Basic research for identification and classification of organophosphorus pesticides in water based on ultraviolet-visible spectroscopy information.

In this study, the goal was to develop a method for detecting and classifying organophosphorus pesticides (OPPs) in bodies of water. Sixty-five samples with different concentrations were prepared for each of the organophosphorus pesticides, namely chlorpyrifos, acephate, parathion-methyl, trichlorphon, dichlorvos, profenofos, malathion, dimethoate, fenthion, and phoxim, respectively. Firstly, the spectral data of all the samples was obtained using a UV-visible spectrometer. Secondly, five preprocessing methods, six manifold learning methods, and five machine learning algorithms were utilized to build detection models for identifying OPPs in water bodies. The findings indicate that the accuracy of machine learning models trained on data preprocessed using convolutional smoothing + first-order derivatives (SG + FD) outperforms that of models trained on data preprocessed using other methods. The backpropagation neural network (BPNN) model exhibited the highest accuracy rate at 99.95%, followed by the support vector machine (SVM) and convolutional neural network (CNN) models, both at 99.92%. The extreme learning machine (ELM) and K-nearest neighbors (KNN) models demonstrated accuracy rates of 99.84% and 99.81%, respectively. Following the application of a manifold learning algorithm to the full-wavelength data set for the purpose of dimensionality reduction, the data was then visualized in the first three dimensions. The results demonstrate that the t-distributed domain embedding (t-SNE) algorithm is superior, exhibiting dense clustering of similar clusters and clear classification of dissimilar ones. SG + FD-t-SNE-SVM ranks highest among the feature extraction models in terms of performance. The feature extraction dimension was set to 4, and the average classification accuracy was 99.98%, which slightly improved the prediction performance over the full-wavelength model. As shown in this study, the ultraviolet-visible (UV-visible) spectroscopy system combined with the t-SNE and SVM algorithms can effectively identify and classify OPPs in waterbodies.

Association between organophosphorus pesticides and obesity among American adults.

OBJECTIVE: To investigate any connections between urinary organophosphorus pesticide (OPP) metabolites and adiposity measures. METHODS: In this study, data from the National Health and Nutrition Examination Survey (NHANES) projects from 2003 to 2008, 2011 to 2012, and 2015 to 2018 were analysed. Obesity was defined as a body mass index (BMI) of 30 kg/m² or higher. Abdominal obesity was defined as a waist circumference (WC) over 102 cm for men and 88 cm for women. Four urinary OPP metabolites (dimethyl phosphate [DMP], diethyl phosphate [DEP], dimethyl phosphorothioate [DMTP], and diethyl phosphorothioate [DETP]) and adiposity measures were examined using multiple linear regression and logistic regression analyses. The correlations between a variety of urinary OPP metabolites and the prevalence of obesity were investigated using weighted quantile sum regression and quantile g-computation regression. RESULTS: In this analysis, a total of 9,505 adults were taken into account. There were 49.81% of male participants, and the average age was 46.00 years old. The median BMI and WC of the subjects were 27.70 kg/m2 and 97.10 cm, respectively. Moreover, 35.60% of the participants were obese, and 54.42% had abdominal obesity. DMP, DMTP, and DETP were discovered to have a negative correlation with WC and BMI in the adjusted models. DMP (OR = 0.93 [95% CI: 0.89-0.98]), DEP (OR = 0.94 [95% CI: 0.90-0.99]), DMTP (OR = 0.91 [95% CI: 0.86-0.95]), and DETP (OR = 0.85 [95% CI: 0.80-0.90]) exhibited negative associations with obesity prevalence. Similar correlations between the prevalence of abdominal obesity and the urine OPP metabolites were discovered. Moreover, the mixture of urinary OPP metabolites showed negative associations with adiposity measures, with DMTP and DETP showing the most significant effects. CONCLUSION: Together, higher levels of urinary OPP metabolites in the urine were linked to a decline in the prevalence of obesity.

Mass spectrometry detection of organophosphorus pesticide adducts on butyrylcholinesterase and albumin.

