Emergence of Lasiodiplodia theobromae induced leaf necrosis in tea (Camellia sinensis [L.] O. Kuntze) from India.

The tea plant, Camellia sinensis [L.] O. Kuntze, is a vital global agricultural commodity, yet faces challenges from fungal infections, which affects its production. To reduce the loss in the tea production, the fungal infections must be removed which is managed with fungicides, which are harmful to the environment. Leaf necrosis, which decreases tea quality and quantity, was investigated across Assam, revealing Lasiodiplodia theobromae as the causative agent. Pathogenicity tests, alongside morphological and molecular analyses, confirmed its role in leaf necrosis. Genome and gene analysis of L. theobromae showed multiple genes related to its pathogenicity. The study also assessed the impact of chemical pesticides on this pathogen. Additionally, the findings in this study highlight the significance of re-assessing management approaches in considering the fungal infection in tea.

Green Synthetic Approach for the Preparation of Blue Emitting Gold Nanoclusters: A Simple Analytical Method for Detection of Hexaconazole Fungicide.

Blue emissive Argyreia nervosa-capped gold nanoclusters (A. nervosa-AuNCs) were synthesized via a simple environment-friendly method. The developed probe exhibits rapid response towards the target analyte (hexaconazole fungicide). Several characterizations, including FT-IR, UV-visible, fluorescence, HR-TEM, XPS, and fluorescence lifetime, were studied to confirm the formation of A. nervosa-AuNCs. The A. nervosa-AuNCs displayed emission and excitation peaks at 470 and 390 nm, respectively. Furthermore, the quantum yield (QY) of A. nervosa-AuNCs was 21.25%. The as-synthesized A. nervosa-AuNCs showed a good linear response with hexaconazole in the concentration range of 0.025-180 µM, with a detection limit (LOD) of 21.94 nM, indicating A. nervosa-AuNCs could be used as a sensitive and selective probe for detecting hexaconazole through a fluorescence "turn-off" mechanism. The A. nervosa-AuNCs were successfully used to detect hexaconazole in real samples. Moreover, A. nervosa-AuNCs were used as a bio-imaging probe for visualization of Saccharomyces cerevisiae cells.

Neurotoxicity of hexaconazole on rat brain: The aspect of biological rhythm.

Hexaconazole is a widely used and frequently detected fungicide which is also reported to be persistent in environment. The toxicity of Hex to non-organisms such as reproductive toxicity, endocrine disrupting toxicity, and carcinogenic toxicity had been reported. However, study on the Hex-induced neurotoxicity is rare and the mechanism is still unclear. Therefore, in this study, environmental related concentrations of Hex were chosen to investigate the effects of Hex on nervous system from the aspect of biological rhythm under 90 d sub-chronic exposure. The results showed that Hex significantly affected the cognitive function of rats resulting in the deterioration of learning and memory ability and induced oxidative stress in rat brain. Moreover, the notable changes of neurotransmitters in rat brain suggested the disorder of nerve signaling conduction induced by Hex. The influence of Hex on biological rhythm was further detected which showed that levels of rhythm regulatory genes and proteins significantly disturbed at four monitored time periods. Based on these results, it was supposed that the underlying mechanism of Hex-induced cognitive dysfunction might through oxidative stress pathway. Our findings could systematically and comprehensively clarify the effects of Hex on nervous system and were helpful for prevention neurological diseases induced by triazole pesticides.

Potential Mechanisms of Hexaconazole Resistance in Fusarium graminearum.

