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Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R-famoxadone was 1.5 times more toxic to HepG2 cells than S-famoxadone. R-famoxadone induced more pronounced ferroptosis compared to S-famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R-famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R-famoxadone in mice was six times higher than that of S-famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R-famoxadone caused its preferential accumulation. Overall, R-famoxadone poses a higher risk than S-famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.

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Thyroid dysfunction has become a serious public health problem, which is considered a trigger of nonalcoholic fatty liver disease (NAFLD). Pesticide exposure could contribute to thyroid dysfunction and NAFLD, but the relationship between these factors remains unclear. In this study, the effects of subchronic famoxadone exposure on thyroid and liver at no observed adverse effect level (NOEL) related concentrations were investigated using in vivo, in vitro, and in silico models. Famoxadone caused hepatic steatosis, lipid metabolism disorder, and liver oxidative stress and induced NAFLD in male mice. The suppression of hepatic fatty acid ß-oxidation was the key factor of NAFLD, which was highly associated with hypothalamic-pituitary-thyroid (HPT) axis hormones disorder. Famoxadone disrupted thyroid hormone biosynthesis by causing thyroid follicle aberrations and abnormal HPT axis-related gene expression. In vitro studies confirmed that famoxadone inhibited the transport of thyroxine (T4) into hepatocytes and the conversion of T4 to triiodothyronine (T3). In silico studies verified that famoxadone interfered with the binding of thyroid hormones to proteins mediating thyroid hormone transport, conversion, and activation. This study comprehensively reported the association between NAFLD and thyroid dysfunction caused by famoxadone, providing new perspectives for the health risk evaluation of pesticides with a similar structure in mammals.

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The bioaccumulation, metabolism, tissue-specific distribution and toxicity of the widely used organophosphorous pesticide malathion to zebrafish were investigated on an enantiomeric level for evaluating the environmental risks. The metabolites were also monitored and evaluated. Malathion was metabolized by zebrafish very fast with the half-life of 0.12 d and showed a middle accumulation capacity in zebrafish with bioaccumulation factor (BCF) of 12.9 after a 15-d exposure. Brain could enrich higher concentration of malathion than other tissues. The metabolites malaoxon, malathion/malaoxon monocarboxylic acid (DMA), malathion/malaoxon dicarboxylic acid (DCA), dimethylthiophosphate (DMTP) and dimethyldithiophosphate (DMDTP) were found, in which DMTP and DCA were in higher level, indicating the metabolism was mainly induced by carboxylesterase degradation. The accumulation of malathion and malaoxon was stereoselective in zebrafish tissues, exhibiting S-enantiomer preferentially enriched. The acute toxicity test showed rac-malathion was low toxic to zebrafish, which was 1.2 and 1.6 folds more toxic than S-malathion and R-malathion respectively. Malaoxon was highly toxic to zebrafish and approximately 32 times more toxic than malathion. The toxicity of other metabolites was lower than malathion. Malathion could cause an apparent developmental toxicity to zebrafish embryo, including bradycardia, hatchability reduction and deformity, and abnormal movement patterns in zebrafish larva. Chronic toxicity indicated that malathion and malaoxon induced oxidative damage and neurotoxicity in the liver, brain and gill of zebrafish, and malaoxon exhibited a relatively high injury to the zebrafish brain. The results can provide information for the comprehensive assessment of the potential risk of malathion to aquatic organisms and highlight the necessity of consideration of stereoselectivity and metabolites when systemically evaluating pesticides.

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Pesticides are widely used and frequently detected in the environment. The evaluation on the toxic effects of the co-exposure of two or more pesticides or related metabolites could reflect the real situation of the exposing risks. In this study, zebrafish was used as a model to investigate the potential toxic interactions of chlorpyrifos and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) on the survival rate, oxidative stress response and neurotoxicity, as well as their bioaccumulation and distribution in tissues. Co-exposure of chlorpyrifos and p,p'-DDE resulted in significant additive acute toxic effects on adult zebrafish with model deviation ratio (MDR) = 1.64. Both 7-day short-term at 1% LC50 and 35-day long-term at 0.5% LC50 co-exposure of chlorpyrifos with p,p'-DDE (50 and 100 µg/L) significantly reduced the survival rate of zebrafish colony to 75 and 82.5%. Co-exposure of chlorpyrifos and p,p'-DDE contributed to increased activity of antioxidant enzyme CAT, SOD and GST and excessive MDA generation, and decreased activity of CarE, CYP450 and AChE, compared with either single exposure of them. In co-exposure, the bioaccumulation of chlorpyrifos and p,p'-DDE was significantly different from the single exposure group. Overall, this study unraveled the potential toxic interaction of chlorpyrifos and p,p'-DDE on zebrafish and provided reference for environmental risk assessment of pesticide mixture.