This study established a method to prepare and detect OPs adducts on butyrylcholinesterase (BChE) and human serum albumin (HSA). OPs (methyl paraoxon, ethyl paraoxon, methyl parathion, parathion) were incubated with BChE or HSA in vitro, and the adducts of OPs-BChE or OPs-HSA were prepared and qualitatively analyzed by ultra-performance liquid chromatography data-dependent high-resolution tandem mass spectrometry (UPLC-ddHRMS/MS). The amounts of BChE and HSA in the incubating systems were varied and the resulting amounts of the adducts were determined using linear regression. OPs-BChE in the blood were isolated by immunomagnetic separation (IMS), and then digested into the OPs-nonapeptide adduct by pepsin. The proteins in the remaining blood plasma were precipitated and digested by pronase to OPs-tyrosines(OPs-Tyr), which were quantified by UPLC-ddHRMS/MS. 4 OPs-nonapeptides and 4 OPs-Tyr adducts were obtained through the process above. The relative mass deviation of incubated adducts between the actual and theoretical exact masses was less than 10 ppm, and further confirmed by fragmentation mass spectra analysis. Calibration curves were linear for all adducts with a coefficient of determination value (R2) ≥0.995. The limits of detection (LOD) and limits of quantification (LOQ) for adducts detected by MS ranged from 0.05 to 1.0 ng/mL, and from 0.1 to 2.0 ng/mL, respectively. The recovery percentages for adducts ranged from 76.1 % to 107.1 %, matrix effects ranged from 83.4 % to 102.1 %. The inter-day and intra-day precision were 6.1-10.1 % and 6.9-12.9 % for adducts. This study provides a new reference method for the detection of organophosphorus pesticide poisoning. In addition, two blood samples with organophosphorus poisoning were tested by the designed method, and the corresponding adducts were detected in both samples.

Real-world evidence of brigatinib as second-line treatment after crizotinib for ALK+ non-small cell lung cancer using South Korean claims data (K-AREAL).

PURPOSE: There is a lack of real-world data in Asian populations for brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor for patients with non-small cell lung cancer (NSCLC). This study analysed real-world outcomes and dosing patterns for brigatinib in patients with crizotinib-refractory ALK+ NSCLC in South Korea. METHODS: This retrospective, non-interventional, cohort study used South Korean Health Insurance and Review Assessment claims data for adults with ALK+ NSCLC who initiated brigatinib between 19 April 2019 and 31 March 2021 after receiving prior crizotinib. Patients' characteristics, time to discontinuation (TTD), time to dose reduction, overall survival (OS) and treatment adherence were assessed. RESULTS: The study included 174 patients (56.9% male; 27.0% with a history of brain metastases). Median duration of prior crizotinib was 17 (range 0.3-48) months. Median follow-up after brigatinib initiation was 18 (range 0-34) months. Overall, 88.5% of patients received full-dose brigatinib (180 mg/day) and 93.1% of patients were adherent (proportion of days covered ≥0.8). The median TTD was 24.9 months (95% CI 15.2-not reached). The probability of continuing treatment was 63.2% at 1 year and 51.5% at 2 years. The probability of continuing at full or peak dose was 79.7% at 1 year and 75.6% at 2 years. Median OS was not reached. The 2-year OS rate was 68.7%. CONCLUSIONS: In this first nationwide retrospective study using national insurance claim data, brigatinib demonstrated real-world clinical benefit as second-line treatment after prior crizotinib in ALK+ NSCLC patients in South Korea.

Association between organophosphorus insecticides exposure and osteoarthritis in patients with arteriosclerotic cardiovascular disease.

BACKGROUND: Organic phosphorus insecticides (OPPs) are a class of environmental pollutants widely used worldwide with potential human health risks. We aimed to assess the association between exposure to OPPs and osteoarthritis (OA) particularly in participants with atherosclerotic cardiovascular disease (ASCVD). METHODS: Participants' information was obtained from data in the National Health and Nutrition Examination (NHANES). Weighted logistic regression models were utilized to detect associations between OPPs metabolites and OA. Restricted cubic spline plots (RCS) were drawn to visualize the dose-response relationship between each metabolite and OA prevalence. Weighted quantile sum (WQS) regression and Bayesian kernel-machine regression (BKMR), were applied to investigate the joint effect of mixtures of OPPs on OA. RESULTS: A total of 6871 samples were included in our study, no significant associations between OPPs exposure and OA incidence were found in whole population. However, in a subset of 475 individuals with ASCVD, significant associations between DMP (odds ratio [OR] as a continuous variable = 1.22, 95% confidence interval [CI]: 1.07,1.28), DEP ((odds ratio [OR] of the highest tertile compared to the lowest = 2.43, 95% confidence interval [CI]: 1.21,4.86), and OA were observed. DMP and DEP showed an increasing dose-response relationship to the prevalence of OA, while DMTP, DETP, DMDTP and DEDTP showed a nonlinear relationship. Multi-contamination modeling revealed a 1.34-fold (95% confidence intervals:0.80, 2.26) higher prevalence of OA in participants with high co-exposure to OPPs compared to those with low co-exposure, with a preponderant weighting (0.87) for the dimethyl dialkyl phosphate metabolites (DMAPs). The BKMR also showed that co-exposure of mixed OPPs was associated with an increased prevalence of OA, with DMP showing a significant dose-response relationship. CONCLUSION: High levels of urine dialkyl phosphate metabolites (DAP) of multiple OPPs are associated with an increased prevalence of OA in patients with ASCVD, suggesting the need to prevent exposure to OPPs in ASCVD patients to avoid triggering OA and further avoid the occurrence of cardiovascular events caused by OA.

