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Chlorfenapyr is a novel broad-spectrum insecticide derived from natural pyrrole derivatives produced by Streptomyces spp. It acts as a pro-insecticide and is metabolically converted to the active metabolite, tralopyril. Chlorfenapyr poisoning is known for its delayed neurological symptoms and high mortality. Unfortunately, information on the toxicokinetics, metabolism and tissue distribution of chlorfenapyr and tralopyril is still lacking. In this study, the metabolic profile, toxicokinetics and tissue distribution of chlorfenapyr and tralopyril after oral administration at a toxic dose in mice were investigated. Twenty metabolites were identified in plasma, urine and feces, which were mainly formed by dealkylation, oxidative dechlorination and reductive dechlorination. Toxicokinetic results showed that chlorfenapyr was rapidly converted to tralopyril after administration, and the in vivo half-life (t1/2), area under the curve (AUC) and peak concentration (Cmax) values of tralopyril were significantly higher than those of chlorfenapyr (P < 0.05). Tissue distribution experiments confirmed that the metabolite tralopyril had a longer half-life, a lower clearance and a wide distribution in different organs and tissues compared to chlorfenapyr. It was also able to cross the blood–brain barrier, suggesting a potential association with brain lesions. In addition, a sensitive and rapid LC–MS/MS analytical method was established for the detection of chlorfenapyr and tralopyril. In conclusion, this study provided valuable metabolic, toxicokinetic and tissue distribution information, contributing to future risk assessment and forensic identification in cases of chlorfenapyr poisoning. We recommend considering the assessment of tralopyril levels, which may be of greater therapeutic importance in the management of chlorfenapyr poisoning. [ABSTRACT FROM AUTHOR]

Tralopyril is a metabolite of the pesticide chlorfenapyr. Direct toxicity by tralopyril has not been described. We report two cases of tralopyril poisoning via inhalation. Two workers developed heat intolerance, diaphoresis, and weight loss after occupational inhalational exposure to tralopyril. Patient 1: The exposure was due to the absence of respiratory protection. Magnetic resonance imaging showed abnormal signals in the bilateral periventricular white matter, corpus callosum, basal ganglia, brainstem, and spinal cord. The patient's blood tralopyril concentrations on days 1, 3, 5, 8, and 11 post-admission were 1.09 mg/L, 1.04 mg/L, 1.01 mg/L, 0.71 mg/L, and 0.313 mg/L, respectively. Haemoperfusion (HA330), haemoperfusion (HA380), and haemodiafiltration were performed on days 1–3, 5–8, and 9–10, respectively. Patient 2: The patient's symptoms followed inappropriate use of respiratory protection. His blood tralopyril concentrations on days 1, 4, 5, and 6 were 0.592 mg/L, 0.482 mg/L, 0.370 mg/L, and 0.228 mg/L, respectively. The patients presented with features typical of chlorfenapyr poisoning, which suggests that tralopyril is the main toxic metabolite of chlorfenapyr. Tralopyril can be absorbed by inhalation, leading to delayed clinical symptoms and organ damage, including toxic encephalopathy and spinal cord damage. [ABSTRACT FROM AUTHOR]

