Organophosphate toxicity patterns: A new approach for assessing organophosphate neurotoxicity.

Organophosphorus compounds or organophosphates (OPs) are widely used as flame retardants, plasticizers, lubricants and pesticides. This contributes to their ubiquitous presence in the environment and to the risk of human exposure. The persistence of OPs and their bioaccumulative characteristics raise serious concerns regarding environmental and human health impacts. To address the need for safer OPs, this study uses a New Approach Method (NAM) to analyze the neurotoxicity pattern of 42 OPs. The NAM consists of a 4-step process that combines computational modeling with in vitro and in vivo experimental studies. Using spherical harmonic-based cluster analysis, the OPs were grouped into four main clusters. Experimental data and quantitative structure-activity relationships (QSARs) analysis were used in conjunction to provide information on the neurotoxicity profile of each group. Results showed that one of the identified clusters had a favorable safety profile, which may help identify safer OPs for industrial applications. In addition, the 3D-computational analysis of each cluster was used to identify meta-molecules with specific 3D features. Toxicity was found to correspond to the level of phosphate surface accessibility. Substances with conformations that minimize phosphate surface accessibility caused less neurotoxic effect. This multi-assay NAM could be used as a guide for the classification of OP toxicity, helping to minimize the health and environmental impacts of OPs, and providing rapid support to the chemical regulators, whilst reducing reliance on animal testing.

[Research progress on pollution status and toxic effects of organophosphorus flame retardants 2-ethylhexyl diphenyl phosphate].

The environmental pollution and health hazards caused by the extensive use of organophosphorus flame retardants (OPFRs) have become a problem of wide concern around the world. As a typical OPFR, 2-ethylhexyl diphenyl phosphate (EHDPP) can be detected in water, atmosphere, soil and other environmental media. It widely exists in production and life and can accumulate in organisms, causing great risks the ecosystem and human health. This paper reviews the research of EHDPP domestically and abroad, and summarizes the physicochemical properties of EHDPP and the population situation of occupational exposure, environmental exposure, and population exposure in recent years. Besides, it summarizes the toxic effects and mechanisms of EHDPP, including acute toxicity, hepatotoxicity, neurotoxicity, reproductive and developmental toxicity, and carcinogenesis effects. This paper also proposes the future direction of toxicity and health risks of EHDPP, which provides a theoretical basis for further research on environmental hazards and safety evaluation of EHDPP.

Actinomycetota, a central constituent microbe during long-term exposure to diazinon, an organophosphorus insecticide.

Microbial biodegradation is a primary pesticide remediation pathway. Despite diazinon is one of the most frequently used organophosphate insecticides worldwide, its effect on soil microbial community remains obscure. We hypothesize that diazinon exposure reshapes microbial community, among them increased microbes may play a crucial role in diazinon degradation. To investigate this, we collected soil from an organic farming environment, introduced diazinon, cultivated it in a greenhouse, and then assessed its effects on soil microbiomes at three distinct time points: 20, 40, and 270 days after treatment (DAT). Results from HPLC showed that the level of diazinon was gradually degraded by 98.8% at 270 DAT when compared with day zero, whereas 16S rRNA gene analysis exhibited a significant reduction in the bacterial diversity, especially at the early two time points, indicating that diazinon may exert selection pressure to the bacteria community. Here, the relative abundance of phylum Actinomycetota increased at 20 and 40 DATs. In addition, the bacterial functional gene profile employing PICRUSt2 prediction also revealed that diazinon exposure induced the genomic function related to xenobiotics biodegradation and metabolism in soil, such as CYB5B, hpaC, acrR, and ppkA. To validate if bacterial function is caused by increased relative abundance in diazinon enriched soil, further bacteria isolation resulted in obtaining 25 diazinon degradation strains out of 103 isolates. Notably, more than 70% (18 out of 25) isolates are identified as phylum Actinomycetota, which empirically confirms and correlates microbiome and PICRUSt2 results. In conclusion, this study provides comprehensive information from microbiome analysis to obtaining several bacteria isolates responsible for diazinon degradation, revealing that the phylum Actinomycetota is as a key taxon that facilitates microbial biodegradation in diazinon spoiled soil. This finding may assist in developing a strategy for microbial detoxification of diazinon, such as using an Actinomycetota rich synthetic community (SynCom).

