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The safety of drinking water has always been a concern for people all over the world. N-nitrosamines (NAs), a kind of nitrogenous disinfection by-products (N-DBPs), are generally detected as a mixture in drinking water at home and abroad. Studies have shown that individual NAs posed strong carcinogenicity at high concentrations. However, health risks of NAs at environmental levels (concentrations in drinking water) are still unclear. Therefore, the potential health risks of environmentally relevant NAs exposure in drinking water needs to be conducted. In this study, blood biochemical analysis and metabolomics based on nuclear magnetic resonance (NMR) were performed to comprehensively investigate NAs induced metabolic disturbance in infant rats at environmental levels. Results of blood biochemical indices analysis indicated that AST in the serum of male rats in NAs-treated group exhibited a significant gender-specific difference. Multivariate statistics showed that two and eight significantly disturbed metabolic pathways were identified in the serum samples of NAs-treated male and female rats, respectively. In the urine samples of NAs-treated female rats, glycine, serine, and threonine metabolism pathway was significantly disturbed; while three significantly disturbed metabolic pathways were found in the urine of NAs-treated male rats. Finally, results of spearman correlation coefficients suggested that the disturbances of metabolism profile in serum and urine were correlated with changes in the gut microbiota (data derived from our published paper). Data presented here aimed to generate new health risk data of NAs mixture exposure at environmental levels and provide theoretical support for drinking water safety management. ENVIRONMENTAL IMPLICATION: N-nitrosamines (NAs) are a kind of nitrogenous disinfection by-products (N-DBPs) generated during drinking water disinfection processes. Herein, health risks of NAs at environmental levels (concentrations in drinking water) are investigated using blood biochemical analysis and nuclear magnetic resonance (NMR)-based metabolomics. Results confirmed NAs induced gender-specific on the metabolism in rat and the disturbances of metabolism profile in serum and urine were correlated with changes in the gut microbiota. Data presented here aimed to generate new health risk data of NAs mixture exposure at environmental levels and provide theoretical support for drinking water safety management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

The emergence of resistance to existing succinate dehydrogenase inhibitor fungicides (SDHIs) calls for the urgent innovation of novel formulations, but also results in an increase information gap on the ecological risks of novel SDHIs especially to non-target organisms. Herein, the environmental behavior and toxicological effects of a novel SDHI, fluindapyr (FIP), were evaluated using earthworm as model non-target organism. Results showed that FIP had a relatively shorter half-live (about 28 days) in artificial soil compared with traditional SDHIs. Besides, FIP exhibited a rapid uptake and bioaccumulation trend in earthworms. For the toxicological effects, FIP suppressed earthworm growth (≥ 5 mg/kg) and reproduction (≥ 1 mg/kg) whereas no lethal effects were observed up to the highest tested concentration of 25 mg/mg. FIP of high exposure concentrations also induced serious epidermis and intestines damage as well as oxidative stress to earthworms after 28-day exposure. In addition, expression of oxidative damage related genes (CAT, CRT, GST, HSP70, SOD) was further verified after FIP exposure. The earthworm Tier 1 RQ also indicated a potential risk for earthworm reproduction. Data presented here may be useful for the risk assessments of FIP in soil ecosystems and help to set appropriate precautions to ensure protection against novel SDHIs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Glufosinate (Glu), a broad-spectrum and highly effective non-selective herbicide, behaves in typical chiral features to target organisms. However, the information on the enantioselective toxicity of DL-Glu and L-Glu against non-target organisms is still limited especially at environmental concentrations. In this study, we investigated the potential mechanism accounting for the enantioselective cytotoxicity of Glu based on cell cycle and apoptosis. Results showed that DL-Glu and L-Glu had no suppression on cell viability at 10 -5  M, however, SH-SY5Y cells were significantly arrested at G 1 /G 0 phase after L-Glu exposure compared with DL-Glu. The apoptosis assay exhibited an increase in late apoptosis cells and a decrease in viable cells for DL-Glu and L-Glu treatment. The bioinformatics analysis demonstrated that alterations in transcription translation and signal transduction including "calcium signaling pathway", "Wnt signaling pathway", "FoxO signaling pathway" were the possible pathways