Chlorfenapyr, a N-substituted halogenated pyrrole, is a broad-spectrum insecticide. The insecticidal activity of chlorfenapyr depends on its biotransformation by hepatic cytochrome P450 monooxygenases to tralopyril, which uncouples mitochondrial oxidative phosphorylation and disrupts adenosine triphosphate production. Neither the metabolism of chlorfenapyr nor the mechanism of tralopyril is completely elucidated. Acute human chlorfenapyr poisoning is not well characterized, and best practice in management following acute exposure is unclear. The purpose of this review is to characterize acute human chlorfenapyr poisoning by its clinical course, laboratory investigations, and imaging findings and propose a management plan for acute human chlorfenapyr exposure. We systematically searched PubMed, Web of Science, Google Scholar, and EMBASE from inception to April 2024 across all languages for human chlorfenapyr and tralopyril cases, with descriptions of exposure, clinical manifestations, and clinical course included. Only manuscripts and abstracts from scientific conferences with sufficient clinical data following acute human exposures were included. In vitro studies, animal studies, agricultural studies, environmental impact studies, and non-clinical human studies were excluded. We then reviewed citations of included studies for additional eligible publications. Non-English publications were translated using Google Translate or primarily translated by our authors. The study adhered to Preferred Reporting for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews. We identified 3,376 publications of which 48 met study inclusion criteria, describing 75 unique cases of human poisoning from ingestion, inhalation, dermal exposure, and intra-abdominal injection of chlorfenapyr. No cases of tralopyril exposure were identified. The median time from exposure to symptom onset was six hours (interquartile range 1–48 hours). The most frequent initial or presenting signs/symptoms included diaphoresis, nausea and/or vomiting, and altered mental status. While hyperthermia (≥38 degrees centigrade) was less common at presentation, hyperthermia developed in 61 percent of all patients and was temporally associated with clinical deterioration and death. Most common laboratory abnormalities included elevated blood creatine kinase activity, hepatic aminotransferase activities, and lactate concentration. Imaging studies of the central nervous system often showed extensive symmetrical white matter abnormalities with swelling. Case fatality was 76 percent, and survivors commonly experienced sustained neurological sequelae. Management strategies were highly varied, and the effectiveness of specific medical interventions was unclear. Acute human chlorfenapyr poisoning is characterized by a latent period as long as 14 days, deterioration over hours to days, and can result in serious morbidity and mortality. Development of hyperthermia, likely driven by oxidative phosphorylation uncoupling by tralopyril, is an ominous clinical sign and is temporally associated with clinical decompensation and death. Laboratory abnormalities, particularly elevated creatine kinase activity, hepatic aminotransferase activities, and lactate concentration, were common, but only creatine kinase activity differed amongst survivors and fatalities. Best clinical practice in the management of patients exposed to chlorfenapyr is unclear, and we opine that a conservative approach with close clinical monitoring and supportive care is prudent. The limitations of all reviews include their inherent retrospective and observational nature as well as publication bias that emphasizes severe outcomes, thus impacting the spectrum of illness and skewing mortality percentage. In addition, we interrogated a finite number of databases for publications on human chlorfenapyr exposure and there were limited cases with laboratory testing to confirm chlorfenapyr poisoning. Analysis of our systematic review was not powered to detect differences between groups, comparative statistics were not performed, and significance is not reported. Acute human chlorfenapyr toxicity is characterized by a latent period following exposure, development of new or progression of established signs/symptoms, potential for critical illness, rapid deterioration, serious morbidity, and mortality. A conservative approach to patient management is prudent. [ABSTRACT FROM AUTHOR]

A simple, low-cost, and highly sensitive method using a modified QuECHERS procedure based on a liquid chromatography-tandem mass spectrometer (LC-MS/MS) was established to simultaneously quantify lufenuron and chlorfenapyr and the corresponding metabolite tralopyril in cabbage for the first time. On the basis of this method, terminal residue and dietary risk of lufenuron and chlorfenapyr in cabbage were investigated. The recoveries of lufenuron, chlorfenapyr, and tralopyril ranged from 88 to 110%, with relative standard deviation of less than 12.4%. The field trial results showed that at the pre-harvest interval (PHI) of 21 days, the terminal residues of lufenuron, chlorfenapyr, and tralopyril in the supervised trials were not higher than 0.02 mg/kg, and the highest detected residue levels of lufenuron, chlorfenapyr, and tralopyril were 0.047, 0.055, and <0.02 mg·kg-1 at 14-day pre-harvest respectively, which were lower than the maximum residue limits (MRLs) for cabbage established in China. For the dietary risk assessment, the national estimated daily intakes (NEDIs) as proportion of acceptable daily intakes (ADIs) were 80.4% and 29.9% for chlorfenapyr and lufenuron respectively indicating an acceptable dietary risk to Chinese population. [ABSTRACT FROM AUTHOR]

The potential hazards of chlorfenapyr warrant attention owing to its widespread application on vegetables. A comprehensive investigation of the fate of chlorfenapyr in the ecosystem is imperative. This paper presents a method for detecting chlorfenapyr and tralopyril in cabbages, which exhibits good linearity (determination coefficients > 0.99) and satisfactory recoveries (82.50 %–108.03 %). Chlorfenapyr residues in cabbages demonstrate a positive correlation with its application dose and time. Tralopyril can inhibit the dissipation of chlorfenapyr, as evidenced by the half-lives of 5.67–11.14 d (chlorfenapyr) and 6.91–14.77 d (total chlorfenapyr). The results of terminal residues (

Background: Conjugating amino acid moieties to active ingredients has been recognized as an effective method for improving the precise targeting of the active form to the specific site. Based on the vectorization strategy, a series of amino acid–tralopyril conjugates were designed and synthesized as novel proinsecticide candidates, with the potential capability of root uptake and translocation to the foliage of crops. Results: Bioassay results showed excellent insecticidal activities of some conjugates, in particular, the conjugates 6b, 6e, and 7e, against the diamondback moth (Plutella xylostella), with equivalent insecticidal activity to chlorfenapyr (CFP). Importantly, conjugate 6e exhibited significantly higher in vivo insecticidal activity against P. xylostella than CFP. Furthermore, the systemic test experiments with Brassica chinensis demonstrated that conjugates 6e and 7e could be transported to the leaves, in contrast to CFP, which remained in the root. Conclusion: This study demonstrated the feasibility of amino acid fragment conjugation as a vectorization strategy for transporting non‐systemic insecticides into the leaves of B. chinensis while maintaining in vivo insecticidal activity. The findings also provide insights for subsequent mechanism studies on the uptake and transport of amino acid–insecticide conjugates in plants. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

