The toxicity and health risk of chlorothalonil to non-target animals and humans: A systematic review.

Chlorothalonil (CTL), an organochloride fungicide applied for decades worldwide, has been found to be present in various matrixes and even accumulates in humans or other mammals through the food chain. Its high residue and diffusion in the environment have severely affected food security and public health. More and more research has considered CTL as a possible toxin to environmental non-target organisms, via influencing multiple systems such as metabolic, developmental, endocrine, genetic, and reproductive pathways. Aquatic organisms and amphibians are the most vulnerable species to CTL exposure, especially during the early period of development. Under experimental conditions, CTL can also have toxic effects on rodents and other non-target organisms. As for humans, CTL exposure is most often reported to be relevant to allergic reactions to the skin and eyes. We hope that this review will improve our understanding of the hazards and risks that CTL poses to non-target organisms and find a strategy for rational use.

Lambda-cyhalothrin alters locomotion, mood and memory abilities in Swiss mice.

Lambda-cyhalothrin (LCT) is a type II pyrethroid widely used in agriculture for plant protection against pests. However, pyrethroids represents a risk for rural female farmworkers, and few studies addressed LCT-behavioural alterations in mice. The present study evaluates the effect of LCT on behaviour of eight weeks aged female mice. Mice were divided into three groups including treated mice that received through gavage (i) 0.5 mg/kg bw and (ii) 2 mg/kg of LCT dissolved in corn oil, and (iii) the vehicle controls. Behavioural tests assess the locomotor activity using open field test, the anxiety by the dark-light box test, the learning memory with novel object recognition test, the memory retention by the elevated plus maze test, and the spatial working memory using the Y-maze test. Subacute treatment with low doses of LCT decreases total distance travelled, induces anxiogenic effect by reducing the time spent in the enlightened compartment, alters memory retention by increasing the latency time, and also affects learning memory by reducing the recognition index parameter. However, LCT does not significantly alter spatial working memory. In conclusion, LCT-treated female mice show an alteration in locomotor activity, mood state and memory abilities probably related to oxidative stress and altered neurotransmission.

Combined toxic effects of polyethylene microplastics and lambda-cyhalothrin on gut of zebrafish (Danio rerio).

Microplastics (MPs), which are prevalent and increasingly accumulating in aquatic environments. Other pollutants coexist with MPs in the water, such as pesticides, and may be carried or transferred to aquatic organisms, posing unpredictable ecological risks. This study sought to assess the adsorption of lambda-cyhalothrin (LCT) by virgin and aged polyethylene MPs (VPE and APE, respectively), and to examine their influence on LCT's toxicity in zebrafish, specifically regarding acute toxicity, oxidative stress, gut microbiota and immunity. The adsorption results showed that VPE and APE could adsorb LCT, with adsorption capacities of 34.4 mg∙g-1 and 39.0 mg∙g-1, respectively. Compared with LCT exposure alone, VPE and APE increased the acute toxicity of LCT to zebrafish. Additionally, exposure to LCT and PE-MPs alone can induce oxidative stress in the zebrafish gut, while combined exposure can exacerbate the oxidative stress response and intensify intestinal lipid peroxidation. Moreover, exposure to LCT or PE-MPs alone promotes inflammation, and combined exposure leads to downregulation of the myd88-nf-κb related gene expression, thus impacting intestinal immunity. Furthermore, exposure to APE increased LCT toxicity to zebrafish more than VPE. Meanwhile, exposure to PE-MPs and LCT alone or in combination has the potential to affect gut microbiota function and alter the abundance and diversity of the zebrafish gut flora. Collectively, the presence of PE-MPs may affect the toxicity of pesticides in zebrafish. The findings emphasize the importance of studying the interaction between MPs and pesticides in the aquatic environment.

Co-exposure to deltamethrin and cyazofamid: variations in enzyme activity and gene transcription in the earthworm (Eisenia fetida).

