Acute exposure to tris(2,4-di-tert-butylphenyl)phosphate elicits cardiotoxicity in zebrafish (Danio rerio) larvae via inducing ferroptosis.

Tris(2,4-di-tert-butylphenyl)phosphate (AO168 =O), a novel organophosphate ester, is prevalent and abundant in the environment, posing great exposure risks to ecological and public health. Nevertheless, the toxicological effects of AO168 =O remain entirely unknown to date. The results in this study indicated that acute exposure to AO168 =O at 10 and 100 µg/L for 5 days obviously impaired cardiac morphology and function of zebrafish larvae, as proofed by decreased heartbeat, stroke volume, and cardiac output and the occurrence of pericardial edema and ventricular hypertrophy. Transcriptomics, polymerase chain reaction, and molecular docking revealed that the strong interaction of AO168 =O and transferrin receptor 1 activated the transportation of ferric iron into intracellular environment. The release of free ferrous ion to cytoplasmic iron pool also contributed to the iron overload in heart region, thus inducing ferroptosis in larvae via generation of excessive reactive oxygen species, glutathione peroxidase 4 inhibition, glutathione depletion and lipid peroxidation. Ferroptosis inhibitor (Fer-1) co-exposure effectively relieved the cardiac dysfunctions of zebrafish, verifying the dominant role of ferroptosis in the cardiotoxicity caused by AO168 =O. This research firstly reported the adverse impact and associated mechanisms of AO168 =O in cardiomyogenesis of vertebrates, underlining the urgency of concerning the health risks of AO168 =O.

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.

Elevated intracellular Ca2+ functions downstream of mitodysfunction to induce Wallerian-like degeneration and necroptosis in organophosphorus-induced delayed neuropathy.

Neurotoxic organophosphorus compounds can induce a type of delayed neuropathy in humans and sensitive animals, known as organophosphorus-induced delayed neuropathy (OPIDN). OPIDN is characterized by axonal degeneration akin to Wallerian-like degeneration, which is thought to be caused by increased intra-axonal Ca2+ concentrations. This study was designed to investigate that deregulated cytosolic Ca2+ may function downstream of mitodysfunction in activating Wallerian-like degeneration and necroptosis in OPIDN. Adult hens were administrated a single dosage of 750 mg/kg tri-ortho-cresyl phosphate (TOCP), and then sacrificed at 1 day, 5 day, 10 day and 21 day post-exposure, respectively. Sciatic nerves and spinal cords were examined for pathological changes and proteins expression related to Wallerian-like degeneration and necroptosis. In vitro experiments using differentiated neuro-2a (N2a) cells were conducted to investigate the relationship among mitochondrial dysfunction, Ca2+ influx, axonal degeneration, and necroptosis. The cells were co-administered with the Ca2+-chelator BAPTA-AM, the TRPA1 channel inhibitor HC030031, the RIPK1 inhibitor Necrostatin-1, and the mitochondrial-targeted antioxidant MitoQ along with TOCP. Results demonstrated an increase in cytosolic calcium concentration and key proteins associated with Wallerian degeneration and necroptosis in both in vivo and in vitro models after TOCP exposure. Moreover, co-administration with BATPA-AM or HC030031 significantly attenuated the loss of NMNAT2 and STMN2 in N2a cells, as well as the upregulation of SARM1, RIPK1 and p-MLKL. In contrast, Necrostatin-1 treatment only inhibited the TOCP-induced elevation of p-MLKL. Notably, pharmacological protection of mitochondrial function with MitoQ effectively alleviated the increase in intracellular Ca2+ following TOCP and mitigated axonal degeneration and necroptosis in N2a cells, supporting mitochondrial dysfunction as an upstream event of the intracellular Ca2+ imbalance and neuronal damage in OPIDN. These findings suggest that mitochondrial dysfunction post-TOCP intoxication leads to an elevated intracellular Ca2+ concentration, which plays a pivotal role in the initiation and development of OPIDN through inducing SARM1-mediated axonal degeneration and activating the necroptotic signaling pathway.

The mitochondria-targeted antioxidant MitoQ ameliorates inorganic arsenic-induced DCs/Th1/Th2/Th17/Treg differentiation partially by activating PINK1-mediated mitophagy in murine liver.

Inorganic arsenic is a well-established environmental toxicant linked to acute liver injury, fibrosis, and cancer. While oxidative stress, pyroptosis, and ferroptosis are known contributors, the role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in arsenic-induced hepatic immunotoxicity remains underexplored. Our study revealed that acute arsenic exposure prompts differentiation of hepatic dendritic cells (DCs) and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells, alongside increased transcription factors and cytokines. Inorganic arsenic triggered liver redox imbalance, leading to elevated alanine transaminase (ALT), hydrogen peroxide (H2O2), malondialdehyde (MDA), and activation of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway. PINK1-mediated mitophagy was initiated, and its inhibition exacerbates H2O2 accumulation while promoting DCs/Th1/Th2/Treg differentiation in the liver of arsenic-exposed mice. Mitoquinone (MitoQ) pretreatment relieved arsenic-induced acute liver injury and immune imbalance by activating Nrf2/HO-1 and PINK1-mediated mitophagy. To our knowledge, this is the first report identifying PINK1-mediated mitophagy as a protective factor against inorganic arsenic-induced hepatic DCs/Th1/Th2 differentiation. This study has provided new insights on the immunotoxicity of inorganic arsenic and established a foundation for exploring preventive and therapeutic strategies targeting PINK1-mediated mitophagy in acute liver injury. Consequently, the application of mitochondrial antioxidant MitoQ may offer a promising treatment for the metalloid-induced acute liver injury.