In order to find novel pesticide-active compounds, a series of new 2-(tralopyril-1-yl) ethyl carboxylic acid derivatives (5a-5m, 6a-6o) were synthesized by nucleophilic substitution with tralopyril as the lead compound. Their structures were confirmed by 1H NMR, 13C NMR and HRMS. The results of fungicidal bioassay showed that compounds 2, 3 and 5m exhibited good fungicidal activity against Magnaporthe oryzae with EC50 values of 0.0532, 0.0470 and 0.0174 mmol/L, respectively, which were better than the control agent fludioxonil (0.0914 mmol/L), but inferior to the control agent azoxystrobin (0.0001 mmol/L). Compound 5m showed a broad spectrum of fungicidal activity, and its EC50 values for the control of Rhizoctonia solani and Bipolaris sorokiniana were 0.0218 and 0.0420 mmol/L, respectively, but inferior to the control agent fludioxonil (EC50 values were 0.0002 and 0.0010 mmol/L, respectively). The bioassay results of insecticidal and acaricidal showed that at the concentration of 0.2 mmol/L, the target compounds had certain insecticidal and acaricidal activity, but they were not as effective as the control agent chlorfenapyr (corrected mortality 100%). The results of nematicidal bioassay showed good nematicidal activity of the target compounds. The LC50 values of compound 2 and 5b against Caenorhabditis elegans were 0.0136 and 0.0109 mmol/L, respectively, which were better than the control agent fosthiazate (0.2798 mmol/L). The preliminary safety test showed that the highly active target compound was safer to Oryza sativa L. and Brassica campestris L. than the parent tralopyril. The target compounds synthesized in this study have certain fungicidal, insecticidal, acaricidal and nematicidal activities, which provide a guideline for the design and transformation of tralopyril derivatives and are of reference significance for exploring the biological activities diversity of tralopyril derivatives. [ABSTRACT FROM AUTHOR]

In order to find new compounds with pesticide activity, a series of N-((5-alkylthio-1,3,4- oxadiazole)-2-methyl) tralopyril were designed and synthesized from tralopyril by nucleophilic substitution, hydrazinolysis and cyclization. The structures of these derivatives were confirmed by 1H NMR and HRMS. The test against 5 pathogenic fungi showed that most of the target compounds had certain fungicidal activity at the concentration of 0.20 mmol/L, and the inhibitory rate of compound 5h against Magnaporthe oryzae was 60.07%, which was better than that of the control agent fludioxonil (58.21%). The results of insecticidal and acaricidal activities showed that at the concentration of 0.20 mmol/L, some of the target compounds had certain insecticidal and acaricidal activities against Spodoptera litura and adult mite of Tetranychus cinnabarinus, while all were lower than the control agent chlorfenapyr (100%). The results of nematicidal activity showed that most of the compounds exhibited excellent nematicidal activity at the concentration of 0.20 mmol/L. The LC50 values of compounds 5k, 5r and 5s against Caenorhabditis elegans were 0.091 8, 0.073 3, 0.081 0 mmol/L respectively, which were better than the control agent fosthiazate (0.279 8 mmol/L). The target compounds synthesized in this study have certain fungicidal, insecticidal, acaricidal and nematicidal activities, which can provide a reference for the design and synthesis of tralopyril derivatives. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recently, chlorfenapyr and diafenthiuron have been widely used to prevent and control diseases and pests in tea production. However, rare studies have investigated the dissipation patterns of chlorfenapyr, diafenthiuron and their metabolites simultaneously in tea matrices. Here, we established an analytical method to investigate the degradation patterns of five target compounds in tea shoots and made tea samples. Moreover, the dietary intake risk assessment of chlorfenapyr–diafenthiuron mixture among Chinese populations was evaluated based on the supervised field experiment. RESULTS: The mean recoveries of the primary analytes at five spiking levels were between 95.6% and 112.6% in tea shoots and made tea, respectively, and the values of RSD (relative standard deviation) were lower than 9.7% for all the target analytes. The field trial results showed that the half‐lives of chlorfenapyr and diafenthiuron based on the residue definition were 10.0–12.4 days and 4.3–5.9 days, respectively, in tea shoots. For the dietary intake risk assessment, the risk quotient (RQ) values in made tea ranged from 30.4% to 73.9% at the pre‐harvest interval of 14 days, which were significantly less than 100%. CONCLUSION: The accuracy and precision of the developed method were satisfied by the measurement requirements according to the validation results. The dynamic dissipation experiments suggested that diafenthiuron was much easier to dissipate than chlorfenapyr. Moreover, the existence of tralopyril made the half‐life of chlorfenapyr significantly increase, indicating that practical application of chlorfenapyr should take careful consideration of its metabolite. Finally, the potential chronic dietary risks of the chlorfenapyr–diafenthiuron mixture to human communities were within the acceptable range. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