Fusarium head blight (FHB) caused by Fusarium graminearum is a serious fungal disease that can dramatically impact wheat production. At present, disease control is mainly achieved by the use of chemical fungicides. Hexaconazole (IUPAC name: 2(2,4-dichlorophenyl)-1-(1,2,4-triazol-1-yl)hexan-2-ol) is a widely used triazole fungicide, but the sensitivity of F. graminearum to this compound has yet to be established. The current study found that the EC50 values of 83 field isolates of F. graminearum ranged between 0.06 and 4.33 µg/ml, with an average EC50 value of 0.78 µg/ml. Assessment of four hexaconazole-resistant laboratory mutants of F. graminearum revealed that their mycelial growth and pathogenicity were reduced compared with their parental isolates and that asexual reproduction was reduced by resistance to hexaconazole. Meanwhile, the mutants appeared to be more sensitive to abiotic stress associated with SDS and H2O2, while their tolerance to high concentrations of Congo red, and Na+ and K+ increased. Molecular analysis revealed numerous point mutations in the FgCYP51 target genes that resulted in amino acid substitutions, including L92P and N123S in FgCYP51A, as well as M331V, F62L, Q252R, A412V, and V488A in FgCYP51B, and S28L, S256A, V307A, D287G, and R515I in FgCYP51C, three of which (S28L, S256A, and V307A) were conserved in all of the resistant mutants. Furthermore, the expression of the FgCYP51 genes in resistant strains was found to be significantly (P < 0.05) reduced compared with their sensitive parental isolates. Positive cross-resistance was found between hexaconazole and metconazole and flutriafol, as well as with the diarylamine fungicide fluazinam, but not with propiconazole, and the phenylpyrrole fungicide fludioxonil, or with tebuconazole, which actually exhibited negative cross-resistance. These results provide valuable insight into resistant mechanisms to triazole fungicides in F. graminearum, as well as the appropriate selection of fungicide combinations for the control of FHB to ensure optimal wheat production.

Sub-chronic exposure to hexaconazole affects the lipid metabolism of rats through mTOR-PPAR-γ/SREBP1 signaling pathway mediated by oxidative stress.

Hexaconazole (Hex) is a widely used and high frequency detected triazole fungicide in agricultural products and environment which may pose potential toxicity to the nontargeted organisms. Hex had been reported to affect lipid homeostasis while the mechanism was undefined. This study aims to explore the characteristic lipidomic profiles and clarify the underlying signaling pathways of Hex-induced lipid metabolism disorder in rat liver. The results showed that sub-chronic exposure to environmental related concentrations of Hex caused histopathological changes, oxidative stress, fat accumulation, lipid biochemical parameter increase in rats. Moreover, the untargeted lipidomic analysis showed that the levels of TAG, PC, and PE and the pathway of glycerophospholipid metabolism were heavily altered by Hex. We further analyzed the lipid metabolism related genes and proteins which revealed that Hex exposure increased amount of lipogenesis by activating oxidative stress-mediated mTOR-PPAR-γ/SREBP1 signaling pathways. The imbalance of lipid homeostasis induced by Hex exposure might further lead to obesity, cardiovascular diseases (CVDs), and hyperlipidemia. Our results provided systematic and comprehensive evidence for the mechanism of Hex-induced lipid metabolism disorder at environmental concentrations and supplied a certain basis for its health risks assessment.

Potency of Hexaconazole to Disrupt Endocrine Function with Sex Hormone-Binding Globulin.

Hexaconazole is widely used as a fungicide for agricultural purposes. However, the endocrine-disrupting potential of hexaconazole is still under investigation. In addition, an experimental study found that hexaconazole may disrupt the normal synthesis of steroidal hormones. The potency of hexaconazole to bind with sex hormone-binding globulin (SHBG), a plasma carrier protein that binds androgens and oestrogens, is unknown. In this study, we evaluated the efficacy of hexaconazole to bind with SHBG by molecular interaction, a molecular dynamics method. In addition, principal component analysis was performed to understand the dynamical behaviour of hexaconazole with SHBG in comparison with dihydrotestosterone and aminoglutethimide. The binding scores of hexaconazole, dihydrotestosterone, and aminoglutethimide with SHBG were found to be -7.12 kcal/mol, -11.41 kcal/mol, and -6.84 kcal/mol, respectively. With respect to stable molecular interaction, hexaconazole showed similar molecular dynamics patterns of root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and hydrogen bonding. The solvent surface area (SASA) and principal component analysis (PCA) of hexaconazole exhibit similar patterns in comparison with dihydrotestosterone and aminoglutethimide. These results show that hexaconazole has a stable molecular interaction with SHBG, which may acquire the active site of the native ligand, resulting in significant endocrine disruption during agricultural work.

