N-nitrosamines induced gender-dimorphic effects on infant rats at environmental levels.

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.

Global trends and hotspots in research on acupuncture for stroke: a bibliometric and visualization analysis.

Acupuncture has been widely used in stroke and post-stroke rehabilitation (PSR), but there is no literature on the bibliometric analysis of acupuncture for stroke. This study aimed to characterize the global publications and analyze the trends of acupuncture for stroke in the past 40 years. We identified 1157 publications from the Web of Science Core Collection. The number of publications grew slowly in the first three decades from 1980 until it started to grow after 2010, with significant growth in 2011-2012 and 2019-2020. China, the USA, and South Korea are the top three countries in this field, and China has formed good internal cooperative relations. Early studies focused on the clinical efficacy of acupuncture for stroke. In the last five years, more emphasis has been placed on the effectiveness of acupuncture in treating sequelae and complications, combined with neuroimaging studies to explore the mechanisms of brain injury repair and neurological recovery. Acupuncture for stroke has a vast research potential, and researchers from different countries/regions and organizations still need to remove academic barriers to enhance communication and collaboration.

Evaluation of the toxic effects of fluindapyr, a novel SDHI fungicide, to the earthworms Eisenia fetida.

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.

The toxic mechanism of 6:2 Cl-PFESA in adolescent male rats: Endocrine disorders and liver inflammation regulated by the gut microbiota-gut-testis/liver axis.

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.

Comparing the enantioselective toxicity on cell cycle and apoptosis of DL-glufosinate and L-glufosinate to SH-SY5Y cells.

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 G1/G0 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.

Frontiers and hotspots evolution in anti-inflammatory studies for coronary heart disease: A bibliometric analysis of 1990-2022.

Background: Coronary heart disease (CHD) is characterized by forming of arterial plaques composed mainly of lipids, calcium, and inflammatory cells. These plaques narrow the lumen of the coronary artery, leading to episodic or persistent angina. Atherosclerosis is not just a lipid deposition disease but an inflammatory process with a high-specificity cellular and molecular response. Anti-inflammatory treatment for CHD is a promising therapy; several recent clinical studies (CANTOS, COCOLT, and LoDoCo2) provide therapeutic directions. However, bibliometric analysis data on anti-inflammatory conditions in CHD are lacking. This study aims to provide a comprehensive visual perspective on the anti-inflammatory research in CHD and will contribute to further research. Materials and methods: All the data were collected from the Web of Science Core Collection (WoSCC) database. We used the Web of Science's systematic tool to analyze the year of countries/regions, organizations, publications, authors, and citations. CiteSpace and VOSviewer were used to construct visual bibliometric networks to reveal the current status and emerging hotspot trends for anti-inflammatory intervention in CHD. Results: 5,818 papers published from 1990 to 2022 were included. The number of publications has been on the rise since 2003. Libby Peter is the most prolific author in the field. "Circulation" was ranked first in the number of journals. The United States has contributed the most to the number of publications. The Harvard University System is the most published organization. The top 5 clusters of keywords co-occurrence are inflammation, C-reactive protein, coronary heart disease, nonsteroidal anti-inflammatory, and myocardial infarction. The top 5 literature citation topics are chronic inflammatory diseases, cardiovascular risk; systematic review, statin therapy; high-density lipoprotein. In the past 2 years, the strongest keyword reference burst is "Nlrp3 inflammasome," and the strongest citation burst is "Ridker PM, 2017 (95.12)." Conclusion: This study analyzes the research hotspots, frontiers, and development trends of anti-inflammatory applications in CHD, which is of great significance for future studies.

Quantifying stiffness and forces of tumor colonies and embryos using a magnetic microrobot.

Stiffness and forces are two fundamental quantities essential to living cells and tissues. However, it has been a challenge to quantify both 3D traction forces and stiffness (or modulus) using the same probe in vivo. Here, we describe an approach that overcomes this challenge by creating a magnetic microrobot probe with controllable functionality. Biocompatible ferromagnetic cobalt-platinum microcrosses were fabricated, and each microcross (about 30 micrometers) was trapped inside an arginine-glycine-apartic acid-conjugated stiff poly(ethylene glycol) (PEG) round microgel (about 50 micrometers) using a microfluidic device. The stiff magnetic microrobot was seeded inside a cell colony and acted as a stiffness probe by rigidly rotating in response to an oscillatory magnetic field. Then, brief episodes of ultraviolet light exposure were applied to dynamically photodegrade and soften the fluorescent nanoparticle-embedded PEG microgel, whose deformation and 3D traction forces were quantified. Using the microrobot probe, we show that malignant tumor-repopulating cell colonies altered their modulus but not traction forces in response to different 3D substrate elasticities. Stiffness and 3D traction forces were measured, and both normal and shear traction force oscillations were observed in zebrafish embryos from blastula to gastrula. Mouse embryos generated larger tensile and compressive traction force oscillations than shear traction force oscillations during blastocyst. The microrobot probe with controllable functionality via magnetic fields could potentially be useful for studying the mechanoregulation of cells, tissues, and embryos.