In order to evaluate the residue behavior and dietary exposure risk of chlorfenapyr and its metabolite tralopyril applied to mustard, the supervised residual trial of chlorfenapyr in mustard were carried out in Shanxi, Beijing, Jilin, Henan, Anhui and Guizhou Provinces in China. A rapid and simple analytical method for determination of chlorfenapyr residues using GC-MS/MS and for tralopyril residues using UPLC-MS/MS in mustard was developed. The final residues and dissipation dynamics were studied, and the long-term and short-term dietary intake risks of the two pesticides to different Chinese populations were evaluated. The results showed that the average recoveries of chlorfenapyr and tralopyril in mustard samples at three spiked levels from 0.01 mg/kg to 30 mg/kg were 89%-105% and 97%-104%, with the relative standard deviation (RSD) ranged from 2% to 4% and 1% to 3%, respectively. The limits of quantification (LOQs) of the two analytes in mustard root and mustard leaf were all 0.01 mg/kg. The dissipation dynamics of chlorfenapyr in mustard leaves accorded with the first-order reaction kinetic equation, and the half-life was 4.2-5.9 days, while the dissipation dynamics of tralopyril could not be fitted with the first-order reaction kinetic equation. The suspension concentrate of chlorfenapyr was sprayed twice at a 5-days interval and a dosage of 105 g a.i./hm² with a pre-harvest sampling interval of 14 days. The long-term dietary intake risk assessment at 97.5% food consumption showed that the contribution rate of mustard leaf residues to the ADI for children aged 3-5 and for the general population was 0.49% and 2.47%, respectively. This indicated that the chronic dietary intake risk of chlorfenapyr and its metabolite through mustard was very low. However, the short-term dietary intake risk assessment showed that the chlorfenapyr in mustard leaves had an unacceptable acute dietary intake risk for both Chinese children aged 1-6 years and the general population. The risk of acute dietary intake for children aged 1-6 years was much higher than for the general population. Changing of the pesticide application methods will lead to differentiated risk assessment results. Increasing the application dose or application times will lead to a higher acute dietary intake risk. Therefore, it is suggested to reduce the level of acute dietary intake risk by prolonging of the pre-harvest interval. [ABSTRACT FROM AUTHOR]

Tralopyril (TP), an antifouling biocide, is widely used to prevent heavy biofouling, and can have potential risks to aquatic organisms. However, there is little information available on the toxicity of tralopyril to aquatic organisms. In this study, the effect of TP on carbohydrate and lipid metabolism, and related mechanisms were evaluated in zebrafish (Danio rerio) larvae. Adverse modifications in carbohydrate metabolism were observed in larvae: hexokinase (HK) activity, succinate dehydrogenase (SDH) activity, and adenosine triphosphate (ATP) content were significantly decreased; and transcript expression of genes (GK, HK1, and PCK1) was also significantly changed. Changes of TG content, FAS activity and transcript expression of genes (ACO, ehhadh, and fas) indicate that TP disrupt lipid metabolism in zebrafish larvae. The change in expression of genes (ndufs4, Sdhα, and uqcrc2) involved in the mitochondrial respiratory complexes, and genes (polg1 and tk2) involved in the mitochondrial DNA replication and transcription indicates that these adverse effects on carbohydrate and lipid metabolism are caused by mitochondrial dysfunction.

Chlorfenapyr is a new contact and stomach insecticide derived from natural pyrroles secreted by Streptomyces spp. It is a pro-insecticide and acts after metabolic transformation to its active metabolite tralopyril. Tralopyril is an uncoupler of oxidative phosphorylation in the mitochondria of the target insects and of experiment animals, leading to the disruption of adenosine triphosphate synthesis and death. Several fatal human poisonings had been reported and no blood chlorfenapyr or tralopyril measurements were available. The treatment remains supportive. A 32-year-old healthy man ingested 200 mL of 10% chlorfenapyr as a suicide attempt. Unfortunately, he succumbed at 157 h post-ingestion, shortly after having fever and seizures. His serum level of chlorfenapyr at 4 h post-exposure was 77.4 ng/mL, and was undetectable at 113 and 156 h, respectively. The serum levels of tralopyril were 723.6, 14,179, and 9654.2 ng/mL at 4, 113, and 156 h post-ingestion, respectively. The delay in the rise of serum tralopyril levels was noticeable, which seems to correlate with the patient’s signs and symptoms. The information may have therapeutic implications in the management of this deadly poisoning.