Recent advances in sensing toxic nerve agents through DMMP model simulant using diverse nanomaterials-based chemical sensors.

Recent terrorist assaults have demonstrated the need for the exploration and design of sustainable and stable chemical sensors with quick reaction times combined with great sensitivity. Among several classes of chemical warfare agents, nerve agents have been proven to be the most hazardous. Even short-term exposure to them can result in severe toxic effects. Human beings inadvertently face the after-effects of these chemicals even several years after these chemicals were used. Due to the extreme toxicity and difficulty in handling, dimethyl methylphosphonate (DMMP), a simulant of nerve agents with much lesser toxicity, is frequently used in laboratories as a substitute. Having a chemical structure almost identical to those of nerve agents, DMMP can mimic the properties of nerve agents. Through this paper, authors have attempted to introduce the evolution of several chemical sensors used to detect DMMP in recent years, including field-effect transistors, chemicapacitors, chemiresistors, and mass-sensitive sensors. A detailed discussion of the role of nanomaterials as chemical sensors in the detection of DMMP has been the main focus of the work through a comprehensive overview of the research on gas sensors that have been reported making use of the properties of a wide range of nanomaterials.

Do the same chlorinated organophosphorus flame retardants that cause cytotoxicity and DNA damage share the same pathway?

Organophosphorus flame retardants (OPFRs) have been frequently detected with relatively high concentrations in various environmental media and are considered emerging environmental pollutants. However, their biological effect and underlying mechanism is still unclear, and whether chlorinated OPFRs (Cl-OPFRs) cause adverse outcomes with the same molecular initial events or share the same key events (KEs) remains unknown. In this study, in vitro bioassays were conducted to analyze the cytotoxicity, mitochondrial impairment, DNA damage and molecular mechanisms of two Cl-OPFRs. The results showed that these two Cl-OPFRs, which have similar structures, induced severe cellular and molecular damages via different underlying mechanisms. Both tris(2-chloroethyl) phosphate (TCEP) and tris(1-chloro-2-propyl) (TCPP) induced oxidative stress-mediated mitochondrial impairment and DNA damage, as shown by the overproduction of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. Furthermore, the DNA damage caused by TCPP resulted in p53/p21-mediated cell cycle arrest, as evidenced by flow cytometry and real-time PCR. At the cellular and molecular levels, TCPP increased the sub-G1 apoptotic peak and upregulated the p53/Bax apoptosis pathway, possibly resulted in apoptosis associated with its stronger cytotoxicity. Although structurally similar to TCPP, TCEP did not induce mitochondrial impairment and DNA damage by the same KEs. These results provide insight into the toxicity of Cl-OPFRs with similar structures but different mechanisms, which is of great significance for constructing adverse outcome pathways or determining intermediate KEs.

The neurotoxicity of organophosphorus flame retardant tris (1,3-dichloro-2-propyl) phosphate (TDCPP): Main effects and its underlying mechanisms.

As a major alternative to the brominated flame retardants, the production and use of organophosphorus flame retardants (OPFRs) are increasing. And tris (1,3-dichloro-2-propyl) phosphate (TDCPP), one of the most widely used OPFRs, is now commonly found in a variety of products, such as building materials, furniture, bedding, electronic equipment, and baby products. TDCPP does not readily degrade in the water and tends to accumulate continuously in the environment. It has been detected in indoor dust, air, water, soil, and human samples. Considered as an emerging environmental pollutant, increasing studies have demonstrated its adverse effects on environmental organisms and human beings, with the nerve system identified as a sensitive target organ. This paper systematically summarized the progress of TDCPP application and its current exposure in the environment, with a focus on its neurotoxicity. In particular, we highlighted that TDCPP can be neurotoxic (including neurodevelopmentally toxic) to humans and animals, primarily through oxidative stress, neuroinflammation, mitochondrial damage, and epigenetic regulation. Additionally, this paper provided an outlook for further studies on neurotoxicity of TDCPP, as well as offered scientific evidence and clues for rational application of TDCPP in daily life and the prevention and control of its environmental impact in the future.