1,3,5-Triaza-7-phosphaadamantane and Cyclohexyl Groups Impart to Di-Iron(I) Complex Aqueous Solubility and Stability, and Prominent Anticancer Activity in Cellular and Animal Models.

Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One compound from the series (FEACYP) emerged for its strong cytotoxicity in vitro against four human cancer cell lines, surpassing the activity of cisplatin by 3-6 times in three cell lines, with an average selectivity index of 6.2 compared to noncancerous HEK293 cells. FEACYP demonstrated outstanding water solubility (15 g/L) and stability in physiological-like solutions. It confirmed its superior antiproliferative activity when tested in 3D spheroids of human pancreatic cancer cells and showed a capacity to inhibit thioredoxin reductase (TrxR) similar to auranofin. In vivo treatment of murine LLC carcinoma with FEACYP (8 mg kg-1 dose) led to excellent tumor growth suppression (88%) on day 15, with no signs of systemic toxicity and only limited body weight loss.

Tripeptide linked dispiro cyclotriphosphazene conjugates: Synthesis, molecular docking analysis of compounds binding within cancer cell line receptors and in vitro cytotoxic and genotoxic activities.

The novel dioxybiphenyl bridged-cyclotriphosphazenes (DPP) bearing tripeptide were synthesized and investigated for their molecular docking analysis, visualizing their binding profiles within various cancer cell line receptors and in vitro cytotoxic and genotoxic properties. The dipeptide compound (Tyr-Phe) was treated with various amino acids to obtain the tripeptide compounds (Tyr-Phe-Gly, Tyr-Phe-Ala, Tyr-Phe-Val, Tyr-Phe-Phe, and Tyr-Phe-Leu). These synthesized tripeptides were subsequently treated with DPP to obtain novel phosphazene compounds bearing tripeptide structures. As a result, the synthesis of target molecules with phosphazene compound in the center and biphenyl and tripeptide groups in the side arms was obtained for the first time in this study. Examining the cytotoxic studies in vitro of our newly synthesized compounds demonstrated the anticancer properties against four selected human cancer cell lines, including breast (MCF-7), ovarian (A2780), prostate (PC-3), and colon (Caco-2) cancer cells. The Comet Assay analysis determined that the cell death mechanism of most of the compounds with cytotoxic activity stemmed from the DNA damage mechanism. Among the compounds, the DPP-Tyr-Phe-Phe compound seems to have the best anticancer activity against the subjected cell lines (Except for A2780) with IC50 values equal to 20.18, 72.14, 12.21, and 5.17 µM against breast, ovarian, prostate, and colon cancer cell lines, respectively. For this reason, the molecular docking analysis was conducted for the DTPP compound to visualize its binding geometry and profile within the target enzyme's binding site associated with the specific cancer cell line. The analysis revealed that the DTPP derivative exhibited an optimal binding conformation and characteristics within the target enzyme's binding site, aligning well with the experimental data. Based on the data, these compounds are believed to be strong candidate molecules for both pharmaceutical and clinical applications.

Covalent adduct formation of histone with organophosphorus pesticides in vitro.