Polyhalogenated carbazoles induce hepatic metabolic disorders in mice via alteration in gut microbiota.

Polyhalogenated carbazoles (PHCZs) have been widely accepted as emerging pollutants, whereas their ecological and health risks remain uncertain. Herein, female and male Sprague-Dawley (SD) mice were treated with four typical PHCZs to investigate their negative consequences, along with alternations in gut microbiota to indicate underlying mechanisms. In female mice, the relative liver weight ratio increased after four PHCZs exposure; 2-bromocarbazole (2-BCZ) increased urine glucose level; 3-bromocarbazole (3-BCZ) decreased the glucose and total cholesterol levels; 3,6-dichlorocarbazole (3,6-DCCZ) decreased glucose level. The only disturbed biochemical index in male mice was the promoted alkaline phosphatase (ALP) level by 3,6-DCCZ. We also found that the differential blood biochemical indices were correlated with gut microbiota. 3-BCZ and 3,6-DCCZ altered Bacteroidetes and Proteobacteria phyla in female and male mice, which were correlated with metabolic disorders. Our findings demonstrated the correlation between PHCZs induced potential hepatotoxicity and metabolic disorders may be due to their dioxin-like potentials and endocrine disrupting activities, and the gender differences might result from their estrogenic activities. Overall, data presented here can help to evaluate the ecological and health risks of PHCZs and reveal the underlying mechanisms.

Enantioselectivity in the toxicological effects of chiral pesticides: A review.

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.

The Use of Non-targeted Lipidomics and Histopathology to Characterize the Neurotoxicity of Bifenthrin to Juvenile Rainbow Trout (Oncorhynchus mykiss).

Due to the detection frequencies and measured concentrations in surface water, the type I pyrethroid insecticide, bifenthrin, has been of particular concern within the Sacramento-San Joaquin Delta in California. Concentrations have been detected above levels previously reported to impair neuroendocrine function and induce neurotoxicity to several species of salmonids. Metabolomic and transcriptomic studies indicated impairment of cellular signaling within the brain of exposed animals and potential alteration of lipid metabolism. To better understand the potential impacts of bifenthrin on brain lipids, juvenile rainbow trout (Oncorhynchus mykiss) were exposed to mean bifenthrin concentrations of 28 or 48 ng/L for 14 days, and non-targeted lipidomic profiling in the brain was conducted. Brain tissue sections were also assessed for histopathological insult following bifenthrin treatment. Bifenthrin-exposed trout had a concentration-dependent decrease in the relative abundance of triglycerides (TGs) with levels of phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) significantly altered following 48 ng/L bifenthrin exposure. An increased incidence of histopathological lesions, such as focal hemorrhages and congestion of blood vessels, was noted in the brains of bifenthrin-treated animals, suggesting an association between altered lipid metabolism and neuronal cell structure and integrity.

Antibiotic treatments to mothers during the perinatal period leaving hidden trouble on infants.

Antibiotic application during the perinatal period is unavoidable in the clinic, but the potential effects on mothers and infants remain unknown. Herein, 25 breast milk samples from mothers who received cefuroxime (CXM) or CXM + cefoxitin (CFX) treatments and fecal samples from their infants were collected to investigate the undesirable effects of antibiotics on the microbiota of mothers and neonates. Furthermore, five fecal samples of infants, whose mothers had antibiotic treatments, were collected at a 6-month postpartum follow-up visit to evaluate the long-term effects on infants' gut microbiota. Moreover, the relative abundance of antibiotic resistance genes (ARGs) in fecal samples was compared to investigate the transfer of ARGs in the infant gut microbiota. The results indicated that the antibiotic treatments had no influence on the microbiota of breast milk. The dominant bacterial phyla in the fecal samples changed to Firmicutes and Proteobacteria after antibiotic treatments, while the bacterial community showed a recuperative trend at the follow-up visits. In addition, the abundance of ARGs in the infant gut microbiota demonstrated a declining trend in the CXM- and CXM + CFX-treated groups, while ARG abundance presented a significant increasing trend after a 6-month recovery period. CONCLUSION: Antibiotic treatments for mothers during the perinatal period disturb the gut microbiota in neonates. The infants' gut microbiota would partly return to their initial state after rehabilitation, but the transfer of ARGs would leave the hidden trouble of antibiotic resistance. Overall, the data presented here can help to guide the scientific use of antibiotics during the perinatal period and provide potential approaches to mitigate the negative consequences. WHAT IS KNOWN: • Antibiotic application during the perinatal period is unavoidable in the clinic. • Misuse of antibiotics can cause various unintended consequences, especially for antibiotic resistance. WHAT IS NEW: • Antibiotic treatments had no influence on the microbiota of breast milk but greatly disturbed the gut microbiota composition in infants. • The gut microbiota in infants would partly return to its initial state after rehabilitation but the transfer of ARGs would leave the hidden trouble of antibiotic resistance.