Behavioral toxicity of TDCPP in marine zooplankton: Evidence from feeding and swimming responses, molecular dynamics and metabolomics of rotifers.

As new organic flame retardants, chlorinated organophosphate esters (Cl-OPEs) have high water solubility and structural similarity to organophosphate pesticides, posing risks to aquatic organisms. The potential neurotoxicity of Cl-OPEs has attracted attention, especially in marine invertebrates with a relatively simple nervous system. In this study, a marine rotifer with a cerebral ganglion, Brachionus plicatilis, was exposed to tris (1,3-dichloro-2-propyl) phosphate (TDCPP) (two environmental concentrations and one extreme level), and the changes in feeding and swimming behaviors and internal mechanism were explored. Exposure to 1.05 nM TDCPP did not change the filtration and ingestion rates of rotifers and average linear velocity. But 0.42 and 4.20 µM TDCPP inhibited these three parameters and reduced unsaturated fatty acid content, reproduction and population growth. All TDCPP test concentrations suppressed AChE activity, causing excessive accumulation of acetylcholine within rotifers, thereby disturbing the neural innervation of corona cilia. Molecular docking and molecular dynamics revealed that this inhibition was because TDCPP can bind to the catalytic active site of rotifer AChE through van der Waals forces and electrostatic interactions. TRP420 was the leading amino residue in the binding, and GLY207 contributed to a hydrogen bond. Nontargeted metabolomics using LC-MS and GC-MS identified differentially expressed metabolites in TDCPP treatments, mainly from lipid and lipid-like molecules, especially sphingolipids. TDCPP decreased ganglioside content but stimulated ceramide generation and the expression levels of 3 genes related to ceramide de novo synthesis. The mitochondrial membrane potential (MMP) and ATP content decreased, and the electron respiratory chain complex and TCA cycle were deactivated. An inhibitor of ceramide synthase, fumonisin, alleviated MMP and ATP, implying a critical role of ceramide in mitochondrial dysfunction. Thus, TDCPP exposure caused an energy supply deficit affecting ciliary movement and ultimately inhibiting rotifer behaviors. Overall, this study promotes the understanding of the neurotoxicity of Cl-OPEs in marine invertebrates.

Chronic exposure to tris (2-chloroethyl) phosphate (TCEP) induces brain structural and functional changes in zebrafish (Danio rerio): A comparative study on the environmental and LC50 concentrations of TCEP.

Tris (2-chloroethyl) phosphate (TCEP) is a crucial organophosphorus flame retardant widely used in many industrial and commercial products. Available reports reported that TCEP could cause various toxicological effects on organisms, including humans. Unfortunately, toxicity data for TCEP (particularly on neurotoxicity) on aquatic organisms are lacking. In the present study, Danio rerio were exposed to different concentrations of TCEP for 42 days (chronic exposure), and oxidative stress, neurotoxicity, sodium, potassium-adenosine triphosphatase (Na+, K+-ATPase) activity, and histopathological changes were evaluated in the brain. The results showed that TCEP (100 and 1500 µg L-1) induced oxidative stress and significantly decreased the activities of antioxidant enzymes (SOD, CAT and GR) in the brain tissue of zebrafish. In contrast, the lipid peroxidation (LPO) level was increased compared to the control group. Exposure to TCEP inhibited the acetylcholinesterase (AChE) and Na+,K+-ATPase activities in the brain tissue. Brain histopathology after 42 days of exposure to TCEP showed cytoplasmic vacuolation, inflammatory cell infiltration, degenerated neurons, degenerated purkinje cells and binucleate. Furthermore, TCEP exposure leads to significant changes in dopamine and 5-HT levels in the brain of zebrafish. The data in the present study suggest that high concentrations of TCEP might affect the fish by altering oxidative balance and inducing marked pathological changes in the brain of zebrafish. These findings indicate that chronic exposure to TCEP may cause a neurotoxic effect in zebrafish.