To improve the proinsecticidal activity and phloem mobility of amino acid–tralopyril conjugates further, nine conjugates were designed and synthesized by introducing glutamic acid to tralopyril, and the length of the linker between glutamic acid and tralopyril ranged from 2 atoms to 10 atoms. The results of insecticidal activity against the third-instar larvae of P. xylostella showed that conjugates 42, 43, 44,and 45 (straight-chain containing 2–5 atoms) exhibited good insecticidal activity, and their LC50 values were 0.2397 ± 0.0366, 0.4413 ± 0.0647, 0.4400 ± 0.0624, and 0.4602 ± 0.0655 mM, respectively. The concentrations of conjugates 43–45 were higher than that of conjugate 42 in the phloem sap at 2 h, and conjugate 43 showed the highest concentration. The introduction of glutamic acid can improve phloem mobility. The in vivo metabolism of conjugates 42 and 43 was investigated in P. xylostella, and the parent compound tralopyril was detected at concentrations of 0.5950 and 0.3172 nmol/kg, respectively. According to the above results, conjugates 42 and 43 were potential phloem mobile pro-insecticide candidates.

Tralopyril was the active agent of a pro-insecticide chlorfenapyr. To simultaneously solve the problems of the phytotoxicity and non-systemic insecticidal activity of tralopyril, four new tralopyril conjugates containing theanine or glutamic acid moieties were designed and synthesized. Their phytotoxicity to tea shoot, phloem systemicity, and insecticidal activity were evaluated. Phytotoxic symptoms were not observed after the tea shoots were exposed to the four conjugates at concentrations of 2 mM. The phloem mobility test on Ricinus communis L. seedlings confirmed that all four conjugates were mobile in the sieve tubes. Results of insecticidal activity against the third-instar larvae of Plutella xylostella showed that only conjugate 20 exhibited activity with an LC 50 value of 0.5882 ± 0.0504 mM. After root application to tea seedlings, conjugate 20 showed obviously systemic insecticidal activity against Dendrothrips minowai Priesner, while chlorfenapyr showed no attribute of that. A new conjugate as potential phloem mobile pro-insecticide candidate was provided and so a novel strategy of pro-insecticide for improved phloem systemicity was proposed. [ABSTRACT FROM AUTHOR]

Six new conjugates were designed and synthesized by introducing glucose, methyl glucuronate or glucuronic acid moieties on tralopyril. Phytotoxicity and phloem mobility results demonstrated that the introduction of glucose, methyl glucuronate or glucuronic acid moieties can simultaneously solve the tough phytotoxicity problem and phloem mobility transformation of tralopyril. Conjugates 12 and 18 containing the glucuronic acid moiety exhibited higher phloem mobility than conjugates 9, 11, 15 and 17. Conjugates 15, 17 and 18 with methoxymethyl groups on the tralopyril pyrrole nitrogen atom showed activity against Plutella xylostella, while conjugates 9, 11 and 12 with a methene group on the pyrrole N showed no activity. Cabbage roots were incubated in a buffered solution containing conjugates 15, 17 and 18 at 4 mM for 72 h. Only 18 showed systemic insecticidal activity with 100% mortalityagainst P. xylostella, while 15 and 17 showed lower activity andchlorfenapyr showed no activity. The glucuronic acid promoiety imparted more phloem mobility to tralopyril than glucose and methyl glucuronate. The methoxymethyl group bond on the tralopyril skeleton was the key factor in determining the insecticidal activity of the conjugates. A promising systemic proinsecticide containing glucuronic acid and tralopyril moieties was proposed. [ABSTRACT FROM AUTHOR]