Triticonazole enantiomers induced enantioselective metabolic phenotypes in Fusarium graminearum and HepG2 cells.

The management of Fusarium head blight relies heavily on triazole fungicides. Most of triazole fungicides are chiral, and their enantioselective effects on metabolic phenotypes are poorly understood. Herein, we analyzed the bioactivity of triticonazole against Fusarium graminearum, and 1H-nuclear magnetic resonance-based metabolomics was used to assess the metabolic disturbances of triticonazole enantiomers in Fusarium graminearum and human hepatocarcinoma cells. Results indicated that the bioactivity of R-triticonazole was 4.28-fold higher than its antipode since it bound stronger with fungal CYP51B and induced more abnormal metabolic processes of Fusarium graminearum, including lipid metabolism, glycolysis, and amino acid metabolism. In human hepatocarcinoma cells, pathways of "alanine, aspartic acid and glutamate metabolism" and "pyruvate metabolism" were disturbed significantly by R-triticonazole; "phenylalanine metabolism" and "taurine-hypotaurine metabolism" were abnormal in the exposure of S-triticonazole. These results suggested that R- and S-triticonazole could affect different metabolic pathways of human hepatocarcinoma cells, and the massively use of inefficient S-triticonazole should be avoided. Our data will help to better understand the enantioselectivity of chiral pesticides and provide a reference for the development of green pesticides.

Bacterial community response to chronic heavy metal contamination in marine sediments of the East China Sea.

Marine sediments act as a sink for various heavy metals, which may have profound impact on sedimentary microbiota. However, our knowledge about the collaborative response of bacterial community to chronic heavy metal contamination remains little. In this study, concentrations of seven heavy metals (As, Cd, Cr, Cu, Hg, Pb, and Zn) in sediments collected from the East China Sea were analyzed and Illumina Miseq 16 S rRNA sequencing was applied to characterize the structure of bacterial community. Microbiota inhabiting sediments in the East China Sea polluted with heavy metals showed different community composition from relatively pristine sites. The response of bacterial community to heavy metal stress was further interrogated with weighted correlation network analysis (WGCNA). WGCNA revealed ten bacterial modules exhibiting distinct co-occurrence patterns and among them, five modules were related to heavy metal pollution. Three of them were positively correlated with an increase in at least one heavy metal concentration, hubs (more influential bacterial taxa) of which were previously reported to be involved in the geochemical cycling of heavy metals or possess tolerance to heavy metals, while another two modules showed opposite patterns. Our research suggested that ecological functional transition might have occurred in East China Sea sediments by shifts of community composition with sensitive modules majorly involved in the meaningful global biogeochemical cycling of carbon, sulfur, and nitrogen replaced by more tolerant groups of bacteria due to long-term exposure to low-concentration heavy metals. Hubs may serve as indicators of perturbations of benthic bacterial community caused by heavy metal pollution and support monitoring remediation of polluted sites in marine environments.

Ear Reconstruction with the Combination of Expanded Skin Flap and Medpor Framework: 20 Years of Experience in a Single Center.

BACKGROUND: In ear reconstruction, the difficulty lies in reestablishing the ear's bionic form with adequate skin coverage and an appropriate framework. Skin expansion and a porous polyethylene (i.e., Medpor) framework are often used for ear reconstruction. However, a long-term review of the combined application of the expanded skin and Medpor framework has not been reported. This article reviews ear reconstruction combining these two factors over the past 20 years in the authors' center to summarize the surgical technique and analyze the postoperative results and complications. METHODS: A retrospective review was performed that included all patients who underwent ear reconstruction with expanded skin and Medpor framework in the authors' center between 1998 and 2018. RESULTS: A total of 68 patients with microtia who were admitted to the authors' center for surgical ear reconstruction were included, and 70 ears were reconstructed. Fifty-seven of the patients (83.82 percent) felt satisfied with their reconstructed ear, five patients (7.35 percent) were not satisfied with the reconstructed ear, and six patients (8.82 percent) had the frameworks removed. Fifteen patients (22.06 percent) developed complications, including framework exposure (13.24 percent), infection (4.41 percent), scar hypertrophy (4.41 percent), and hematoma (2.94 percent). CONCLUSIONS: Framework exposure limits the combined application of expanded skin flap and Medpor framework when reconstructing the ear without additional fascial interposition. Using a temporoparietal fascia or postauricular fascia flap during the operation is effective to decrease the exposure rate; however, this complication cannot be completely avoided. Using postauricular fascia and skin graft may lead to scar hypertrophy; thus, these techniques should be used with caution. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Old pesticide, new use: Smart and safe enantiomer of isocarbophos in locust control.