Human blood markers of cholinergic neurotoxicity and neuropathy: A useful guide for laboratory applications.

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are useful markers to assess the effects of exposure to anticholinesterase insecticides (Anti-AChE). In addition, lymphocyte neuropathy target esterase (LNTE) has been used as biomarker of neuropathic organophosphate compounds (OPs). Thus, this study evaluates the main types of circulating biomarkers related to the cholinergic system and to the neuropathy induced by OPs in standardized human samples. To achieve this objective, total protein of human plasma, erythrocytes and lymphocytes were first standardized, and then AChE, BChE and LNTE activities in human blood were evaluated in the presence of inhibitors. The acceptance criteria of the regulatory agency were respected with coefficients of regression of curves of 0.9972 for cholinesterase and 0.9956 for LNTE analyses. The wavelength established to perform cholinesterase assay was 450 nm and the time of incubation of the enzymes with inhibitors was 30 min. Differences were observed among the IC50 values regarding the in vitro inhibition of AChE, BChE and LNTE in the presence of OPs. In conclusion, the procedures demonstrated by the present work were simple, fast, inexpensive, sensitive, easy to be replicated and suitable to make conclusions about the neurotoxicity induced by Anti-AChE and neuropathic OPs.

The phosphylated butyrylcholinesterase-derived tetrapeptide GlyGluSerAla proves exposure to organophosphorus agents with enantioselectivity.

We herein present for the first time the phosphylated (*) tetrapeptide (TP)-adduct GlyGluSer198*Ala generated from butyrylcholinesterase (BChE) with proteinase K excellently suited for the verification of exposure to toxic organophosphorus nerve agents (OPNA). Verification requires bioanalytical methods mandatory for toxicological and legal reasons. OPNA react with BChE by phosphonylation of the active site serine residue (Ser198) forming one of the major target protein adducts for verification. After its enzymatic cleavage with pepsin, the nonapeptide (NP) PheGlyGluSer*AlaGlyAlaAlaSer is typically produced as biomarker. Usually OPNA occur as racemic mixtures of phosphonic acid derivatives with the stereocenter at the phosphorus atom, e.g. (±)-VX. Both enantiomers react with BChE, but the adducted NP does not allow their chromatographic distinction. In contrast, the herein introduced TP-adducts appeared as two peaks when using a stationary reversed phase (1.8 µm) in micro-liquid chromatography-electrospray ionisation tandem-mass spectrometry (µLC-ESI MS/MS) analysis. These two peaks represent diastereomers of the (+)- and (-)-OPNA adducted to the peptide that comprises chiral L-amino acids exclusively. Concentration- and time-dependent effects of adduct formation with (±)-VX and its pure enantiomers (+)- and (-)-VX as well as with (±)-cyclosarin (GF) were investigated in detail characterising enantioselective adduct formation, stability, ageing and spontaneous reactivation. The method was also successfully applied to samples from a real case of pesticide poisoning as well as to samples of biomedical proficiency tests provided by the Organisation for the Prohibition of Chemical Weapons.

Ecological risk assessment for typical organophosphorus pesticides in surface water of China based on a species sensitivity distribution model.