Pesticide formulations are typically applied as mixtures, and their synergistic effects can increase toxicity to the organisms in the environment. Despite pesticide mixtures being the leading cause of pesticide exposure incidents, little attention has been given to assessing their combined toxicity and interactions. This survey purposed to reveal the cumulative toxic effects of deltamethrin (DEL) and cyazofamid (CYA) on earthworms (Eisenia fetida) by examining multiple endpoints. Our findings revealed that the LC50 values of DEL for E. fetida, following 7- and 14-day exposures, ranged from 887.7 (728-1095) to 1552 (1226-2298) mg kg-1, while those of CYA ranged from 316.8 (246.2-489.4) to 483.2 (326.1-1202) mg kg-1. The combinations of DEL and CYA induced synergistic influences on the organisms. The contents of Cu/Zn-SOD and CarE showed significant variations when exposed to DEL, CYA, and their combinations compared to the untreated group. Furthermore, the mixture administration resulted in more pronounced alterations in the expression of five genes (hsp70, tctp, gst, mt, and crt) associated with cellular stress, carcinogenesis, detoxification, and endoplasmic reticulum compared to single exposures. In conclusion, our comprehensive findings provided detailed insights into the cumulative toxic effects of chemical mixtures across miscellaneous endpoints and concentration ranges. These results underscored the importance of considering mixture administration during ecological risk evaluations of chemicals.

Daily temperature fluctuation interacts with the mean temperature to increase the toxicity of a pyrethroid insecticide in a moth.

Climate change complicates ecotoxicology studies because species responses to pesticides depend on temperature. Classically illustrated by the effect of constant laboratory temperatures, a recent review revealed that the toxicity of pesticides is also often increased by daily temperature fluctuations. Here, we investigated the combined effects of daily temperature fluctuation and mean temperature on the toxicity of two insecticides in the moth Spodoptera littoralis. Our study tested the toxicity of chlorpyrifos and deltamethrin on larvae of six experimental groups that crossed three treatments of daily temperature fluctuations (0, 5 or 10 °C) and two treatments of mean temperatures (25 or 33 °C). We showed that daily temperature fluctuation increased larval mortality induced by chlorpyrifos and deltamethrin. However, the response differed between the organophosphorus insecticide chlorpyrifos and the pyrethroid insecticide deltamethrin. The increase in chlorpyrifos toxicity by daily temperature fluctuation did not differ between mean temperatures of 25 and 33 °C. Remarkably, the increase in deltamethrin toxicity by daily temperature fluctuation was dependent on the crossed effects of the amplitude of daily fluctuation and mean temperature. This increase in deltamethrin toxicity occurred with a daily fluctuation of only 5 °C for larvae reared at 25 °C and a daily fluctuation of 10 °C in larvae reared at 33 °C. To confidently quantify the responses of insecticide toxicity to temperature, future ecotoxicology studies will have to evaluate the generality of the interaction between the effects of daily temperature fluctuation and mean temperature.

Biochemical and molecular-level effects of co-exposure to chlorpyrifos and lambda-cyhalothrin on the earthworm (Eisenia fetida).

Farmland soil organisms frequently encounter pesticide mixtures presented in their living environment. However, the underlying toxic mechanisms employed by soil animals to cope with such combined pollution have yet to be explored. This investigation aimed to reveal the changes in cellular and mRNA levels under chlorpyrifos (CPF) and lambda-cyhalothrin (LCT) co-exposures in earthworms (Eisenia fetida). Results exhibited that the combination of CPF and LCT triggered an acute synergistic influence on the animals. Most exposures resulted in significant alterations in the activities of total superoxide dismutase (T-SOD), copper/zinc superoxide dismutase (Cu/Zn-SOD), caspase 3, and carboxylesterase (CarE) compared to the basal level. Moreover, when exposed to chemical mixtures, the transcription levels of four genes [heat shock protein 70 (hsp70), gst, sod, and calreticulin (crt)] also displayed more pronounced changes compared with their individual exposures. These changes in determined parameters indicated the occurrence of oxidative stress, cell death, detoxification dysfunction, and endoplasmic reticulum damage after co-exposure to CPF and LCT in E. fetida. The comprehensive examination of mixture toxicities of CPF and LCT at different endpoints would help to understand the overall toxicity they cause to soil invertebrates. The augmented deleterious effect of these pesticides in a mixture suggested that mixture toxicity assessment was necessary for the safety evaluation and application of pesticide mixtures.