Effect of Processing on Reduction in Chiral Pesticide Hexaconazole for Kiwifruit Juice.

In this study, the residue levels of chiral pesticide hexaconazole during kiwifruit juice processing (peeling, homogenization, and sterilization) were investigated by using high-performance liquid chromatography (HPLC), and the dietary risk during these processes was also assessed. Hexaconazole was applied at dosages of 173.33 and 346.66 mg/L (recommended and double recommended dosage) in kiwifruit. In the peeling process, 87.7% to 89.2% of the residues were decreased after peeling. Levels of hexaconazole residues in homogenization and sterilization processes further increased from 0.49% to 24.3% and from 0.2% to 3.0%, respectively. Processing factors (PFs) for (+)- and (-)-hexaconazole after peeling, homogenization, and sterilization were 0.12, 0.88, 0.99 for low-dose treatment and 0.12, 0.87, 0.99 for high-dose treatment, respectively. The enantioselectivity of hexaconazole during these procedures was evaluated by enantiomeric fractions (EFs) values, which were around 0.5 throughout all the procedures, indicating that hexaconazole enantiomers had similar dissipation behaviors during kiwifruit juice processing. The RQc of hexaconazole in pre-peeling samples was significantly greater than 100% under two dosages, while the peeling process can notably decrease the values to an acceptable level. The results of this study could provide guidance for agriculture applications and kiwi commodity production to decrease the risk of hexaconazole residue.

The discovery of combined toxicity effects and mechanisms of hexaconazole and arsenic to mice based on untargeted metabolomics.

The high detected frequencies of hexaconazole (Hex) and arsenic (As) increased the probabilities of their co-existence in agricultural products. However, the combined toxicity effect and mechanism of action for these two pollutants were still unclear. In this study, an untargeted metabolomics method with ultra high performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS) was developed to monitor the changes of endogenous metabolites and metabolism pathways in mice liver. Our study revealed that significant differences in metabolomics profiles were observed after Hex, As, and Hex+As exposure for 90 d. Hex exposure altered 54 metabolites and 11 pathways significantly which were mainly lipid-related. For As exposure, 63 metabolites and 9 pathways were affected most of which were amino acid-related. Hex+As induced 93 metabolites changes with 34% was lipids and lipid-like molecules and 22% was organic acids and derivatives. Hex+As exposure shared the pathways that altered by Hex and As indicated that the interaction of Hex and As might be independent action. The results of this study could provide an important insight for understanding the mechanism of combined toxicity for Hex and As and be helpful for evaluating their health risk to human.

Hexaconazole-Micelle Nanodelivery System Prepared Using Different Surfactants for Ganoderma Antifungal Application.

Reports on fungicide-based agronanochemicals in combating disastrous basal stem rot disease in the oil palm industry are scant. Herein, we describe the potential of fungicide nanodelivery agents based on hexaconazole-micelle systems produced using three different surfactants; sodium dodecylbenze sulfonate (SDBS), sodium dodecyl sulfate (SDS) and Tween 80 (T80). The resulting nanodelivery systems were characterized and the results supported the encapsulation of the fungicide into the micelles of the surfactants. We have investigated in detail the size-dependent effects of the as-synthesized micelles towards the inhibition growth of Ganoderma Boninense fungi. All the nanodelivery systems indicate that their size decreased as the surfactant concentration was increased, and it directly affects the fungal inhibition. It was also found that Tween 80, a non-ionic surfactant gave the lowest effective concentration, the EC50 value of 2, on the pathogenic fungus Ganoderma boninense compared to the other anionic surfactants; SDBS and SDS. This study opens up a new generation of agronanofungicide of better efficacy for Ganoderma disease treatment.