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After application, pesticides remained in the field may contaminate water resources through surface runoff and leaching, posing a threat to aquatic ecosystem. In the current study, the accumulation, translocation, distribution and removal of four triazine pesticides (simazine, atrazine, terbuthylazine and metribuzin) by free floating aquatic plant Eichhornia crassipes (E. crassipes) in water-sediment microcosm were investigated and the removal mechanisms were explored. E. crassipes was exposed to an initial concentration of 50 µg·L-1 and the pesticide levels in water, sediment, roots and shoots of E. crassipes were monitored during 30 days. The results demonstrated that E. crassipes was capable of accumulating triazine pesticides with the bio-concentration factor (BCF) ranging from 0.8 to 18.4. Triazine pesticides were mainly stored in roots, and root accumulation and translocation amount depend on the hydrophobicity of the pesticides. The removal of the pesticides in water were significantly accelerated by the presence of E. crassipes, with the removal efficiency ranging from 66% to 79% after 30 days of treatment. Though phytoaccumulation only constituted 2-18% of the total spiked pesticides in the microcosm, E. crassipes played a vital role in removing simazine, atrazine and metribuzin. However, microbial degradation in sediment was the main pathway for the removal of terbuthylazine in the microcosm. This study demonstrated the potential application of E. crassipes to accelerate removal of contaminants from aquatic environment.

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Pyriproxyfen is a juvenile hormone analogue insecticide used worldwide. At present, the potential threat of pyriproxyfen to aquatic organism has not been well explored. In this work, the bioaccumulation, metabolic profile and toxicity of pyriproxyfen and its metabolites to zebrafish were studied, and the enantioselectivity of pyriproxyfen and the major chiral metabolites were also determined. Sixteen metabolites of pyriproxyfen in zebrafish were identified. Hydroxylation, ether linkage cleavage and oxidation in phase I metabolism, followed by sulfate and glucuronic acid conjugation. The bioconcentration factors ranged from 1175 to 1246. Hydroxylation metabolites of pyriproxyfen showed enantioselective behavior in zebrafish with enantiomer fractions (EFs) of 4'-OH- pyriproxyfen and 5″-OH- pyriproxyfen ranged from 0.50 to 0.71. Toxicological indexes including acute toxicity, joint toxicity and oxidative stress were tested. Among all the metabolites, 4'-OH- pyriproxyfen was found 2 folds more toxic to zebrafish than pyriproxyfen. (-)-Pyriproxyfen was found 2 folds more toxic than rac- and (+)-pyriproxyfen. Antagonistic effects were found in binary joint toxicity of pyriproxyfen and its hydroxylated metabolites. Pyriproxyfen and its metabolites also showed oxidative stress damage by inhibiting the activity of CAT and SOD and increasing MDA. This work provided deep insight into the metabolism and the potential risks of pyriproxyfen to aquatic organisms.

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Ethiprole is effective against a wide range of insects and has been used throughout the world. In this work, the toxicity, bioaccumulation and elimination of ethiprole and its main metabolites (ethiprole sulfone (M1), ethiprole sulfide (M2), ethiprole amide (M3), ethiprole sulfone amide (M4) and desethylsulfinyl ethiprole (M5)) in zebrafish Danio rerio were investigated at enantiomeric level. Rac-ethiprole showed high toxicity (96 h LC50 = 708 µg L-1) and M2 was six times more toxic than ethiprole (111 µg L-1). Enantioselective toxicity was observed, with the S-ethiprole (924 µg L-1) being more toxic than R-ethiprole (2195 µg·L-1). Rac-ethiprole and M2 could induce oxidative stress in the liver of adult zebrafish and developmental toxicity in zebrafish embryos. Zebrafish were exposed to 100 µg L-1 rac-/R-/S-ethiprole and the bioaccumulation was monitored during a 21 d period followed by a 7 d metabolism. The bioconcentration factor (BCF) of rac-ethiprole was 17, and the half-lives of rac-ethiprole and metabolites varied between 0.44 and 2.99 d. R-ethiprole was preferentially accumulated and metabolized in zebrafish. Besides, the metabolic pathways of R- and S-ethiprole were found to be different. This study indicated assessment of metabolites and enantioselectivity should be taken into consideration in evaluating environmental risks of ethiprole.

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Antibiotics are currently extensively used in human medicine, animal farming, agriculture and aquaculture, and their residue has become a global environmental problem. However, the effects of antibiotic on other pollutants in aquatic environment are still poorly understood. In this study, the influences of norfloxacin on the residue, degradation and distribution of the herbicides (simazine, atrazine, terbuthylazine, acetochlor and metolachlor) and the enantioselectivity of acetochlor in sediment and water-sediment microcosm system were investigated. Sediment was spiked with norfloxacin and water was contaminated by herbicides to simulate environmental pollution. The amounts of herbicides in water and sediment samples were analyzed within 30 days of cultivation. The results showed that norfloxacin could significantly inhibit the dissipation, lengthen the half-lives and enhance the residues of herbicides in sediment. Take simazine as an example, its half-life significantly increased from 16.1 days to 19.3 days and its residual percentage grew from 24.2% to 30.4% when sediment was contaminated with 5 mg·kg-1 norfloxacin. However, only acetochlor degradation was significantly inhibited by norfloxacin in water-sediment microcosm and the distribution of the herbicides were not affected. Enantioselective degradation of acetochlor was observed both in control and norfloxacin-treated water-sediment system, with R-acetochlor preferential elimination, suggesting the co-existence of norfloxacin had very limited influence on the enantioselectivity. The findings indicated that co-contamination with norfloxacin could increase the persistence of herbicides in aquatic environment, thus increasing the environmental risks to aquatic organisms.