The ecological risks posed by widespread organophosphorus pesticide (OPs) pollution in the surface waters of China remain unclear. In this study, species sensitivity distribution (SSD) parametric statistical approaches were coupled with fully acute and chronic toxicity data to fit the sensitivity distributions of different aquatic species to five typical OPs: dimethoate, malathion, parathion-methyl, trichlorfon, and dichlorvos. Crustaceans exhibit the highest sensitivity to OPs, whereas algae are the least sensitive. The acute hazardous concentrations that affected 5 % of the species (HC5) were 0.112, 0.001, 0.001, 0.001, and 0.001 mg/L for dimethoate, malathion, parathion-methyl, trichlorfon, and dichlorvos, respectively, whereas their chronic HC5 values were 0.004, 0.004, 0.053, 0.001, and 0.0005 mg/L, respectively. Hence, dichlorvos is highly toxic and poses greater risk to non-target aquatic species. The evaluation data revealed varying geographical distribution characteristics of the ecological risks from OPs in 15 freshwater aquatic systems across different regions of China. Dichlorvos posed the highest risk in the basins of Zhejiang and Guangdong Provinces, with the highest chronic Risk Quotient (RQ) and Hazard Index (HI) at 9.34 and 9.92, respectively. This is much higher than what was collected and evaluated for foreign rivers (the highest chronic RQ and HI in foreign rivers were 1.65 and 2.24, respectively). Thus, dichlorvos in the surface waters of China poses a substantial ecological risk to aquatic organisms, and may endanger human health.

Astaxanthin activates the Nrf2/Keap1/HO-1 pathway to inhibit oxidative stress and ferroptosis, reducing triphenyl phosphate (TPhP)-induced neurodevelopmental toxicity.

Triphenyl phosphate (TPhP) serves as a major organophosphorus flame retardant, and its induced neurodevelopmental toxicity has attracted widespread attention, but the mechanism remains unclear. In this study, we involved zebrafish to explore the new mechanism of TPhP inducing oxidative stress and ferroptosis to promote neurodevelopmental toxicity. The results suggested that TPhP affected the embryonic development, reduced the number of new neurons, and led to abnormal neural behavior in zebrafish larvae. TPhP also induced ROS accumulation, activated the antioxidant defense signal Nrf2 and Keap1, and significantly changed the activities of Acetylcholinesterase (AChE), Adenosine triphosphatase (ATPase) and glutathione S-transferase (GST). In addition, TPhP induced ferroptosis in zebrafish, which was reflected in the increase of Fe2+ content, the abnormal expression of GPX4 protein and genes related to iron metabolism (gpx4a, slc7a11, acsl4b, tfa, slc40a1, fth1b, tfr2, tfr1a, tfr1b and ncoa4). Astaxanthin intervention specifically inhibited ROS levels, and reversed SLC7A11 and GPX4 expression levels and Fe2+ metabolism thus alleviating ferroptosis induced by TPhP. Astaxanthin also partially reversed the activity of AChE, GST and the expression of neurodevelopmental-related genes (gap43, gfap, neurog1 and syn2a), so as to partially rescue the embryonic developmental abnormalities and motor behavior disorders induced by TPhP. More interestingly, the expression of mitochondrial apoptosis-related protein BAX, anti-apoptotic protein BCL-2, Caspase3 and Caspase9 was significantly altered in the TPhP exposed group, which could be also reversed by Astaxanthin intervention. In summary, our results suggested that TPhP exposure can induce oxidative stress and ferroptosis, thereby causing neurodevelopment toxicity to zebrafish, while Astaxanthin can partially reverse oxidative stress and reduce the neurodevelopmental toxicity of zebrafish larvae by activating Nrf2/Keap1/HO-1 signaling pathway.

A quantitative proteomic study reveals oxidative stress and synapse-related proteins contributed to TDCIPP exposure induced neurotoxicity.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been consistently identified in various environmental media and biological specimens. Current understanding of the in vivo toxicities of TDCIPP is limited, especially for potential for neurotoxic and cognitive impairment effects. To better evaluate the potential adverse effect of the chemical on learning and memory, Sprague Dawley (SD) rats were administered TDCIPP via gavage at doses of 40, 120, and 360 mg/kg/day for a period of 90 days. Quantitative proteomic analysis, immunohistochemistry, and Western blotting were employed to assess alterations in proteins following exposure to TDCIPP. An open field test and the Morris Water Maze were used to assess anxiety and spatial learning memory capacity. Administration of TDCIPP induced anxiety and cognitive impairments in rats. Additionally, a noteworthy decrease in the number of neurons was observed in the hippocampal CA3 and dentate gyrus (DG) regions. Proteomic and bioinformatic analyses revealed dysregulation of numerous hippocampal proteins, particularly those associated with synapses (PKN1) or oxidative stress (GSTM4, NQO1, and BMAL1), which was further confirmed by Western blot analysis. In sum, the cognitive impairment of rats caused by TDCIPP exposure was associated with dysregulation of synaptic and oxidative stress-related proteins.