Fungicide tolerant Bradyrhizobium japonicum mitigate toxicity and enhance greengram production under hexaconazole stress.

Bacterial strain RV9 recovered from greengram nodules tolerated 2400µg/mL of hexaconazole and was identified by 16S rDNA sequence analysis as Bradyrhizobium japonicum (KY940048). Strain RV9 produced IAA (61.6µg/mL), ACC deaminase (51.7mg/(protein·hr)), solubilized TCP (105µg/mL), secreted 337.6µg/mL EPS, and produced SA (52.2µg/mL) and 2,3-DHBA (28.3µg/mL). Exopolysaccharides produced by strain RV9 was quantified and characterized by SEM, AFM, EDX and FTIR. Beyond tolerance limit, hexaconazole caused cellular impairment and reduced the viability of strain RV9 revealed by SEM and CLSM. Hexaconazole distorted the root tips and altered nodule structure leading thereby to reduction in the performance of greengram. Also, the level of antioxidant enzymes, proline, TBARS, ROS and cell death was increased in hexaconazole treated plants. CLSM images revealed a concentration dependent increase in the characteristic green and blue fluorescence of hexaconazole treated roots. The application of B. japonicum strain RV9 alleviated the fungicide toxicity and improved the measured plant characteristics. Also, rhizobial cells were localized inside tissues as revealed by CLSM. Colonization of B. japonicum strain RV9 decreased the levels of CAT, POD, APX, GPX and TBARS by 80%, 5%, 13%, 13% and 19%, respectively over plants grown at 80µg/(hexaconazole·kg) soil. The ability to detoxify hexaconazole, colonize plant tissues, secrete PGP bioactive molecules even under fungicide pressure and its unique ability to diminish oxidative stress make B. japonicum an attractive choice for remediation of fungicide polluted soils and to concurrently enhance greengram production under stressed environment.

Evaluation of the safe application of copper nonylphenolsulfonate and hexaconazole in wax gourd under field conditions.

Wax gourd is a popular vegetable and the new organic copper pesticide product of copper nonylphenolsulfonate and hexaconazole was firstly recommended to control the serious disease powdery mildew frequently occurred in wax gourd. However, it is still a concern for data deficiency of residue amounts of these two pesticides in edible portion of wax gourd and the persistence in environment. In this study, the dissipation and residue of copper nonylphenolsulfonate and hexaconazole in wax gourd and soil were investigated. The experiment results demonstrated that the dissipation half-lives of copper nonylphenolsulfonate and hexaconazole in wax gourd and soil were 4.6-5.8 days and 7.1-21.7 days, respectively. After 3 days from the last treatment, the residues of copper nonylphenolsulfonate were below 0.38 mg kg-1 in wax gourd and were below 0.21 mg kg-1 in soil, and the residues of hexaconazole ranged from < 0.01 to 0.19 mg kg-1 in wax gourd and from 0.01 to 0.63 mg kg-1 in soil. The long-term dietary risk assessment was done based on the supervised trial median residue and Chinese dietary pattern combining corresponding standards, by comparing with national estimated daily intake, the results showed that it was safe to use copper nonylphenolsulfonate·hexaconazole 20% microemulsion (ME) at the dosage of 420 g a.i. ha-1 with the pre-harvest interval of 3 days in China. And it also supplied authorities with important data for establishing MRL standards of copper nonylphenolsulfonate and hexaconazole in wax gourd in China.

Hexaconazole-Cu complex improves the salt tolerance of Triticum aestivum seedlings.