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Tributyltin (TBT), an organotin compound once widely used in agriculture and industry, has been reported to induce obesity and endocrine disruption. Gut microbiota has a strong connection with the host's physiology. Nevertheless, the influences of TBT exposure on gut microbiota and whether TBT-influenced gut microbiota is related to TBT-induced toxicity remain unclear. To fill these gaps, ICR (CD-1) mice were respectively exposed to TBT at NOEL (L-TBT) and tenfold NOEL (H-TBT) daily by gavage for 8 weeks in the current study. The results showed that TBT exposure significantly increased body weight as well as epididymal fat, and led to adipocyte hypertrophy, dyslipidemia and impaired glucose and insulin homeostasis in mice. Additionally, TBT exposure significantly decreased the levels of T4, T3 and testosterone in serum. Also of note, TBT exposure changed gut microbiota composition mainly by decreasing Bacteroidetes and increasing Firmicutes proportions. To confirm the role of gut microbiota in TBT-induced overweight and hormonal disorders, fecal microbiota transplantation was performed and the mice receiving gut microbiota from H-TBT mice had similar phenotypes with their donor mice including significant body weight and epididymal fat gain, glucose and insulin dysbiosis and hormonal disorders. These results suggested that gut microbiome altered by TBT exposure was involved in the TBT-induced increased body weight, impaired glucose and insulin homeostasis and endocrine disruption in mice, providing significant evidence and a novel perspective for better understanding the mechanism by which TBT induces toxicity.

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Carbosulfan is a carbamate insecticide that has been widely used in agriculture. However, studies showed that carbosulfan could be highly toxic to aquatic organisms. The metabolism of carbosulfan in adult zebrafish is still largely unexplored, and the metabolites in individual or in combination may pose a potential threat to zebrafish. In the present study, the bioaccumulation and metabolism of carbosulfan in zebrafish (Danio rerio) were assessed, and the main metabolites, including carbofuran and 3-hydroxycarbofuran, were determined. The toxicity of carbosulfan and its metabolites individually or in combination to zebrafish was also investigated. The bioaccumulation and metabolism experiment indicated that carbosulfan was not highly accumulated in zebrafish, with a bioaccumulation factor of 18 after being exposed to carbosulfan for 15 days, and the metabolism was fast, with a half-life of 1.63 d. The two main metabolites were relatively persistent, with half-lives of 3.33 and 5.68 d for carbofuran and 3-hydroxycarbofuran, respectively. The acute toxicity assay showed that carbofuran and 3-hydroxycarbofuran had 96-h LC50 values of 0.15 and 0.36 mg/L, showing them to be more toxic than carbosulfan (96-h LC50 = 0.53 mg/L). Combinations of binary or ternary mixtures of carbosulfan and its metabolites displayed coincident synergistic effects on acute toxicity, with additive index (AI) values of 1.9-14.3. In the livers and gills of zebrafish exposed to carbosulfan, carbofuran, and 3-hydroxycarbofuran, activities of catalase, superoxide dismutase, and glutathione-S-transferase were significantly changed in most cases, and the content of malondialdehyde was greatly increased, indicating that carbosulfan and its metabolites induced varying degrees of oxidative stress. The metabolites were more persistent and toxic to zebrafish and exhibit coincident synergistic effects in combination. These results can provide evidence for the potential risk of pesticides and highlight the importance of a systematic assessment for the combination of the precursor and its metabolites.

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Chiral fungicide prothioconazole has a wide range of antifungal spectrum; however, little research has been conducted to evaluate prothioconazole on an enantiomeric level. Five target pathogens and three common aquatic organisms were tested for the enantioselective bioactivity and toxicity of prothioconazole in this work. The antifungal activity of the enantiomers against wheat phytoalexin, rice blast fungus, exserohilum turcicum, Alternaria triticina, and Fusarium avenaceum was determined, and it was found that (-)-prothioconazole were 85 to 2768 times more active than (+)-prothioconazole toward these target organisms. In order to reflect the risk to aquatic ecosystem, the acute toxicity of the enantiomers to Daphnia magna, Chlorella pyrenoidosa, and Lemna minor L. was assessed. It was observed that the toxicity of (-)-prothioconazole to D. magna was 2.2 times higher than (+)-prothioconazole, but it was lower to C. pyrenoidosa and L. minor L. The toxicities of (+)-enantiomer and (-)-enantiomer to D. magna and C. pyrenoidosa were synergy, indicating that the racemate had higher threat to the organisms. It could be concluded that the effects of prothioconazole on target organisms and the acute toxicity to nontarget species were enantioselective with (-)-enantiomer possessing higher efficiency and lower toxicity. Such enantiomeric differences should be taken into consideration when assessing the performance of prothioconazole.

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