Antifouling (AF) systems are used worldwide as one of the most cost-effective ways of protecting submerged structures against heavy biofouling. The emergence of environmentally friendly AF biocides requires knowledge on their environmental fate and toxicity. In this study we measured the bioconcentration of the emerging AF biocide tralopyril (TP) in the Mediterranean mussel Mytilus galloprovincialis and investigated the effects of TP on the mussel gill proteome following acute (2 days) and chronic (30 days) exposure, as well as after a 10-day depuration period. The experiments were carried out with 1 μg/L TP; blank and solvent (5 × 10 −5 % DMSO) controls were also included. Proteomics analysis was performed by mass spectrometry-based multidimensional protein identification technology (MudPIT). Differentially expressed proteins were identified using a label-free approach based on spectral counts and G-test. Our results show that TP is rapidly accumulated by mussels at concentrations up to 362 ng/g dw (whole tissues), reaching steady-state condition within 13 days. Ten days of depuration resulted in 80% elimination of accumulated TP from the organism, suggesting that a complete elimination could be reached with longer depuration times. In total, 46 proteins were found to be regulated in the different exposure scenarios. Interestingly, not only TP but also DMSO alone significantly modulated the protein expression in mussel gills following acute and chronic exposure. Both compounds regulated proteins involved in bioenergetics, immune system, active efflux and oxidative stress, often in the opposite way. Alterations of several proteins, notably several cytoskeletal ones, were still observed after the depuration period. These may reflect either the continuing chemical effect due to incomplete elimination or an onset of recovery processes in the mussel gills. Our study shows that exposure of adult mussels to sublethal TP concentration results in the bioconcentration of this biocide in the tissues and modulates the expression of several proteins that may intervene in important metabolic pathways. [ABSTRACT FROM AUTHOR]

A targeted analytical method was established to determine tralopyril (4-bromo-2-(4-chlorophenyl)-5-(trifluoromethyl)-1 H -pyrrole-3-carbonitrile) in water. This compound has been recently introduced as a biocide in ship antifouling paints, becoming a potential new environmental contaminant. The method presented here allows for the first time the direct determination of tralopyril in environmental samples without the need of a pre-concentration step. The injected sample is separated by a 30 min HPLC-gradient on a reversed phase column and the compound identified and quantified by negative ion LC-MS/MS. Tralopyril solutions in DMSO, seawater, river Glatt water and E3 medium (used for zebrafish experiments) were analysed to demonstrate the applicability of the method. The method provides good retention time reproducibility and a quantitation limit (LOQ) of 0.025 μg L −1 for DMSO, seawater and E3 exposure medium and 0.05 μg L −1 for river Glatt water. Calculated tralopyril half-lives were 6.1 h for seawater, 8.1 h for river Glatt water and 7.4 h for E3 medium at 18 °C. [ABSTRACT FROM AUTHOR]

The combined effects of emerging pollutants and ocean acidification (OA) on marine organisms and marine ecosystems have attracted increasing attention. However, the combined effects of tralopyril and OA on marine organisms and marine ecosystems remain unclear. In this study, Crassostrea gigas (C. gigas) were exposed to tralopyril (1 μg/L) and/or OA (PH = 7.7) for 21 days and a 14-day recovery acclimation. To investigate the stress response and potential molecular mechanisms of C. gigas to OA and tralopyril exposure alone or in combination, as well as the effects of OA and/or tralopyril on bivalve biomineralization and marine carbon cycling. The results showed that the combined toxicity was between that of acidification and tralopyril alone. Single or combined exposure activated the general stress defense responses of C. gigas mantle, affected energy metabolism and biomineralization of the organism and the carbon cycle of the marine ecosystem. Moreover, acidification-induced and tralopyril-induced toxicity showed potential recoverability at molecular and biochemical levels. This study provides a new perspective on the molecular mechanisms of tralopyril toxicity to bivalve shellfish and reveals the potential role of tralopyril and OA on marine carbon cycling. [Display omitted] • The toxicity of combined exposure fell in between tralopyril and OA alone. • Tralopyril and/or OA activates stress defense and interferes with energy metabolism. • Tralopyril and/or OA affects bivalve biomineralization and marine carbon cycling. [ABSTRACT FROM AUTHOR]

Tralopyril is an emerging marine antifouling agent with limited data on its effects on fish growth and calcium regulation. To determine the changes induced by long-term exposure to tralopyril, multi-levels (such as molecular, biochemical, and individual levels) responses were measured in turbot at different concentrations (1 μg/L, 20 μg/L). The results showed that 1 μg/L mainly affected the immune response, while 20 μg/L affected the synthesis and metabolism of steroids and fat. However, different concentrations of tralopyril affected the synthesis, secretion and action of parathyroid hormone and growth hormone. The expression of GH/IGF axis gene and the level of growth hormone increased significantly, leading to abnormal growth. The energy tradeoff between immunity and growth at 1 μg/L tralopyril pressure may inhibit growth. The change of Ca2+ level was accompanied by the disturbance of PTH-related gene expression. The results of molecular docking showed that the disturbance of Ca2+ regulation might be attributed to the inhibition of vitamin D receptor by tralopyril, which affected the vitamin D signaling pathway. This study provides scientific data for the in-depth understanding and risk assessment of the toxicological effects of tralopyril and reveals the potential threat of tralopyril to environmental health. [Display omitted] • Tralopyril caused transcriptome changes in fish liver. • Tralopyril induced GH elevation and GH/IGF axis gene disturbance, resulting in abnormal growth. • Tralopyril interferes with vitamin D signaling pathway and PTH genes, causing Ca2+ regulation disorder. • Tralopyril is a potential threat to environmental health. [ABSTRACT FROM AUTHOR]