Hexaconazole is one of the triazole complexes that are broadly used as systemic fungicides with non-traditional plant growth regulator properties. Hexaconazole-Cu complex (Hex-Cu) is a new triazole derivative, and the biological effect of Hex-Cu has been rarely studied. In this work, we investigated the functions of Hex-Cu in regulating growth and the response to salt stress in the seedlings of Triticum aestivum. Pretreated with 60µmolL(-1) Hex-Cu, the seedling plants got increased root/shoot ratio by 42.0%, and the contents of chlorophyll and soluble protein were also increased by 38.1% and 27.9%, respectively. Furthermore, Hex-Cu alleviated the growth inhibition caused by salt stress, enabled the seedlings to maintain a higher proline content and lower malondialdehyde accumulation. The functions of Hex-Cu in regulating the expression of proline synthetase (P5CS and P5CR) genes were investigated by quantitative real-time PCR (qPCR). Under 100mmolL(-1) NaCl stress, the expression of P5CS and P5CR in the seedlings by Hex-Cu pretreatment were significantly up-regulated. It attributed to the enhanced salt tolerance in plants.

Study on the stereoselective degradation of three triazole fungicides in sediment.

The stereoselective degradation behaviors of chiral triazole fungicides (hexaconazole, flutriafol and tebuconazole) in sediment were investigated under laboratory conditions. The enantiomers were completely separated by high-performance liquid chromatography on a cellulose tris(3-chloro-4-methylphenylcarbamate) (Lux Cellulose-2) column. The mean recoveries of hexaconazole, flutriafol and tebuconazole in sediment ranged from 86.7% to 105.9%. The methods were successfully applied for the enantioselective degradation analysis of fungicides in sediment. The results showed that the dissipation of hexaconazole, flutriafol and tebuconazole stereoisomers in sediment followed first-order kinetics (R(2)>0.95). The degradation rate of the enantiomers was different in sediment, and the (-)-enantiomer (t(1/2) was 86 days for hexaconazole, 139 for flutriafol and 136 for tebuconazole) degraded faster than the (+)-enantiomer (t(1/2) was 94 days for hexaconazole, 144 for flutriafol and 151 for tebuconazole) in native condition. The fungicides were degraded slowly, and no significant enantioselective degradation were observed under sterilized conditions. The results may hold promising implications for the environmental and ecological risk assessment of three important chiral triazole fungicides.

Hexaconazole exposure may lead to Parkinson via disrupting glucocerebrosidase and parkin: molecular interaction, dynamics, MMPBSA and DFT based in-silico predictive toxicology.

Hexaconazole is a known fungicide for agricultural purposes. It has bioaccumulation ability which makes it important for its toxicological characterization. There are various neurological impacts of pollutants on human health. Therefore, in this study, we have done predictive analyses of the interaction mechanism of hexaconazole by molecular interaction analysis, molecular dynamics simulation, and Poisson-Boltzmann surface area (MM-PBSA) to assess hexaconazole's potency to disrupt the homeostasis of glucocerebrosidase (-7.9 kcal/mol) and parkin (-5.67 kcal/mol) proteins which have significant roles in the manifestation of Parkinson disease. The findings reveal that hexaconazole has the potency to form stable interactions with glucocerebrosidase and parkin. This research provides a molecular and atomic-level understanding of how hexaconazole exposure may disrupt the homeostasis of glucocerebrosidase and parkin. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration, and hydrogen bonding exhibited the potent molecular interactions of hexaconazole, which may lead to neurological manifestations such as Parkinson disease.

Hexaconazole induces developmental toxicities via apoptosis, inflammation, and alterations of Akt and MAPK signaling cascades.

