantages over other assay technologies because no separation as well as washing steps are required to remove unbound ligands. Assay precision and solvent tolerance were validated according to the guidelines for validation of bioanalytical methods of the Food and Drug Administration (FDA) and European Medicines Agency (EMA). The newly developed binding assay was successfully implemented on an automated pipetting platform and is suitable for high-throughput-screening of receptor-ligand interactions at the nAChR. Furthermore, it allows to investigate/quantify competition of highly toxic agents such as nerve agents or structurally similar pesticides at the orthosteric binding site. Related to further pharmacological results, the affinity to [3H]epibatidine binding sites can provide additional information on whether potential drug candidates would be suitable for treatment of nerve agent poisoning.

Organophosphate esters in reservoir water from a metropolitan city in the Guangdong-Hong Kong-Macao Greater Bay Area, China, and their ecological risk

Organophosphate esters (OPEs) are emerging flame retardants widely used in products such as furniture, electronic equipment, construction, and plastics. It has been demonstrated that OPEs are harmful to humans and aquatic organisms, thus posing a threat to ecosystems. Considering that reservoirs are critical sources of drinking water for residents in Southern China, this study quantified nine OPEs in water samples collected from 29 reservoirs and their tributaries. The temporal and spatial distributions of OPEs were analyzed and their ecological risks were assessed. The results showed an extensive presence of OPEs in reservoirs, and the median concentration of Σ9OPEs was much higher in the dry season (65.3 ng/L) than in the wet season (21.3 ng/L). Triisobutyl phosphate (TiBP) (median: 5.24 ng/L) and tris(2-ethylhexyl) phosphate (TEHP) (median: 10.8 ng/L) dominated in the wet and dry seasons, respectively. Other OPEs varied considerably in concentrations over time, related to their physical and chemical properties, environmental factors (e.g., precipitation and temperature), and varied applications. Furthermore, the significant correlations of individual OPEs suggest their shared utilization, emission sources, and environmental behaviors. Spatially, there was no significant difference (P > 0.05) among the Σ9OPEs concentrations in water samples from different sites (inlet, reservoir, outlet, and tributary) of the reservoirs. Additionally, the concentrations of OPEs in reservoir water samples could be linked to industrial development, economic conditions, and population density. OPEs in the reservoir pose low ecological risks (RQ < 0.1), except for EDHPP and TEHP, which present median ecological risks (RQ = 0.54 and 0.38, respectively). Future studies could investigate more OPEs and their joint effects with other organic pollutants, as well as survey the chemical reactions and degradation pathways of OPEs in different environmental matrices to assess their potential ecotoxicity more comprehensively.

Tangeretin alleviates malathion-instigated testicular toxicity via ameliorating biochemical, apoptotic, hormonal & steroidogenic markers

Malathion (MLT) is an organophosphate pesticide that instigates severe injuries in the testicular tissues. Tangeretin (TGN) is an important naturally present flavone that shows potential antioxidant and anti-apoptotic activities. This research was planned to ascertain the palliative role of TGN against MLT-instigated testicular toxicity in male Sprague-Dawley (SD) rats. 48 rats were distributed into 4 groups: control, MLT (100 mgkg−1), MLT+TGN (100 + 50 mgkg−1 respectively), and TGN (50 mgkg−1). The results showed that MLT exposure reduced the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH), whereas escalated the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). Moreover, it decreased the levels of luteinizing hormone (LH), plasma testosterone, and follicle-stimulating hormone (FSH). MLT also reduced the expressions of steroidogenic enzymes, including StAR, 3β-HSD, and 17β-HSD. Additionally, MLT exposure increased the expressions of Bax and Caspase-3, while reducing the Bcl-2 expressions. MLT administration also increased the levels of inflammatory markers such as nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (1L-1β) as well as cyclooxygenase-2 (COX-2) activity in testes. Nonetheless, TGN recovered all the MLT induced damages in testes. In conclusion, TGN could ameliorate MLT instigated testicular impairment because of its anti-apoptotic, androgenic and anti-oxidant properties.

Concentration-dependent effects of the nerve agents cyclosarin and VX on cytochrome P450 in a HepaRG cell-based liver model.