responsible for Glu-induced enantioselectivity in cell cycle and apoptosis. Interestingly, the Gene Set Enrichment Analysis (GSEA) also revealed the probable association between DL-Glu exposure and degenerative diseases. These findings serve as a reminder that caution should be exercised not only when using pesticide racemates but also when promoting or applying single- or enriched-isomer pesticides., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In previous studies, 6:2 chlorinated polyfluorinated ether sulfonic acid (6:2 Cl-PFESA), a perfluorooctanesulfonate alternative, has been demonstrated to be toxic to mammals. However, the toxic mechanism of 6:2 Cl-PFESA in mammals is unknown. Herein, adolescent male rats were administered 50 μg/kg/Day 6:2 Cl-PFESA for 28 days (oral gavage) to estimate the toxicity of 6:2 Cl-PFESA and investigate its toxic mechanism. Significant changes in some hematological indicators (e.g., aspartate transaminase and neutrophils) and liver sections (inflammatory cell infiltration) indicated that 6:2 Cl-PFESA exposure caused rat hepatotoxicity. Six steroid hormones (e.g., testosterone, progesterone, and cortisol) in serum and thirteen genes in testicles (related to the pathway of steroid hormone biosynthesis) were significantly regulated in 6:2 Cl-PFESA-treated rats. This suggested that 6:2 Cl-PFESA induced rat endocrine disorders. Compared to the controls, the mean relative abundance of Ruminococcaceae, Pasteurellaceae, Micrococcaceae, and Desulfovibrionaceae was significantly regulated by 1.3-, 0.40-, 0.32-, and 3.2-fold in the 6:2 Cl-PFESA rats, respectively. The 6:2 Cl-PFESA treatment also significantly disturbed 47 gut metabolites (29 upregulated and 18 downregulated), mainly bile acids, short-chain fatty acids, and amino acids. In summary, 6:2 Cl-PFESA induced endocrine disorders and liver inflammation in rats by altering the gut microbiota-gut-testis/liver axis. This study first reveals the toxic mechanism of 6:2 Cl-PFESA in mammals through a multiomics approach and provides comprehensive insight into the toxic mechanism of 6:2 Cl-PFESA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

As a special category of pesticides, chiral pesticides have increased the difficulty in investigating pesticide toxicity. Based on their usage, chiral pesticides can be divided into insecticides, herbicides, and fungicides. Over the past decades, great efforts have been made on elucidating their toxicological effects. However, no literature has reviewed the enantioselective toxicity of chiral pesticides since 2014. In recent years, more chiral pesticides have been registered for application. As such, huge research progresses have been achieved in enantioselective toxicity of chiral pesticides. Generally, more researches have remedied the knowledge gap in toxicological effects of old and new chiral pesticides. And the toxicological endpoints being evaluated have become more specific rather than centering on basic toxicity and target organisms. Besides, the underlying mechanisms accounting for the enantioselectivity in toxicological effects of chiral pesticides have been discussed as well. All in all, this review provides the critical knowledge for risk assessments, and help to drive the green-technology of single- or enriched-enantiomer pesticides and formulation of relevant laws and regulations., Competing Interests: Declaration of competing interest The authors declare no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Locust plagues are still worldwide problems. Selecting active enantiomers from current chiral insecticides is necessary for controlling locusts and mitigating the pesticide pollution in agricultural lands. Herein, two enantiomers of isocarbophos (ICP) were separated and the enantioselectivity in insecticidal activity against the pest Locusta migratoria manilensis (L. migratoria) and mechanisms were investigated. The significant difference of LD 50 between (+)-ICP (0.609 mg/kg bw) and (-)-ICP (79.412 mg/kg bw) demonstrated that (+)-ICP was a more effective enantiomer. The enantioselectivity in insecticidal activity of ICP enantiomers could be attributed to the selective affinity to acetylcholinesterase (AChE). Results of in vivo and in vitro assays suggested that AChE was more sensitive to (+)-ICP. In addition, molecular docking showed that the -CDOKER energies of (+)-ICP and (-)-ICP were 25.6652 and 24.4169, respectively, which suggested a stronger affinity between (+)-ICP and AChE. Significant selectivity also occurred in detoxifying enzymes activities (carboxylesterases (CarEs) and glutathione S-transferases (GSTs)) and related gene expressions. Suppression of detoxifying enzymes activities with (+)-ICP treatment suggested that (-)-ICP may induce the detoxifying enzyme-mediated ICP resistance. A more comprehensive understanding of the enantioselectivity of ICP is necessary for improving regulation and risk assessment of ICP., (Copyright © 2021. Published by Elsevier Inc.)