Prenatal and childhood exposure to organophosphate pesticides and functional brain imaging in young adults.

BACKGROUND: Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years. METHODS: We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language. RESULTS: There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (ß per ten-fold increase in DAPs = 3.37; 95% CI: -0.02, 6.77 and ß = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (ß = -3.10; 95% CI: -6.43, 0.22 and ß = -3.67; 95% CI: -7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task. DISCUSSION: We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts.

Non-negligible vector effect of micro(nano)plastics on tris(1,3-dichloro-2-propyl) phosphate in zebrafish quantified by toxicokinetic model.

Micro(nano)plastics (MNPs) inevitably interact with coexisting contaminants and can act as vectors to affect their fate in organisms. However, the quantitative contribution of MNPs in the in vivo bioaccumulation and distribution of their coexisting contaminants remains unclear. Here, by selecting tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) as the typical coexisting contaminant, we quantified the contribution of MNPs to bioaccumulation and distribution of TDCIPP with toxicokinetic models. Results indicated that MNPs differentially facilitated TDCIPP bioaccumulation and distribution, and NPs slowed down TDCIPP depuration more significantly than MPs. Model analysis further revealed increasing contributions of MNPs to whole-fish TDCIPP bioaccumulation over time, with NPs (33-42%) contributing more than MPs (12-32%) at 48 h exposure. NPs contributed more than MPs to TDCIPP distribution in the liver (13-19% for MPs; 36-52% for NPs) and carcass (24-45% for MPs; 57-71% for NPs). The size-dependent vector effect might be attributed to the fact that MNPs promote contaminant transfer by damaging biofilm structure and increasing tissue membrane permeability, with NPs exerting stronger effects. This work demonstrated the effectiveness of using modeling tools to understand the relative importance of MNPs as contaminant vectors in the TK process and highlighted the higher contaminant transfer potential of NPs under combined exposure scenarios.

AChE reactivation in precision-cut lung slices following organophosphorus compound poisoning.

Precision-cut lung slices (PCLS) are a suitable model for analyzing the acetylcholinesterase (AChE) activity and subsequent effects after exposure to organophosphorus (OP) compounds. In this study, the AChE activity was determined in intact PCLS for the first time. Since the current standard therapy for OP poisoning (atropine + oxime + benzodiazepine) lacks efficiency, reliable models to study novel therapeutic substances are needed. Models should depict pathophysiological mechanisms and help to evaluate the beneficial effects of new therapeutics. Here PCLS were exposed to three organophosphorus nerve agents (OPNAs): sarin (GB), cyclosarin (GF), and VX. They were then treated with three reactivators: HI-6, obidoxime (OBI), and a non-oxime (NOX-6). The endpoints investigated in this study were the AChE activity and the airway area (AA) change. OPNA exposure led to very low residual AChE activities. Depending on the reactivator properties different AChE reactivation results were measured. GB-inhibited PCLS-AChE was reactivated best, followed by VX and GF. To substantiate these findings and to understand the connection between the molecular and the functional levels in a more profound way the results were correlated to the AA changes. These investigations underline the importance of reactivator use and point to the possibilities for future improvements in the treatment of OPNA-exposed victims.

Organophosphorus flame retardants and their metabolites in paired human blood and urine.