The exposure to highly toxic organophosphorus (OP) compounds, including pesticides and nerve agents, is an ongoing medical challenge. OP can induce the uncontrolled overstimulation of the cholinergic system through inhibition of the enzyme acetylcholinesterase (AChE). The cytochrome P450 (CYP) enzymes in the liver play a predominant role in the metabolism of xenobiotics and are involved in the oxidative biotransformation of most clinical drugs. Previous research concerning the interactions between OP and CYP has usually focused on organothiophosphate pesticides that require CYP-mediated bioactivation to their active oxon metabolites to act as inhibitors of AChE. Since there has been little data available concerning the effect of nerve agents on CYP, we performed a study with cyclosarin (GF) and O-ethyl-S-[2-(diisopropylamino)-ethyl]-methylphosphonothioate (VX) by using a well-established, metabolically competent in vitro liver model (HepaRG cells). The inhibitory effect of the nerve agents GF and VX on the CYP3A4 enzyme was investigated showing a low CYP3A4 inhibitory potency. Changes on the transcription level of CYP and associated oxygenases were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using the two nerve agent concentrations 250 nM and 250 μM. In conclusion, the results demonstrated various effects on oxygenase-associated genes in dependence of the concentration and the structure of the nerve agent. Such information might be of relevance for potential interactions between nerve agents, antidotes or other clinically administered drugs, which are metabolized by the affected CYP, for example, for the therapy with benzodiazepines, that are used for the symptomatic treatment of OP poisoning and that require CYP-mediated biotransformation.

Potential mechanisms and modifications of dietary antioxidants on the associations between co-exposure to plastic additives and diabetes

BackgroundThe association of plastic additive mixture exposure with diabetes and the modifying effects of dietary antioxidants are unclear.MethodsThe data from the NHANES 2011–2018 were retrieved, and phthalates and organophosphate esters (OPEs) were selected as exposures. The coexposure effect was analyzed by the environmental risk score (ERS) and quantile g-computation. To mitigate any potential bias caused by using the internal weights, another version of ERS was constructed using the cross-validation approach. The level of dietary antioxidant intake was measured by the composite dietary antioxidant index (CDAI). The biological mechanism underlying the association was studied by the adverse outcome pathway (AOP) framework.ResultsFifteen chemicals (ten phthalates and five OPEs) were measured in 2824 adult participants. A higher ERS was significantly associated with an increased risk of diabetes (OR per 1-SD increment of ERS: 1.25, 95% CI: 1.13–1.39). This association apparently interacted with the CDAI level (ORlow: 1.83, 95% CI: 1.37–2.55; ORhigh: 1.28, 95% CI: 1.15–1.45; Pinteraction = 0.038). Moreover, quantile g-computation also revealed higher level of combined exposure was positively associated with diabetes (OR: 1.27, 95% CI: 1.05–2.87), and the addition of dietary antioxidants showed a null association (OR: 1.09, 95% CI: 0.85–2.34). The AOP study identified TCPP and TCEP as key chemicals that cause aberrant glucose metabolism and insulin signaling pathways and result in diabetes.ConclusionsCoexposure to phthalates and OPEs is positively associated with diabetes, where an antioxidative diet plays a modifying role. Several potential mechanisms have been proposed by AOP framework.

Mediated self-assembled gold nanoclusters with mesoporous silica particles to boost fluorescence for enhanced on-site monitoring of organophosphate pesticides

Accurate detection of organophosphate pesticides (OPs) is paramount for ensuring food safety. Dendritic mesoporous silica sphere was employed to confine gold nanoclusters (AuNCs@dmSiO2) to ameliorate fluorescent property of AuNCs. A AuNCs@dmSiO2-based fluorescent method was developed for OPs sensing. Identification of Cu2+ by AuNCs quenched AuNCs@dmSiO2 fluorescence. Interaction between Cu2+ and generated thiocholine in catalysis of acetylcholinesterase (AChE) caused fluorescence enhancement. OPs, an inhibitor of AChE, suppressed thiocholine production to cause fluorescence quenching. Based on fluorescent variation, a fluorescent method was proposed for OPs by selecting paraoxon as a model within range of 0.05–25.0 ng/mL with a limit of detection (LOD) of 0.032 ng/mL. Besides, a portable test swab was prepared for on-site monitoring OP paraoxon with a smartphone-based 3D-printing portable device with a LOD of 0.65 ng/mL. This work is highlighted by the inspiration of designing highly fluorescent AuNCs, and the provision of a viable avenue for OPs-related food analysis.