It is established that organophosphorus pesticide (OPP) toxicity results from modification of amino acids in active sites of target proteins. OPPs can also modify unrelated target proteins such as histones and such covalent histone modifications can alter DNA-binding properties and lead to aberrant gene expression. In the present study, we report on non-enzymatic covalent modifications of calf thymus histones adducted to selected OPPs and organophosphate flame retardants (OPFRs) in vitro using a bottom-up proteomics method approach. Histones were not found to form detectable adducts with the two tested OPFRs but were avidly modified by a few of the seven OPPs that were tested in vitro. Dimethyl phosphate (or diethyl phosphate) adducts were identified on Tyr, Lys and Ser residues. Most of the dialkyl phosphate adducts were identified on Tyr residues. Methyl and ethyl modified histones were also detected. Eleven amino residues in histones showed non-enzymatic covalent methylation by exposure of dichlorvos and malathion. Our bottom-up proteomics approach showing histone-OPP adduct formation warrants future studies on the underlying mechanism of chronic illness from exposure to OPPs.

Nephrotoxicity of organophosphate flame retardants in patients with chronic kidney disease: A 2-year longitudinal study.

Humans are extensively exposed to organophosphate flame retardants (OPFRs), an emerging group of organic contaminants with potential nephrotoxicity. Nevertheless, the estimated daily intake (EDI) and prognostic impacts of OPFRs have not been assessed in individuals with chronic kidney disease (CKD). In this 2-year longitudinal study of 169 patients with CKD, we calculated the EDIs of five OPFR triesters from urinary biomonitoring data of their degradation products and analyzed the effects of OPFR exposure on adverse renal outcomes and renal function deterioration. Our analysis demonstrated universal OPFR exposure in the CKD population, with a median EDIΣOPFR of 360.45 ng/kg body weight/day (interquartile range, 198.35-775.94). Additionally, our study revealed that high tris(2-chloroethyl) phosphate (TCEP) exposure independently correlated with composite adverse events and composite renal events (hazard ratio [95 % confidence interval; CI]: 4.616 [1.060-20.096], p = 0.042; 3.053 [1.075-8.674], p = 0.036) and served as an independent predictor for renal function deterioration throughout the study period, with a decline in estimated glomerular filtration rate of 4.127 mL/min/1.73 m2 (95 % CI, -8.127--0.126; p = 0.043) per log ng/kg body weight/day of EDITCEP. Furthermore, the EDITCEP and EDIΣOPFR were positively associated with elevations in urinary 8-hydroxy-2'-deoxyguanosine and kidney injury molecule-1 during the study period, indicating the roles of oxidative damage and renal tubular injury in the nephrotoxicity of OPFR exposure. To conclude, our findings highlight the widespread OPFR exposure and its possible nephrotoxicity in the CKD population.

Triphenylphosphonium-Conjugated Palmitic Acid for Mitochondrial Targeting of Pancreatic Cancer Cells: Proteomic and Molecular Evidence.

Pancreatic ductal adenocarcinoma (PDAC)'s resistance to therapies is mainly attributed to pancreatic cancer stem cells (PCSCs). Mitochondria-impairing agents can be used to hamper PCSC propagation and reduce PDAC progression. Therefore, to develop an efficient vector for delivering drugs to the mitochondria, we synthesized tris(3,5-dimethylphenyl)phosphonium-conjugated palmitic acid. Triphenylphosphonium (TPP) is a lipophilic cationic moiety that promotes the accumulation of conjugated agents in the mitochondrion. Palmitic acid (PA), the most common saturated fatty acid, has pro-apoptotic activity in different types of cancer cells. TPP-PA was prepared by the reaction of 16-bromopalmitic acid with TPP, and its structure was characterized by 1H and 13C NMR and HRMS. We compared the proteomes of TPP-PA-treated and untreated PDAC cells and PCSCs, identifying dysregulated proteins and pathways. Furthermore, assessments of mitochondrial membrane potential, intracellular ROS, cardiolipin content and lipid peroxidation, ER stress, and autophagy markers provided information on the mechanism of action of TPP-PA. The findings showed that TPP-PA reduces PDAC cell proliferation through mitochondrial disruption that leads to increased ROS, activation of ER stress, and autophagy. Hence, TPP-PA might offer a new approach for eliminating both the primary population of cancer cells and PCSCs, which highlights the promise of TPP-derived compounds as anticancer agents for PDAC.

Environmental exposures to organophosphorus flame retardants in early pregnancy and risks of gestational diabetes mellitus: a nested case-control study.