• Tralopyril induced oxidative stress in turbot. • Tralopyril affected energy metabolism in turbot. • Tralopyril disrupted the thyroid endocrine system in turbot. • Tralopyril's competitive binding to thyroid hormone receptors was weak. Tralopyril is an emerging marine antifouling agent with potential toxic effects on non-target aquatic organisms. To evaluate the toxicity of tralopyril, to turbot (Scophthalmus maximus), we assessed biomarkers, including oxidative stress, neurotoxicity, and osmotic homeostasis regulation enzymes, after a 7-day exposure to tralopyril (5 μg/L, 15 μg/L, 30 μg/L). Superoxide dismutase activity was significantly decreased at 30 μg/L, and Ca2+-Mg2+-ATPase activity in the gills was significantly increased at 15 μg/L and 30 μg/L. No statistically significant differences in the responses of acetylcholinesterase and nitric oxide were detected. In addition, 15 μg/L and 30 μg/L tralopyril induced hyperthyroidism, reflected by significantly increased of T3 levels. The expression levels of hypothalamus–pituitary–thyroid axis-related genes were also upregulated. The molecular docking results showed that the thyroid system disruption was not caused by competitive binding to the receptor. In addition, the integrated biomarker response index showed that 15 μg/L tralopyril had the greatest effect on turbot. In general, tralopyril caused oxidative damage, affected energy metabolism, and interfered with the endocrine system. These findings could provide reference data for assessing the ecological risk of tralopyril in marine environments. [ABSTRACT FROM AUTHOR]

Recently, the toxic effects of tralopyril, as a new antifouling biocide, on aquatic organisms have aroused widespread attention about the potential toxicity. However, the mechanism of tralopyril on marine mollusks has not been elaborated clearly. In this study, the histological, biochemical and molecular impacts of tralopyril on adult Crassostrea gigas were investigated. The results indicated that the 96 h LC50 of tralopyril to adult Crassostrea gigas was 911 μg/L. After exposure to tralopyril (0, 40, 80 and 160 μg/L) for 6 days, the mantle mucus secretion coverage ratio of Crassostrea gigas was increased with a dose-dependent pattern. Catalase (CAT) activity was significantly increased, amylase (AMS) activity, acid phosphatase (ACP) activity and calcium ion (Ca2+) concentration significantly decreased. Meanwhile, integrated biomarker responses (IBR) index suggested that higher concentrations of tralopyril caused severer damage to Crassostrea gigas. In addition, the mRNA expression levels of biomineralization related genes in the mantle were significantly upregulated. Collectively, this study firstly revealed the histological, biochemical and molecular impacts of tralopyril exposure on adult Crassostrea gigas , which provided new insights for understanding the toxicity of tralopyril in marine mollusks. Effect of tralopyril exposure (6 days' exposure) on mucus secretion coverage ratio of C. gigas mantle according to AB-PAS staining. [Display omitted] • Tralopyril exposure increased the mantle mucus secretion coverage ratio in Pacific oyster. • Tralopyril affected antioxidant defense systems、digestive enzyme and biomineralization capacity in Pacific oyster. • Tralopyril disrupted the mRNA expression levels of biomineralization related genes. [ABSTRACT FROM AUTHOR]

Tralopyril (TP), an antifouling biocide, is widely used to prevent heavy biofouling, and can have potential risks to aquatic organisms. In this study, the effect of TP on locomotor activity and related mechanisms were evaluated in zebrafish (Danio rerio) larvae. TP significantly reduced locomotor activity after 168 -h exposure. Adverse modifications in tail muscle tissue, the nervous system, and energy metabolism were also observed in larvae. TP caused thinning of the muscle bundle in the tail of larvae. In conjunction with the metabolomics results, changes in dopamine (DA) and acetylcholine (ACh), acetylcholinesterase (AChE) activity, and the expression of genes involved in neurodevelopment, indicate that TP may disrupt the nervous system in zebrafish larvae. The change in metabolites (e.g., glucose 6-phosphate, cis -Aconitic acid, acetoacetyl-CoA, coenzyme-A and 3-Oxohexanoyl-CoA) involved in carbohydrate and lipid metabolism indicates that TP may disrupt energy metabolism. TP exposure may inhibit the locomotor activity of zebrafish larvae by impairing tail muscle tissue, the nervous system, and energy metabolism. [Display omitted] • Tralopyril significantly inhibited the locomotor activity of zebrafish larvae. • Tail muscle tissue of zebrafish larvae was impaired by tralopyril. • Nervous system disruption was observed following exposure. • Tralopyril disrupted carbohydrate and lipid metabolism in zebrafish larvae. [ABSTRACT FROM AUTHOR]