Myclobutanil induces neurotoxicity by activating autophagy and apoptosis in zebrafish larvae (Danio rerio).

Myclobutanil (MYC), a typical broad-spectrum triazole fungicide, is often detected in surface water. This study aimed to explore the neurotoxicity of MYC and the underlying mechanisms in zebrafish and in PC12 cells. In this study, zebrafish embryos were exposed to 0, 0.5 and 1 mg/L of MYC from 4 to 96 h post fertilization (hpf) and neurobehavior was evaluated. Our data showed that MYC decreased the survival rate, hatching rate and heart rate, but increased the malformation rate and spontaneous movement. MYC caused abnormal neurobehaviors characterized by decreased swimming distance and movement time. MYC impaired cerebral histopathological morphology and inhibited neurogenesis in HuC:egfp transgenic zebrafish. MYC also reduced the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and downregulated neurodevelopment related genes (gfap, syn2a, gap43 and mbp) in zebrafish and PC12 cells. Besides, MYC activated autophagy through enhanced expression of the LC3-II protein and suppressed expression of the p62 protein and autophagosome formation, subsequently triggering apoptosis by upregulating apoptotic genes (p53, bax, bcl-2 and caspase 3) and the cleaved caspase-3 protein in zebrafish and PC12 cells. These processes were restored by the autophagy inhibitor 3-methyladenine (3-MA) both in vivo and in vitro, indicating that MYC induces neurotoxicity by activating autophagy and apoptosis. Overall, this study revealed the potential autophagy and apoptosis mechanisms of MYC-induced neurotoxicity and provided novel strategies to counteract its toxicity.

A relaxin receptor gene RpGPCR41 is involved in the resistance of Rhopalosiphum padi to pyrethroids.

Rhopalosiphum padi is a global pest that poses a significant threat to wheat crops and has developed resistance to various insecticides. G protein-coupled receptors (GPCRs), known for their crucial role in signaling and biological processes across insect species, have recently gained attention as a potential target for insecticides. GPCR has the potential to contribute to insect resistance through the regulation of P450 gene expression. However, GPCRs in R. padi remained unexplored until this study. We identified a total of 102 GPCRs in R. padi, including 81 receptors from family A, 10 receptors from family B, 8 receptors from family C, and 3 receptors from family D. Among these GPCR genes, 16 were up-regulated in both lambda-cyhalothrin and bifenthrin-resistant strains of R. padi (LC-R and BIF-R). A relaxin receptor gene, RpGPCR41, showed the highest up-regulated expression in both the resistant strains, with a significant increase of 14.3-fold and 22.7-fold compared to the susceptible strain (SS). RNA interference (RNAi) experiments targeting the relaxin receptor significantly increase the mortality of R. padi when exposed to the LC50 concentration of lambda-cyhalothrin and bifenthrin. The expression levels of five P450 genes (RpCYP6CY8, RpCYP6DC1, RpCYP380B1, RpCYP4CH2, and RpCYP4C1) were significantly down-regulated following knockdown of RpGPCR41 in LC-R and BIF-R strains. Our results highlight the involvement of GPCR gene overexpression in the resistance of R. padi to pyrethroids, providing valuable insights into the mechanisms underlying aphid resistance and a potential target for aphid control.

Predictions of tissue concentrations of myclobutanil, oxyfluorfen, and pronamide in rat and human after oral exposures via GastroPlusTM physiologically based pharmacokinetic modelling.

Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals. This study addresses the absence of PBPK-type data for myclobutanil, oxyfluorfen, and pronamide by generating in vitro data for key input PBPK parameters (Caco-2 permeability, rat plasma binding, rat blood to plasma ratio, and rat liver microsomal half-life), followed by generation of PBPK models for these three chemicals via the GastroPlusTM software. Incorporating these experimental input parameters into PBPK models, the prediction accuracy of plasma AUC (area under curve) was significantly improved. Validation against rat oral administration data demonstrated substantial enhancement. Steady-state plasma concentrations (Css) of pronamide aligned well with published data using measured PBPK parameters. Following validation, parent-based tissue concentrations for these agrochemicals were predicted in humans and rats after single or 30-day repeat exposure of 10 mg/kg/day. These predicted concentrations contribute valuable information for future human toxicity risk assessments of these agrochemicals.

Cyfluthrin exposure during pregnancy causes neurotoxicity in offspring-Ca2+ overload via IP3R-GRP75-VDAC1 pathway.

Cyfluthrin (Cy) is a widely used pyrethroid insecticide. There is growing evidence that Cy can cause damage to the nervous, reproductive, and immune systems, but there is limited evidence on the potential effects of maternal Cy exposure on offspring. A model of maternal Cy exposure was used to assess its neurobehavioral effects on young-adult offspring. We found that gestational Cy exposure affected pregnancy outcomes and fetal development, and that offspring showed impairments in anxiety as well as learning and memory, accompanied by impairments in hippocampal synaptic ultrastructure and synaptic plasticity. In addition, the IP3R-GRP75-VDAC1 apoptogenic pathway was also upregulated, and in vitro models showed that inhibition of this pathway alleviated neuronal apoptosis as well as synaptic plasticity damage. In conclusion, maternal Cy exposure during pregnancy can cause neurobehavioral abnormalities and synaptic damage in offspring, which may be related to neuronal apoptosis induced by activation of the IP3R-GRP75-VDAC1 pathway in the hippocampus of offspring. Our findings provide clues to understand the neurotoxicity mechanism of maternal Cy exposure to offspring during pregnancy.

The crosstalk between Toll and AMPK signaling pathways mediates growth inhibition of Eriocheir sinensis under deltamethrin stress.

Hepatopancreatic necrosis disease (HPND) broke out in 2015 in the Eriocheir sinensis aquaculture region of Xinghua, Jiangsu Province; however, the specific cause of HPND remains unclear. A correlation was found between HPND outbreak and the use of deltamethrin by farmers. In this study, E. sinensis specimens developed the clinical symptoms of HPND after 93 days of deltamethrin stress. The growth of E. sinensis with HPND was inhibited. Adenosine monophosphate-activated protein kinase (AMPK) is a central regulator of energy homeostasis, and its expression was up-regulated in the intestine of E. sinensis with HPND. Growth inhibitory genes (EsCabut, Es4E-BP, and EsCG6770) were also up-regulated in the intestine of E. sinensis with HPND. The expression levels of EsCabut, Es4E-BP, and EsCG6770 decreased after EsAMPK knockdown. Therefore, AMPK mediated the growth inhibition of E. sinensis with HPND. Further analysis indicated the presence of a crosstalk between the Toll and AMPK signaling pathways in E. sinensis with HPND. Multiple genes in the Toll signaling pathway were upregulated in E. sinensis under 93 days of deltamethrin stress. EsAMPK and its regulated growth inhibition genes were down-regulated after the knockdown of genes in the Toll pathway. In summary, the crosstalk between the Toll and AMPK signaling pathways mediates the growth inhibition of E. sinensis under deltamethrin stress.

Biomarker responses and lethal dietary doses of tau-fluvalinate and coumaphos in honey bees: Implications for chronic acaricide toxicity.