Hexaconazole is a highly effective triazole fungicide that is frequently applied in various countries to elevate crop productivity. Given its long half-life and high water solubility, this fungicide is frequently detected in the environment, including water sources. Moreover, hexaconazole exerts hazardous effects on nontarget organisms. However, little is known about the toxic effects of hexaconazole on animal development. Thus, this study aimed to investigate the developmental toxicity of hexaconazole to zebrafish, a valuable animal model for toxicological studies, and elucidate the underlying mechanisms. Results showed that hexaconazole affected the viability and hatching rate of zebrafish at 96 h postfertilization. Hexaconazole-treated zebrafish showed phenotypic defects, such as reduced size of head and eyes and enlarged pericardiac edema. Moreover, hexaconazole induced apoptosis, DNA fragmentation, and inflammation in developing zebrafish. Various organ defects, including neurotoxicity, cardiovascular toxicity, and hepatotoxicity, were observed in transgenic zebrafish models olig2:dsRed, fli1:eGFP, and l-fabp:dsRed. Furthermore, hexaconazole treatment altered the Akt and MAPK signaling pathways, which possibly triggered the organ defects and other toxic mechanisms. This study demonstrated the developmental toxicity of hexaconazole to zebrafish and elucidated the underlying mechanisms.

Identification of potential chemical biomarkers of hexaconazole using in vitro metabolite profiling in rat and human liver microsomes and in vivo confirmation through urinary excretion study in rats.

Hexaconazole (HEX) is an azole fungicide widely used in agricultural practices across various countries and numerous studies have reported the toxic effects of HEX, such as endocrine disruption, immunotoxicity, neurotoxicity and carcinogenicity. Despite its widespread agricultural use and toxic effects, the metabolism of HEX is not completely understood, and information on urinary elimination of HEX or its metabolites is limited. Therefore, in the present study, we aimed to identify HEX metabolites in rat and human liver microsomes followed by their in vivo confirmation using a urinary excretion study in rats to identify potential candidate for exposure biomarkers for human biomonitoring studies. From the in vitro assay, a total of 12 metabolites were observed, where the single oxidation metabolites (M5 and M6) were the most abundant metabolites in both rat and human liver microsomes. The triple oxidation followed by dehydration metabolite, M8 (which could also be hexaconazole acid or hydroxy keto-hexaconazole), and the double oxidation metabolite (M9) were the major metabolites found in rat urine and were detectable in rat urine longer than the parent. These metabolites increased with decreasing concentrations of HEX in the rat urine samples. Therefore, metabolites M8, M9 and M5 could be pursued further as potential biomarkers for assessing and monitoring human exposure to HEX.

Gender-related in vitro metabolism of hexaconazole and its enantiomers in rats.

In the present study we investigated the enantioselective disappearance of hexaconazole in rat liver microsomes system prepared from both genders. High-performance liquid chromatography (HPLC) was used for identification and quantification. The degradation of the (+)-hexaconazole was faster than that of the (-)-hexaconazole in racemic hexaconazole and single enantiomer incubation in both sexes. The degradation half-life of the (+)-hexaconazole or (-)-hexaconazole was also gender-related. The metabolism of (+)-hexaconazole and (-)-hexaconazole were faster in male rat hepatic microsomes than that in female, suggesting that at least one of the cytochrome P450s (CYP) in the male rat liver microsomes system responsible for hexaconazole metabolism was male-specific or considerably more active. Kinetic assays showed that the intrinsic clearance in male rat liver microsomes was higher than that in female. All these results strongly suggest that sexual dimorphic metabolism of hexaconazole exists in rats. The inhibition experiments with CYP inhibitors showed that the inhibitory effect of inhibitors was enantioselective and affected by sex. The results suggest that the enantioselective metabolism of hexaconazole was determined by the amount of hepatic cytochrome P450 and the expression of individual isoforms of CYPs.

Stereoselective Toxicokinetic and Distribution Study on the Hexaconazole Enantiomers in Mice.