OPFRs are emerging environmental pollutants with reproductive and endocrine toxicity. This study aimed to examine the association between environmental exposure to OPFRs during early pregnancy and GDM. This nested case-control study was based on a birth cohort that was constructed at a maternal and child health hospital, including 74 cases of GDM among 512 pregnant women. The OPFRs, including TBP, TBEP, TCEP, TDCPP, TMCP, TOCP, and TPHP during 10-14 weeks of pregnancy were determined using GC-MS. The association between the OPFRs and GDM was assessed using WQS and BKMR models. The levels of OPFRs were significantly elevated in GDM patients (60) compared with the controls (90). The WQS analysis showed that mixtures of the OPFRs were significantly associated with GDM (OR 1.370, 95% CI 1.036-1.810, P = 0.027), and TBP, TPHP, and TMCP were the major contributors to the mixed exposure effect. In the BKMR model, individual exposure to TBP, TPHP, and TMCP, and the interaction of TMCP with TBP and TPHP were significantly associated with GDM. Environmental exposure to OPFRs is positively associated with GDM. These findings provide evidence for the adverse effects of OPFR exposure on the health of pregnant women.

Polyphosphazene Microparticles with High Free Radical Scavenging Activity for Skin Photoprotection.

Ultraviolet (UV) filters are the core ingredients in sunscreens and protect against UV-induced skin damage. Nevertheless, their safety and effectiveness have been questioned in terms of their poor photostability, skin penetration, and UV-induced generation of deleterious reactive oxygen species (ROS). Herein, an organic UV filter self-framed microparticle sunblock was exploited, in which quercetin (QC) and hexachlorocyclotriphosphazene (HCCP) were self-constructed into microparticles (HCCP-QC MPs) by facile precipitation polymerization without any carriers. HCCP-QC MPs could not only significantly extend the UV shielding range to the whole UV region but also remarkably reduce UV-induced ROS while avoiding direct skin contact and the resulting epidermal penetration of small-molecule QC. Meanwhile, HCCP-QC MPs possess a high QC-loading ability (697 mg g-1) by QC itself as the microparticles' building blocks. In addition, there is no leakage issue with small molecules due to its covalently cross-linked structure. In vitro and vivo experiments also demonstrated that the HCCP-QC MPs have excellent UV protection properties and effective ROS scavenging ability without toxicity. In summary, effective UV-shielding and ROS scavenging ability coupled with excellent biocompatibility and nonpenetration of small molecules make it a broad prospect in skin protection.

Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors.

BACKGROUND: NF2-related schwannomatosis (NF2-SWN, formerly called neurofibromatosis type 2) is a tumor predisposition syndrome that is manifested by multiple vestibular schwannomas, nonvestibular schwannomas, meningiomas, and ependymomas. The condition is relentlessly progressive with no approved therapies. On the basis of preclinical activity of brigatinib (an inhibitor of multiple tyrosine kinases) in NF2-driven nonvestibular schwannoma and meningioma, data were needed on the use of brigatinib in patients with multiple types of progressive NF2-SWN tumors. METHODS: In this phase 2 platform trial with a basket design, patients who were 12 years of age or older with NF2-SWN and progressive tumors were treated with oral brigatinib at a dose of 180 mg daily. A central review committee evaluated one target tumor and up to five nontarget tumors in each patient. The primary outcome was radiographic response in target tumors. Key secondary outcomes were safety, response rate in all tumors, hearing response, and patient-reported outcomes. RESULTS: A total of 40 patients (median age, 26 years) with progressive target tumors (10 vestibular schwannomas, 8 nonvestibular schwannomas, 20 meningiomas, and 2 ependymomas) received treatment with brigatinib. After a median follow-up of 10.4 months, the percentage of tumors with a radiographic response was 10% (95% confidence interval [CI], 3 to 24) for target tumors and 23% (95% CI, 16 to 30) for all tumors; meningiomas and nonvestibular schwannomas had the greatest benefit. Annualized growth rates decreased for all tumor types during treatment. Hearing improvement occurred in 35% (95% CI, 20 to 53) of eligible ears. Exploratory analyses suggested a decrease in self-reported pain severity during treatment (-0.013 units per month; 95% CI, -0.002 to -0.029) on a scale from 0 (no pain) to 3 (severe pain). No grade 4 or 5 treatment-related adverse events were reported. CONCLUSIONS: Brigatinib treatment resulted in radiographic responses in multiple tumor types and clinical benefit in a heavily pretreated cohort of patients with NF2-SWN. (Funded by the Children's Tumor Foundation and others; INTUITT-NF2 ClinicalTrials.gov number, NCT04374305.).