Potential adverse outcome pathway of neurodevelopmental toxicity, inflammatory response, and oxidative stress induction mediated by three alkyl organophosphate flame retardants in zebrafish larvae.

Following restrictions on polybrominated flame retardants, trimethyl phosphate (TMP), triethyl phosphate (TEP), and tris(2-butoxyethyl) phosphate (TBEP) have been frequently used as plasticizers for fire-resistant plastics. This study investigated the neurodevelopmental effects, inflammatory response, and oxidative stress induction of three alkyl organophosphate flame retardants using a zebrafish embryo/larvae model. After exposure of zebrafish embryos to TMP, TEP, and TBEP (0, 0.02, 0.2, 2, 20, and 200 µg L-1) for 96 h, survival, development, swimming behavior, changes in acetylcholinesterase (AChE) activity, dopamine, tumor necrosis factor-alpha (TNF-α), interleukin (IL), reactive oxygen species (ROS), and antioxidant enzyme activities were observed. Concentrations of TMP, TEP, and TBEP were also measured in the whole body of exposed larvae. Our results showed that exposure to 200 µg L-1 TEP and ≥20 µg L-1 TBEP significantly reduced larval body length; however, TMP had no significant effects on developmental parameters up to 200 µg L-1. After 96 h of exposure to TBEP, total distance moved, mean velocity, AChE, and dopamine concentrations were significantly decreased. Exposure to TEP and TBEP decreased the expression of genes that regulate central nervous system development (e.g. gap43 and mbpa), whereas ROS, antioxidant enzymes, TNF-α, and IL-1ß concentrations were significantly increased. Notably, pretreatment with an antioxidant N-acetylcysteine reduced neurotoxicity and oxidative stress caused by TEP and TBEP. The results of this study demonstrated that exposure to TEP and TBEP causes oxidative stress and has adverse effects on the neurobehavioral and immune system of zebrafish, leading to hypoactivity and ultimately impairing development.

[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).

Evaluation of organophosphorus pesticide tyrosine adducts for postmortem change by human serum albumin with liquid chromatography quadrupole Orbitrap mass spectrometry.

Organophosphorus pesticides (OPPs) having a phosphate ester moiety, such as malathion (MA) and methidathion (DMTP), are widely used and have been detected in many fatal cases of accidental exposure or suicide in Japan. In forensic toxicology, the accurate determination of blood OPP concentration is mandatory to prove death by OPP poisoning. However, fatal pesticide concentration in blood at autopsy varies depending on the circumstances surrounding the dead body. In this study, we found that 16 OPPs were degraded by human serum albumin (HSA) in a temperature-dependent fashion. The mechanism underlying MA, DMTP, azinphos-methyl, etrimfos, fenthion (MPP), pirimiphos-methyl, (E)-dimethylvinphos, (Z)-dimethylvinphos, vamidothion, edifenphos (EDDP), fosthiazate, and pyraclofos degradation involves the formation of adducts with tyrosine residues in HSA. The mass spectra obtained by liquid chromatography quadrupole Orbitrap mass spectrometry revealed that phosphate ester amino acid adducts such as Y-adduct1, Y-adduct2, Y-adduct3, Y-adduct4, and Y-adduct5 were formed in HSA solution incubated with OPPs. These results indicate that the 16 OPPs are postmortem changed by HSA. The detection of phosphate ester amino acid adducts such as Y-adduct1, Y-adduct2, Y-adduct3, Y-adduct4, and Y-adduct5, instead of MA, DMTP, azinphos-methyl, etrimfos, MPP, pirimiphos-methyl, (E)-dimethylvinphos, (Z)-dimethylvinphos, vamidothion, EDDP, fosthiazate, and pyraclofos per se, may be used to determine death by these OPPs poisoning.

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.

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.

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.

Unlocking the interaction of organophosphorus pesticide residues with ecosystem: Toxicity and bioremediation.

Organophosphorus adulteration in the environment creates terrestrial and aquatic pollution. It causes acute and subacute toxicity in plants, humans, insects, and animals. Due to the excessive use of organophosphorus pesticides, there is a need to develop environmentally friendly, economical, and bio-based strategies. The microbiomes, that exist in the soil, can reduce the devastating effects of organophosphates. The use of cell-free enzymes and yeast is also an advanced method for the degradation of organophosphates. Plant-friendly bacterial strains, that exist in the soil, can help to degrade these contaminants by oxidation-reduction reactions, enzymatic breakdown, and adsorption. The bacterial strains mostly from the genus Bacillus, Pseudomonas, Acinetobacter, Agrobacterium, and Rhizobium have the ability to hydrolyze the bonds of organophosphate compounds like profenofos, quinalphos, malathion, methyl-parathion, and chlorpyrifos. The native bacterial strains also promote the growth abilities of plants and help in detoxification of organophosphate residues. This bioremediation technique is easy to use, relatively cost-effective, very efficient, and ensures the safety of the environment. This review covers the literature gap by describing the major effects of organophosphates on the ecosystem and their bioremediation by using native bacterial strains.

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.

A single post-exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides.

Millions of individuals globally suffer from inadvertent, occupational or self-harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP-inhibited AChE. However, animal model studies and recent clinical trials using insecticide-poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood-brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP-inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post-exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1-2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non-invasive treatment, especially in isolated rural settings.