Tralopyril (TP), an antifouling biocide, is widely used to prevent heavy biofouling, and can have potential risks to aquatic organisms. However, there is little information available on the toxicity of tralopyril to aquatic organisms. In this study, the effect of TP on carbohydrate and lipid metabolism, and related mechanisms were evaluated in zebrafish (Danio rerio) larvae. Adverse modifications in carbohydrate metabolism were observed in larvae: hexokinase (HK) activity, succinate dehydrogenase (SDH) activity, and adenosine triphosphate (ATP) content were significantly decreased; and transcript expression of genes (GK , HK1 , and PCK1) was also significantly changed. Changes of TG content, FAS activity and transcript expression of genes (ACO , ehhadh , and fas) indicate that TP disrupt lipid metabolism in zebrafish larvae. The change in expression of genes (ndufs4 , Sdhα , and uqcrc2) involved in the mitochondrial respiratory complexes, and genes (polg1 and tk2) involved in the mitochondrial DNA replication and transcription indicates that these adverse effects on carbohydrate and lipid metabolism are caused by mitochondrial dysfunction. [Display omitted] • Tralopyril disrupted carbohydrate metabolism in zebrafish larvae. • Tralopyril disrupted lipid metabolism in zebrafish larvae. • Tralopyril impaired the mitochondrial respiratory complexes. • Tralopyril may disrupt energy metabolism by impairing mitochondrial function. [ABSTRACT FROM AUTHOR]

To improve the proinsecticidal activity and phloem mobility of amino acid–tralopyril conjugates further, nine conjugates were designed and synthesized by introducing glutamic acid to tralopyril, and the length of the linker between glutamic acid and tralopyril ranged from 2 atoms to 10 atoms. The results of insecticidal activity against the third-instar larvae of P. xylostella showed that conjugates 42, 43, 44,and 45 (straight-chain containing 2–5 atoms) exhibited good insecticidal activity, and their LC50 values were 0.2397 ± 0.0366, 0.4413 ± 0.0647, 0.4400 ± 0.0624, and 0.4602 ± 0.0655 mM, respectively. The concentrations of conjugates 43–45 were higher than that of conjugate 42 in the phloem sap at 2 h, and conjugate 43 showed the highest concentration. The introduction of glutamic acid can improve phloem mobility. The in vivo metabolism of conjugates 42 and 43 was investigated in P. xylostella, and the parent compound tralopyril was detected at concentrations of 0.5950 and 0.3172 nmol/kg, respectively. According to the above results, conjugates 42 and 43 were potential phloem mobile pro-insecticide candidates. [ABSTRACT FROM AUTHOR]

Tralopyril, an antifouling biocide, widely used in antifouling systems to prevent underwater equipment from biological contamination, which can pose a potential risk to aquatic organisms and human health. However, there is little information available on the toxicity of tralopyril to aquatic organisms. Herein, zebrafish (Danio rerio) were used to investigate the toxicity mechanisms of tralopyril and a series of developmental indicators, thyroid hormones, gene expression and metabolomics were measured. Results showed that tralopyril significantly decreased the heart-beat and body length of zebrafish embryos-larvae exposed to 4.20 μg/L or higher concentrations of tralopyril and also induced developmental defects including pericardial hemorrhage, spine deformation, pericardial edema, tail malformation and uninflated gas bladder. Tralopyril decreased the thyroid hormone concentrations in embryos and changed the transcriptions of the related genes (TRHR , TSHβ , TSHR , Nkx2.1 , Dio1 , TRα , TRβ , TTR and UGT1ab). Additionally, metabolomics analysis showed that tralopyril affected the metabolism of amino acids, energy and lipids, which was associated with regulation of thyroid system. Furthermore, this study demonstrated that alterations of endogenous metabolites induced the thyroid endocrine disruption in zebrafish following the tralopyril treatment. Therefore, the results showed that tralopyril can induce adverse developmental effects on zebrafish embryos by disrupting the thyroid system and metabolism. Unlabelled Image • Tralopyril induced developmental toxicity in zebrafish embryos. • Tralopyril decreased thyroid hormone concentrations in zebrafish embryos. • Tralopyril altered expression of genes related to the thyroid system in zebrafish embryos. • Tralopyril affected amino acids, energy and lipids metabolism in zebrafish embryos. • Developmental toxicity in zebrafish embryos by tralopyril might be associated with the thyroid system and metabolic disorders. [ABSTRACT FROM AUTHOR]