Synthesis and anti-proliferative effect of novel 4-Aryl-1, 3-Thiazole-TPP conjugates via mitochondrial uncoupling process.

With the advent of mitochondrial targeting moiety such as triphenlyphosphonium cation (TPP+), targeting mitochondria in cancer cells has become a promising strategy for combating tumors. Herein, a series of novel 4-aryl-1,3-thiazole derivatives linked to TPP+ moiety were designed and synthesized. The cytotoxicity against a panel of four cancer cell lines was evaluated by CCK-8 assay. Most of these compounds exhibited moderate to good inhibitory activity over HeLa, PC-3 and HCT-15 cells while MCF-7 cells were less sensitive to most compounds. Among them, compound 12a exhibited a significant anti-proliferative activity against HeLa cells, and prompted for further investigation. Specifically, 12a decreased mitochondrial membrane potential and enhanced levels of reactive oxygen species (ROS). The flow cytometry analysis revealed that compound 12a could induce apoptosis and cell cycle arrest at G0/G1 phase in HeLa cells. In addition, mitochondrial bioenergetics assay revealed that 12a displayed mild mitochondrial uncoupling effect. Taken together, these findings suggest the therapeutic potential of compound 12a as an antitumor agent targeting mitochondria.

Degradation and detection of organophosphorus pesticides based on peptides and MXene-peptide composite materials.

Safety problems caused by organophosphorus pesticide (OP) residues are constantly occurring, so the development of new methods for the degradation and detection of OPs is of great scientific significance. In the present study, ß-sheet peptides and ß-hairpin peptides for catalyzing the hydrolysis of OPs were designed and synthesized. The peptide sequences with the highest hydrolytic activity (EHSGGVTVDPPLTVEHSAG) were screened by investigating the effect of the location of the active sites of the peptide and the peptide's structure on the degradation of OPs. In addition, the relationship between the peptides' conformation and hydrolytic activity was further analyzed based on density functional theory calculations. The noncovalent interactions of the peptides with the OPs and the electrostatic potential on the molecular surface and molecular docking properties were also investigated. It was found that peptides with approximate active amino acids consisting of the catalytic triad and with the hairpin structure had enhanced hydrolytic activity toward the hydrolysis of OPs. To develop an electrochemical sensor technique to detect OPs, the conductive MXene (Ti3C2) material was first immobilized with a caffeic acid monolayer via enediol-metal complex chemistry and then bound with the ß-hairpin peptide (EHSGGVTVDPPLTVEHSAG) via carboxy-amine condensation chemistry between the -COOH of caffeic acid and the -NH2 of the peptide to prepare a MXene-peptide composite. Then, the prepared composite was modified on the surface of a glassy carbon electrode to construct an electrochemical sensor for the detection of OPs. The developed technique could be used to monitor OPs within 15 min with a two orders of linear working range and with a detection limit of 0.15 µM. Meanwhile, the sensor showed good reliability for the detection of OPs in real vegetables.

Serum Organophosphorus compound levels as a surrogate marker for severity assessment and management in Acute Organophosphorus Poisoning - A novel approach.

Organophosphorus (OP) compounds are the most extensively used pesticides' class worldwide; cause most self­poisoning deaths especially in India. Thus, it is utmost important for early identification and aggressive management of OP poisoning from the clinical perspective to prevent serious complications by using sophisticated LC-MS/MS approach. This was a prospective study involving 103 patients of OP cases admitted to Karnataka Institute of Medical Sciences from June 2022 to May 2023, based on the inclusion and exclusion criteria patients were subjected to study. On admission, venous blood was collected from patient with Malathion and Profenofos OP poisoning history and subjected to serum biomarker and to LC-MS/MS analysis. Out of the 103 patients, 68 patients consumed Profenofos (66%) and 35 patients consumed Malathion (34%). Pseudocholinesterase levels among the of OP cases revealed that the 33 patients had mild toxicity, 40 patients had moderate toxicity and 30 patients had severe toxicity of OP poisoning. Subsequently LC-MS/MS analysis showed that the results obtained are not in correlation with indirect serum marker pseudocholinesterase levels. On the other side, LC-MS/MS results are in correlation with the clinical outcome of the patients with respect to morbidity and mortality. Thus, LC-MS/MS approach to assess the OP levels in patients could be used as potential diagnostic and prognostic marker for the absolute quantification of OP compounds compared to indirect OP levels estimation.