Evidence suggests that acaricide residues, such as tau-fluvalinate and coumaphos, are very prevalent in honey bee colonies worldwide. However, the endpoints and effects of chronic oral exposure to these compounds remain poorly understood. In this study, we calculated LC50 and LDD50 endpoints for coumaphos and tau-fluvalinate, and then evaluated in vivo and in vitro effects on honey bees using different biomarkers. The LDD50 values for coumaphos were 0.539, and for tau-fluvalinate, they were 12.742 in the spring trial and 8.844 in the autumn trial. Chronic exposure to tau-fluvalinate and coumaphos resulted in significant changes in key biomarkers, indicating potential neurotoxicity, xenobiotic biotransformation, and oxidative stress. The Integrated Biomarker Response was stronger for coumaphos than for tau-fluvalinate, supporting their relative lethality. This study highlights the chronic toxicity of these acaricides and presents the first LDD50 values for tau-fluvalinate and coumaphos in honey bees, providing insights into the risks faced by colonies.

JH degradation pathway participates in hormonal regulation of larval development of Bombyx mori following λ-cyhalothrin exposure.

λ-Cyhalothrin (λ-cyh), a widely utilized pyrethroid insecticide, poses serious threats to non-target organisms due to its persistence nature in the environment. Exposure to low concentrations of λ-cyh has been observed to result in prolonged larval development in Bombyx mori, leading to substantial financial losses in sericulture. The present study was undertaken to elucidate the underlying mechanisms for prolonged development caused by λ-cyh (LC10) exposure. The results showed that the JH Ⅲ titer was significantly increased at 24 h of λ-cyh exposure, and the JH interacting genes Methoprene-tolerant 2, Steroid Receptor Co-activator, Krüppel-homolog 1, and JH binding proteins were also up-regulated. Although the target of rapamycin (Tor) genes were induced by λ-cyh, the biosynthesis of JH in the corpora allata was not promoted. Notably, 13 JH degradation genes were found to be significantly down-regulated in the midgut of B. mori. The mRNA levels and enzyme activity assays indicated that λ-cyh had inhibitory effects on JH esterase, JH epoxide hydrolase, and JH diol kinase (JHDK). Furthermore, the suppression of JHDK (KWMTBOMO01580) was further confirmed by both western blot and immunohistochemistry. This study has offered a comprehensive perspective on the mechanisms underlying the prolonged development caused by insecticides, and our results also hold significant implications for the safe production of sericulture.

Oxidative stress and mitochondrial damage in lambda-cyhalothrin toxicity: A comprehensive review of antioxidant mechanisms.

Lambda-cyhalothrin, also known as cyhalothrin, is an efficient, broad-spectrum, quick-acting pyrethroid insecticide and acaricide and the most powerful pyrethroid insecticide in the world. However, there is increasing evidence that lambda-cyhalothrin is closely related to a variety of toxicity drawbacks (hepatotoxicity, nephrotoxicity, neurotoxicity and reproductive toxicity, among others) in non-target organisms, and oxidative stress seems to be the main mechanism of toxicity. This manuscript reviews the oxidative and mitochondrial damage induced by lambda-cyhalothrin and the signalling pathways involved in this process, indicating that oxidative stress occupies an important position in lambda-cyhalothrin toxicity. The mechanism of antioxidants to alleviate the toxicity of lambda-cyhalothrin is also discussed. In addition, the metabolites of lambda-cyhalothrin and the major metabolic enzymes involved in metabolic reactions are summarized. This review article reveals a key mechanism of lambda-cyhalothrin toxicity-oxidative damage and suggests that the use of antioxidants seems to be an effective method for preventing toxicity.

Breast Tumor Cells Evade the Cytotoxic Action of Anastrozole, Aspirin, and Clopidogrel Cocktail.