Hexaconazole (Hex) has been widely used in agricultural products, and its residues may pose a potential risk to human health. However, the metabolic behavior of Hex enantiomers in mammal organisms is still unknown, which is important for evaluating the differences in their toxicity. In this study, the distribution of S-(+)- and R-(-)-Hex in mice was detected by an ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS), and the mechanism differences in the toxicokinetic behavior were analyzed by molecular docking. Good linearities, accuracies, and precisions were achieved for S-(+)- and R-(-)-Hex, with recoveries of 88.7~104.2% and RSDs less than 9.45% in nine tissues of mice. This established method was then used to detect the toxicokinetic of Hex enantiomers in mice after oral administration within 96 h. The results showed that the half-lives of S-(+)- and R-(-)-Hex were 3.07 and 3.71 h in plasma. Hex was mainly accumulated in the liver, followed by the kidneys, brain, lungs, spleen, and heart. The enantiomeric fraction (EF) values of Hex enantiomers in most of the samples were below 1, indicating that S-(+)-Hex decreased faster than its antipode. The molecular docking showed that the binding of S-(+)-Hex with P450arom was much more stable than R-(-)-Hex, which verified the fact that S-(+)-Hex was prefer to decrease in most of the tissues. The results of this study could be helpful for further evaluating the potential toxic risk of Hex enantiomers and for the development and usage of its pure monomer.

Hexaconazole exposure disrupt acetylcholinesterase, leading to mental illness.

Hexaconazole is widely used in agricultural work, and it has been observed that it has potential to disrupt endocrine function and it has also capacity of bioaccumulation. In this study, we examined how the hexaconazole disrupts the usual balance of acetylcholinesterase. It has been already reported that heavy pesticide exposures may be a reason for several mental illnesses because these pesticides may disrupt normal balance of acetylcholinesterase. In this paper, we have done a complete molecular and dynamics analysis to understand the behavior of hexaconazole with acetylcholinesterase so that its toxicological aspect may be explored. Our findings revealed that hexaconazole has potency to interact with acetylcholinesterase in a stable manner. The binding energy of hexaconazole was found to be -7.95 kcal/mol. However, chlorpyrifos, known inhibitors of acetylcholinesterase, has binding energy of -7.17 kcal/mol. With respect to stability analysis, hexaconazole has similar stability like chlorpyrifos. Root-mean-square deviation, root-mean-square fluctuation, radius of gyration, hydrogen bonding, and solvent accessible surface area were similar to chlorpyrifos. In addition, density functional theory computations analysis reveals that hexaconazole is energetically stable like chlorpyrifos, which is necessary for establishing a stable ligand-protein complex. The result of this complete molecular analysis reveals that hexaconazole may disrupt the acetylcholinesterase balance, which leads to mental illness.

Enantioselective toxicity effect and mechanism of hexaconazole enantiomers to human breast cancer cells.

The toxicity effects of chiral pesticides on living organisms have attracted an increasing public attention. This study aims to investigate the toxicity effect and mechanism of hexaconazole (HEX) to human breast cancer cell (MCF-7) at enantiomer levels. HEX exposure obviously inhibited cells activities in a dose-dependent manner. Under the conditions of VIP >1 and p < 0.05, a total of 255 and 177 differential metabolites (DMs), 17 and 15 amino acid- and lipid-related metabolic pathways were disturbed after (+)-HEX and (-)-HEX exposure, respectively. HEX exposure may affect cell membrane function, signal transduction, and cell differentiation. We further investigated the mechanism of enantioselective differences by using molecular docking which showed that CYP17A1 was the main enzyme that leading to endocrine disrupting effects with the binding energy of -6.30 and -6.08 kcal/mol compared to CYP19A1 enzyme which were -5.81 and -5.93 kcal/mol for (+)-HEX and (-)-HEX, respectively. The docking results explained the reasons why (+)-HEX achieved higher cytotoxicity and induced more seriously metabolic profiles than its antipode. These findings could provide a new insight to understand the enantioselective cytotoxicity effect and mechanism of HEX and will be conducive to assessing its risk to human health at enantiomer levels.