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 LD50 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.

Stage Dependent Enantioselective Metabolism of Bifenthrin in Embryos of Zebrafish (Danio rerio) and Japanese Medaka (Oryzias latipes).

Bifenthrin (BF) is a widely used pyrethroid that has been frequently detected in surface waters. Previous studies indicated that BF had antiestrogenic activity in zebrafish embryos but estrogenic activity in posthatch fish. To determine whether age-related differences in metabolism contribute to the endocrine effects in developing fish, embryos from zebrafish and Japanese medaka were exposed to BF before and after liver development. Since the commercial mixture of BF is an isomer-enriched product containing two enantiomers (1R-cis-BF and 1S-cis-BF), enantioselective metabolism was also evaluated. The estrogenic metabolite, 4-hydroxybifenthrin (4-OH-BF) was identified in zebrafish embryos, and formation was higher in animals after liver development (>48 hpf). Treatments with ß-glucuronidase indicated that 4-OH-BF underwent conjugation in embryos. Formation was reduced by cotreatment of the cytochrome P450 (CYP450) inhibitor, ketoconazole. Formation of 4-OH-BF was greater when treated with 1R-cis-BF compared to the S-enantiomer. However, metabolites were not observed in medaka embryos. These data indicate enantioselective oxidation of BF to an estrogenic metabolite occurs in zebrafish embryos and, since it is increased after liver development, may partially explain estrogenic activity observed in older animals. The lack of activity in medaka suggests species-specific effects with BF metabolism and may influence risk assessment strategies in wildlife.

Systematic investigation of stereochemistry, stereoselective bioactivity, and antifungal mechanism of chiral triazole fungicide metconazole.

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.

New insight into the enantioselective cytotoxicity of cypermethrin: imbalance between cell cycle and apoptosis.

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.

Environmental behavior and safety of polyhalogenated carbazoles (PHCZs): A review.

Polyhalogenated carbazoles (PHCZs) are well-known as emergent environmental contaminants. Given their wide distribution in the environment and structural similarity with dioxins and dioxin-like chemicals (DLCs), the environmental behavior and ecological risks of these chemicals have become the major issue concerned by the governments and scientists. Since the initial report of PHCZ residues in the environment in the 1980s, over 20 PHCZ congeners with different residual levels had been identified in various environmental media all over the world. Nevertheless, researches concerning the toxicological effects of PHCZs are of an urgent need for the relatively lagging study of their ecological risks. Currently, only limited evidence has indicated that PHCZs would pose dioxin-like toxicity, including developmental toxicity, cardiotoxicity, etc; and their toxicological effects were partially consistent with AhR activation. And yet, much remains to be done to fill in the knowledge gaps of their toxicological effects. In this review, the research progresses in environmental behavior and toxicology study of PHCZs were remarked; and the lack of current research, as well as future research prospects, were discussed.

Four cypermethrin isomers induced stereoselective metabolism in H295R cells.

Cypermethrin (CP) is widely used for controlling agricultural and indoor vermin. Previous studies have reported the stereoselective difference of CP in biological activities. However, little is known about their potential mechanisms between metabolic phenotypes and endocrine-disrupting effects. Herein, nuclear magnetic resonance (NMR)-based metabolomics combining metabolite identification and pathway analysis were applied to evaluate the stereoselective metabolic cdisorders induced by CP isomers in human adrenocortical carcinoma cells (H295R) culture medium. Then, gene expression levels related to disturbed metabolic pathways were assessed to verify according to metabolic phenotypes. Metabolomics profiles showed that [(S)-cyano(3-phenoxyphenyl)methyl](1R,3R)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate [(1R,3R,αS)-CP] induced the most significant changes in metabolic phenotypes than did the other stereoisomers. There are 10 differential metabolites (isoleucine, valine, leucine, ethanol, alanine, acetate, aspartate, arginine, lactate, and glucose) as well as two significantly disturbed pathways, including "pyruvate metabolism" and "alanine, aspartate, and glutamate metabolism," that were confirmed in H295R cells culture medium of (1R,3R,αS)-CP compared with other stereoisomers. Polymerase chain reaction (PCR) array also confirmed the results of metabolomics. Our results can help to understand the potential mechanisms between the isomer selectivity in metabolic phenotypes and endocrine-disrupting effects. Data provided here not only lend authenticity to the cautions issued by the scientists and researchers but also offer a solution for the balance between environment and political regulations.