Globally, breast cancer is among the most frequently diagnosed and common cause of death among women. Aromatase inhibitors, such as anastrozole, are one of the first-line therapies used in the treatment of breast cancer in postmenopausal women; however, thromboembolic complications are common. Thus, this study investigated the combined effects of anastrozole and antiplatelet therapies, aspirin and clopidogrel, on breast cancer cytotoxicity and survival in vitro. Breast cancer cell lines (MCF-7 and T47D) were treated with varying Cmax concentrations of anastrozole and/or antiplatelet therapies for 24 h. A wound-healing scratch assay was used to measure migration and the WST-1 assay for cellular proliferation. An autophagy/cytotoxicity dual staining kit was used to assay cell death and survival. Changes in cell morphology were assessed using scanning electron microscopy. Data were analyzed with Statistica software. Our findings showed that sub-phenotypic differences exist between the luminal-A breast cancer cell lines, with T47D cells being more aggressive than MCF-7 cells. Cellular proliferation and migration responded in a dose-dependent manner for the different treatment groups. Notably, anastrozole combined with aspirin and clopidogrel mediated higher levels of cell survival than each agent individually, with autophagy levels being significantly increased in comparison to that induced with antiplatelet therapy alone.

Interaction of chlorothalonil and Varroa destructor on immature honey bees rearing in vitro.

Under realistic environmental conditions, bees are often exposed to multiple stressors, especially Varroa destructor and pesticides. In this study, the effects of exposure to NOAEC of chlorothalonil during the larval stage, in the presence or absence of V. destructor, was examined in terms of survival, morphological and transcriptional changes. The interaction between chlorothalonil and V. destructor on the survival of honey bee was additive. V. destructor are the dominant factor in the interaction for survival and transcriptome alternation. The downregulation of the genes related to tissue growth and caste differentiation may directly link to the mortality of honey bees. Either chlorothalonil or V. destructor induces the irregular morphology of trophocytes and oenocytes in the fat body. In addition to irregular shapes, oenocytes in V. destructor alone and double-stressor treatment group showed altered nuclei and vacuoles in the cytoplasm. The interaction of V. destructor and chlorothalonil at the larval stage have potential adverse effects on the subsequent adult bees, with up-regulation of genes involved in lipid metabolism and detoxification/defense in fat body tissue. Our findings provide a comprehensive understanding of combinatorial effects between biotic and abiotic stressors on one of the most important pollinators, honey bees.

ABCH2 transporter mediates deltamethrin uptake and toxicity in the malaria vector Anopheles coluzzii.

Contact insecticides are primarily used for the control of Anopheles malaria vectors. These chemicals penetrate mosquito legs and other appendages; the first barriers to reaching their neuronal targets. An ATP-Binding Cassette transporter from the H family (ABCH2) is highly expressed in Anopheles coluzzii legs, and further induced upon insecticide exposure. RNAi-mediated silencing of the ABCH2 caused a significant increase in deltamethrin mortality compared to control mosquitoes, coincident with a corresponding increase in 14C-deltamethrin penetration. RT-qPCR analysis and immunolocalization revealed ABCH2 to be mainly localized in the legs and head appendages, and more specifically, the apical part of the epidermis, underneath the cuticle. To unravel the molecular mechanism underlying the role of ABCH2 in modulating pyrethroid toxicity, two hypotheses were investigated: An indirect role, based on the orthology with other insect ABCH transporters involved with lipid transport and deposition of CHC lipids in Anopheles legs which may increase cuticle thickness, slowing down the penetration rate of deltamethrin; or the direct pumping of deltamethrin out of the organism. Evaluation of the leg cuticular hydrocarbon (CHC) content showed no affect by ABCH2 silencing, indicating this protein is not associated with the transport of leg CHCs. Homology-based modeling suggested that the ABCH2 half-transporter adopts a physiological homodimeric state, in line with its ability to hydrolyze ATP in vitro when expressed on its own in insect cells. Docking analysis revealed a deltamethrin pocket in the homodimeric transporter. Furthermore, deltamethrin-induced ATP hydrolysis in ABCH2-expressing cell membranes, further supports that deltamethrin is indeed an ABCH2 substrate. Overall, our findings pinpoint ABCH2 participating in deltamethrin toxicity regulation.

Can infection with Trypanosoma cruzi modify the toxicological response of Triatoma infestans susceptible and resistant to deltamethrin?