A new approach to monitoring typical organophosphorus compounds (OPs) in environmental media: From database building to suspect screening.

Organophosphorus compounds (OPs) are widely used as flame retardants (FRs) and plasticizers, yet strategies for comprehensively screening of suspect OPs in environmental samples are still lacking. In this work, a neoteric, robust, and general suspect screening technique was developed to identify novel chemical exposures by use of ultra-high performance liquid chromatography-Q Exactive hybrid quadrupole-Orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). We firstly established a suspect chemical database which had 7,922 OPs with 4,686 molecular formulas, and then conducted suspect screening in n = 50 indoor dust samples, n = 76 sediment samples, and n = 111 water samples. By use of scoring criteria such as retention time prediction models, we successfully confirmed five compounds by comparison with their authentic standards, and prioritized three OPs candidates including a nitrogen/fluorine-containing compound, that is dimethyl {1H-indol-3-yl[3-(trifluoromethyl)anilino]methyl} phosphonate (DMITFMAMP). Given that the biodegradation half-life values in water (t1/2,w) of DMITFMAMP calculated by EPI Suite is 180 d, it is considered to be potentially persistent. This strategy shows promising potential in environmental pollution assessment, and can be expected to be widely used in future research.

Melatonin improves mouse oocyte quality from 2-ethylhexyl diphenyl phosphate-induced toxicity by enhancing mitochondrial function.

2-Ethylhexyl diphenyl phosphate (EHDPP) is a representative organophosphorus flame retardant (OPFR) that has garnered attention due to its widespread use and potential adverse effects. EHDPP exhibits cytotoxicity, genotoxicity, developmental toxicity, and endocrine disruption. However, the toxicity of EHDPP in mammalian oocytes and the underlying mechanisms remain poorly understood. Melatonin is a natural free radical scavenger that has demonstrated cytoprotective properties. In this study, we investigated the effect of EHDPP on mouse oocytes in vitro culture system and evaluated the rescue effect of melatonin on oocytes exposed to EHDPP. Our results indicated that EHDPP disrupted oocyte maturation, resulting in the majority of oocytes arrested at the metaphase I (MI) stage, accompanied by cytoskeletal damage and elevated levels of reactive oxygen species (ROS). Nevertheless, melatonin supplementation partially rescued EHDPP-induced mouse oocyte maturation impairment. Results of single-cell RNA sequencing (scRNA-seq) analysis elucidated potential mechanisms underlying these protective effects. According to the results of scRNA-seq, we conducted further tests and found that EHDPP primarily disrupts mitochondrial distribution and function, kinetochore-microtubule (K-MT) attachment, DNA damage, apoptosis, and histone modification, which were rescued upon the supplementation of melatonin. This study reveals the mechanisms of EHDPP on female reproduction and indicates the efficacy of melatonin as a therapeutic intervention for EHDPP-induced defects in mouse oocytes.

Toxicity comparison and risk assessment of two chlorinated organophosphate flame retardants (TCEP and TCPP) on Polypedates megacephalus tadpoles.

Tris(2-chloroethyl) phosphate (TCEP) and tris(1­chloro-2-propyl) phosphate (TCPP) are widely used as chlorinated organophosphate flame retardants (OPFRs) due to their fire-resistance capabilities. However, their extensive use has led to their permeation and pollution in aquatic environments. Using amphibians, which are non-model organisms, to test the toxic effects of OPFRs is relatively uncommon. This study examined the acute and chronic toxicity differences between TCEP and TCPP on Polypedates megacephalus tadpoles and evaluated the potential ecological risks to tadpoles in different aquatic environments using the risk quotient (RQ). In acute toxicity assay, the tadpole survival rates decreased with increased exposure time and concentrations, with TCEP exhibiting higher LC50 values than TCPP, at 305.5 mg/L and 70 mg/L, respectively. In the chronic assay, prolonged exposure to 300 µg/L of both substances resulted in similar adverse effects on tadpole growth, metamorphosis, and hepatic antioxidant function. Based on RQ values, most aquatic environments did not pose an ecological risk to tadpoles. However, the analysis showed that wastewater presented higher risks than rivers and drinking water, and TCPP posed a higher potential risk than TCEP in all examined aquatic environments. These findings provide empirical evidence to comprehend the toxicological effects of OPFRs on aquatic organisms and to assess the safety of aquatic environments.