In this study, the stereochemistry, stereoselective fungicidal bioactivity, and antifungal mechanism of chiral triazole fungicide metconazole were investigated. The configurations of metconazole stereoisomers were determined to be (1R, 5R)-metconazole, (1R, 5S)-metconazole, (1S, 5S)-metconazole, and (1S, 5R)-metconazole through using electronic circular dichroism spectroscopy. The bioactivities of four stereoisomers and their stereoisomer mixture toward Fusarium graminearum Schw and Alternaria triticina were found to be in the following order: (1S, 5R)-metconazole > the stereoisomer mixture > (1S, 5S)-metconazole > (1R, 5R)-metconazole > (1R, 5S)-metconazole. In addition, the fungicidal activities of (1S, 5R)-metconazole against two tested pathogens was 13.9-23.4 times higher than those of (1R, 5S)-metconazole. Molecular docking methodology was applied to characterize the docking energy and distances between Cytochrome P450 CYP51B and the metconazole stereoisomers, and (1S, 5R)-metconazole showed the strongest binding energy and the shortest distance binding to CYP51B than the other three stereoisomers. Moreover, enantioselective metabolisms of (1S, 5R)-metconazole and (1R, 5S)-metconazole by Fusarium graminearum Schw were investigated through NMR-based metabolomics. The amounts of alanine, arginine, acetate, ethanol, and dimethylamine produced in the presence of (1R, 5S)-metconazole were significantly higher than corresponding amounts in the presence of (1S, 5R)-metconazole, whereas the amounts of glucose, glycerol, glutamate, methionine, and trimethylamine formed in the presence of (1R, 5S)-metconazole were much less than those in the presence of (1S, 5R)-metconazole. This systematic investigation of metconazole stereoisomers would provide a new perception of metconazole in stereoisomeric level, including bioactivities, metabolic behaviors and antifungal mechanism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cypermethrin (CP) is a frequently used chiral pesticide comprised of different enantiomers that can induce a variable toxic response in biota, dependent on conformational change. However, the potential mechanism accounting for the enantioselective toxicity induced by CP enantiomers remains unknown. Herein, to shed light on the underlying mechanism of enantioselective cytotoxicity on cell cycle and apoptotic function, an MTT assay, flow cytometric (FCM) approach, and qPCR arrays combining bioinformatic analysis were conducted on HepG2 cell lines following exposure to CP enantiomers. Decreased cell viability in keeping with increased cell arrest and apoptosis was observed in cells exposed to (1S,3R,αR)-CP, relative to the (1R,3S,αS)-CP treatment group. PCR array also reflected an enantioselective difference in expression of cell cycle and apoptosis-related genes. Ingenuity pathway analysis (IPA) showed that cell cycle checkpoints, arrest in interphase, death receptor signaling, and apoptosis were among the top canonical and disease and functions predicted to be affected between CP enantiomers. Data presented here not only provide potential molecular endpoints for evaluating toxicity by cell cycle and apoptosis but also help to guide the scientific application of chiral pesticides., (Copyright © 2020 Elsevier B.V. All rights reserved.)

2,7-Dibromocarbazole (2,7-DBCZ) is one of the most frequently detected polyhalogenated carbazoles (PHCZs) in the environmental media. 2,7-DBCZ has attracted public attention for its potential for dioxin-like toxicity and cardiovascular toxicity. However, researches on the potential mechanism of angiogenesis inhibition by 2,7-DBCZ is still insufficient. Herein, human umbilical vein endothelial cells (HUVECs) were applied to explore the angiogenic effect of 2,7-DBCZ and the potential underlying mechanisms. 2,7-DBCZ significantly inhibited tube formation in HUVECs in the non-toxic concentration range. PCR array showed that 2,7-DBCZ reduced the expression proportion between VEGFs and Ang2, thereby inhibiting tube formation in HUVECs. Then, small RNA interference and DNA methylation assays were adopted to explore the potential mechanisms. It has been found that angiopoietin2 (Ang2)-silencing recovered the tube formation inhibited by 2,7-DBCZ. The DNA methylation status of Ang2 promoter also showed a demethylation tendency after exposure. In conclusion, 2,7-DBCZ could demethylate the Ang2 promoter to potentiate Ang2 expression, thus altering angiogenic phenotype of HUVECs by reducing the proportion between Ang2 and VEGFs. The data presented here can help to guide safety measures on the use of dioxin-like PHCZs for their potential adverse effects and provide a method for identifying the relevant biomarkers to assess their cardiovascular toxicity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Polyhalogenated carbazoles (PHCZs), which have the similar structure of dioxin, have been reported ubiquitous in the environments and drawn wide concerns. However, their potential ecological and health risks are still poorly understood. Here, wildtype zebrafish embryos were used to evaluate the environmental risks of 2,7-dibromocarbazole (2,7-DBCZ), 3,6-dibromocarbazole (3,6-DBCZ), and 3,6-dichlorocarbazole (3,6-DCCZ). 2,7-DBCZ was the most toxic compound with the 96-h LC 50 value of 581.8 ± 29.3 μg·L -1 and the EC 50 value of 201.5 ± 6.5 μg·L -1 for pericardial edema. The teratogenic effects of 2,7-DBCZ were tested using transgenic zebrafish larvae. The transcriptomic analysis revealed that 90 genes in zebrafish expressed differently after exposure to 2,7-DBCZ, and many pathways were related to aryl hydrocarbon receptor (AhR) activation. The qRT-PCR also showed that expression levels of AhR1 and CYP1 A in zebrafish were significantly up-regulated after exposure to 2,7-DBCZ. In conclusion, 2,7-DBCZ exhibited more potent toxicity and cardiac teratogenic effects, and presented developmental toxicity partially consistent with AhR activation. Our results will be of great help to the risk assessment and regulation-making of PHCZs. Meanwhile, further studies should be promoted to illustrate the potential mechanism between PHCZs and AhR in the near future., (Copyright © 2019 Elsevier B.V. All rights reserved.)