Organophosphorus flame retardants (OPFRs) have been shown to be carcinogenic, neurotoxic, and endocrine disruptive, so it is important to understand the levels of OPFRs in human body as well as the modes of external exposure. In this study, we investigated the levels of 13 OPFRs and 7 phosphodiester metabolites in paired human blood and urine, as well as the influencing factors (region, age and gender), and studied the relationship between OPFRs and oxidative stress by urinary metabolites. We found that the concentrations of triphenyl phosphate (TPhP) and tris-(2-ethylhexyl) phosphate (TEHP) in the blood of urban populations were higher than those of rural populations, and that younger populations suffered higher TPhP and 2-ethylhexyl diphenyl phosphate (EHDPP) exposures than older populations. In addition, we found that tris-(2-chloroethyl) phosphate (TCEP), tributyl phosphate (TnBP), TPhP and EHDPP exposure induced oxidative stress. The results of the internal load principal component analysis indicated that dust ingestion, skin exposure, respiration and dietary intake may be the most important sources of TCEP, tris(2-butoxyethyl) phosphate (TBOEP), tri(2-chloroisopropyl) phosphate (TCIPP) and TEHP, respectively, and dust ingestion and skin exposure may be the main sources of TPhP for humans.

Organophosphorus poisoning induced delayed neurotoxicity: a report of two cases.

INTRODUCTION: Organophosphorus compounds (OPC) are one of the most commonly used pesticides worldwide and are often misused for suicidal poisoning due to their easy availability. Acute manifestations and management of organophosphorus (OP) poisoning have been reported several times. Organophosphorus-induced delayed neurotoxicity (OPIDN) is a rare delayed presentation of OP poisoning that involves central-peripheral distal axonopathy. CASE PRESENTATION: In this study, we report two cases of OPIDN developed after a few weeks of OP poisoning. Clinical features, electrodiagnostic study findings, and rehabilitative measures adopted for the patients and their follow-up have been described in the report. DISCUSSION: Organophosphorus (OP) poisoning may rarely produce features of delayed neurotoxicity, which may gradually appear after acute cholinergic symptoms. This report shows the importance of considering the delayed presentation of possible OPC toxicity in patients with neurological symptoms and a history of OPC exposure.

Role of voltage-dependent calcium channels on the striatal in vivo dopamine release induced by the organophosphorus pesticide glyphosate.

In the present study, we investigated the role of voltage-sensitive calcium channels (VSCCs) on the striatal dopamine release induced by the pesticide glyphosate (GLY) using selective VSCC inhibitors. The dopamine levels were measured by in vivo cerebral microdialysis coupled to HPLC-ED. Nicardipine (L-type VSCC antagonist) or ω-conotoxin MVIIC (non-selective P/Q-type antagonist) had no effect on dopamine release induced by 5 mM GLY. In contrast, flunarizine (T-type antagonist) or ω-conotoxin GVIA (neuronal N-type antagonist) significantly reduced GLY-stimulated dopamine release. These results suggest that GLY-induced dopamine release depends on extracellular calcium and its influx through the T- and N-type VSCCs. These findings were corroborated by molecular docking, which allowed us to establish a correlation between the effect of GLY on blocked VSCC with the observed dopamine release. We propose new molecular targets of GLY in the dorsal striatum, which could have important implications for the assessment of pesticide risks in non-target organisms.

The susceptibility of humans to neurodegenerative and neurodevelopmental toxicities caused by organophosphorus pesticides.

The toxicology field is concerned with the impact of organophosphorus (OP) compounds on human health. These compounds have been linked to an increased risk of neurological disorders, including neurodegenerative and neurodevelopmental diseases. This article aims to review studies on the role of OP compounds in developing these neurological disorders and explore how genetic variations can affect susceptibility to the neurotoxicity of these pesticides. Studies have shown that exposure to OP compounds can lead to the development of various neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD), autism, intellectual disability, and other developmental neurotoxicities. Apart from inhibiting the cholinesterase enzyme, OP compounds are believed to cause other pathological mechanisms at both the extracellular level (cholinergic, serotonergic, dopaminergic, glutamatergic, and GABAergic synapses) and the intracellular level (oxidative stress, mitochondrial dysfunction, inflammation, autophagy, and apoptosis) that contribute to these disorders. Specific genetic polymorphisms, including PON1, ABCB1, NOS, DRD4, GST, CYP, and APOE, have increased the risk of developing OP-related neurological disorders.