Chemical control plays a central role in interrupting the vector transmission of Chagas disease. In recent years, high levels of resistance to pyrethroids have been detected in the main vector Triatoma infestans, which were associated with less effectiveness in chemical control campaigns in different regions of Argentina and Bolivia. The presence of the parasite within its vector can modify a wide range of insect physiological processes, including toxicological susceptibility and the expression of resistance to insecticides. This study examined for the first time the possible effects of Trypanosoma cruzi infection on susceptibility and resistance to deltamethrin in T. infestans. Using WHO protocol resistance monitoring assays, we exposed resistant and susceptible strains of T. infestans, uninfected and infected with T. cruzi to different concentrations of deltamethrin in fourth-instar nymphs at days 10-20 post-emergence and monitored survival at 24, 48, and 72 h. Our findings suggest that the infection affected the toxicological susceptibility of the susceptible strain, showing higher mortality than uninfected susceptible insects when exposed to both deltamethrin and acetone. On the other hand, the infection did not affect the toxicological susceptibility of the resistant strain, infected and uninfected showed similar toxic responses and the resistance ratios was not modified. This is the first report of the effect of T. cruzi on the toxicological susceptibility of T. infestans and triatomines in general and, to our knowledge, one of the few on the effect of a parasite on the insecticide susceptibility of its insect vector.

Mechanism of non-steroidal anti-androgen-induced liver injury: Reactive metabolites of flutamide and bicalutamide activate inflammasomes.

Flutamide is a non-steroidal anti-androgen agent, which is mainly used for the treatment of prostate cancer. Flutamide is known to cause severe adverse events, which includes idiosyncratic liver injury. However, details of the mechanism of these adverse reactions have not been elucidated. We investigated whether flutamide induces the release of damage-associated molecular patterns (DAMPs) that activate inflammasomes. We also tested bicalutamide, enzalutamide, apalutamide, and darolutamide for their ability to activate inflammasomes in differentiated THP-1 cells. The supernatant from the incubation of flutamide and bicalutamide with human hepatocarcinoma functional liver cell-4 (FLC-4) cells increased caspase-1 activity and production of IL-1ß by differentiated THP-1 cells. In the supernatant of FLC-4 cells with flutamide and bicalutamide, the heat shock protein (HSP) 40 or 60 was significantly increased. Addition of a carboxylesterase or a CYP inhibitor to the FLC-4 cells prevented release of HSPs from the FLC-4 cells. These results suggested that the reactive metabolites of flutamide and bicalutamide can cause the release of DAMPs from hepatocytes and activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by flutamide or bicalutamide, which in some patients, can cause immune-related adverse events.

Predatory stink bug, Eocanthecona furcellata (Wolff) responses to oral exposure route of λ-cyhalothrin via sex-specific modulation manner.

The toxic effects of insecticides on predatory arthropods have closely related to their exposure routes. However, little is known about the effects of insecticide on reproductive parameters when the route of exposure occurs at a trophic level via prey intake. We therefore conducted current studies assessing whether Eocanthecona furcellata adults would be affected by feeding with λ-cyhalothrin-contaminated prey. Reproductive parameters, i.e. prolonged premating and preoviposition durations, reduced number of egg batches and egg amount, disturbed ovarian development, and suppressed expression of reproductive related genes were observed in E. furcellata females by feeding with treated prey. Moreover, reduced survival rate and altered carbohydrate metabolism parameters were detected in male bugs. Biochemical parameters, including MDA content, the activities of three antioxidant enzymes and three detoxification enzymes exhibited sex-specific responses after oral-exposure to λ-cyhalothrin in E. furcellata. The results indicate that the insecticide affects the fitness and leads to impairing reproductive potential via sex-specific modulation manner in predator insects. Taken together, our results provide a comprehensive assessment about detrimental impacts of λ-cyhalothrin-exposure on predators via prey intake, as well as a solid basis for further research to protect the predators from hazardous impacts of insecticides.