Highly sensitive assaying study based on three-dimensional graphene/cerium oxide nanoparticle nanozyme for the detecting of organophosphate pesticides in vegetable

As an important chemical pollutant affecting the safety of agricultural products, the on-site and efficient detection of pesticide residues has become a global trend and hotspot in research. Herein, this work present a highly sensitive assaying study based on three-dimensional graphene/cerium oxide nanoparticle nanozyme for the detection of organophosphate pesticides (OPs) in vegetable. The detection mechanism is because OPs can inhibit the activity of alkaline phosphatase (ALP). Cerium oxide nanoparticles exhibited intrinsic biomimetic oxidase activity and catalyzed the oxidation of the colorless 3,3′,5,5′-tetramethylbenzidine (TMB) into blue oxidized oxTMB. Upon the introduction of ALP, L-ascorbic acid-2-phosphate can be dephosphorylated to ascorbic acid, which aroused the disintegration of cerium oxide nanoparticles into Ce3+ ions. This disintegration weakened the enzyme-mimicking activity, thus impeding the oxidation of TMB. The absorbance at 652 nm exhibited a linear relationship with the concentration of phorate in the range of 0.15–50 μg/mL, generating a limit of detection of 0.13 μg/mL, Phorate recovery in the spiked samples for the absorption detection mode was 81.0 %–96.7 %. The relative standard deviations (RSD) of the absorption were in the range of 2.18 %–4.12 %. The results in terms of detecting pesticide residues collected from food samples via this method satisfactorily agree with those obtained via gas chromatography–mass spectrometry. This simple assay is therefore suitable for sensing pesticides in complex samples, especially in combination with other portable platforms.

Exposure to organophosphate ester flame retardants and plasticizers and associations with preeclampsia and blood pressure in pregnancy

BackgroundOrganophosphate esters (OPEs), flame retardants and plasticizers found widely in consumer products, may impact vascularization processes in pregnancy. Yet, the association between maternal exposure to OPEs and both preeclampsia and blood pressure during pregnancy remains understudied. MethodsWithin the LIFECODES Fetal Growth Study (N = 900), we quantified 8 OPE metabolites from maternal urine collected at up to 3 time points during pregnancy and created within-subject geometric means. Outcomes included diagnosis of preeclampsia and longitudinal systolic (SBP) and diastolic (DBP) blood pressure measurements (mean = 14 per participant). Cox proportional hazards models were used to estimate associations between OPE metabolites and preeclampsia. Associations between average OPE metabolite concentrations and repeated blood pressure measurements were estimated using generalized estimating equations. ResultsFive OPE metabolites were detected in at least 60% of samples; 3 metabolites detected less frequently (5–39%) were examined in an exploratory analysis as ever vs. never detectable in pregnancy. There were 46 cases of preeclampsia in our study population. Associations between OPE metabolites and preeclampsia were null. We noted several divergent associations between OPE metabolites and longitudinal blood pressure measurements. An interquartile range (IQR) difference in average bis(2-chloroethyl) phosphate concentrations was associated with a decrease in SBP (−0.81 mmHg, 95% confidence interval [CI]: −1.62, 0.00), and, conversely, bis(1-chloro-2-propyl) phosphate was associated with a slight increase in SBP (0.94 mmHg, 95% CI: 0.28, 1.61). We also noted a decrease in SBP in association with several metabolites with low detection frequency. ConclusionsWe observed null associations between OPE metabolites and preeclampsia, but some positive and some inverse associations with blood pressure in pregnancy. While our study was well-designed to assess associations with blood pressure, future studies with a larger number of preeclampsia cases may be better poised to investigate the association between OPE metabolites and phenotypes of this heterogenous hypertensive disorder of pregnancy.