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Thallium exposure has been associated with female reproductive health, but little is known about its potential association with premature ovarian insufficiency (POI). In this study, a total of 169 patients with POI and 209 healthy women were recruited from Zhejiang province, China. Urinary thallium concentrations were significantly positively associated with the risk of POI [adjusted odds ratio (OR) = 1.63, 95% CI: 1.25-2.13, p < 0.001], geometric mean values of which were significantly higher in POI cases (0.213 μg/L, 0.302 μg/g for creatinine adjustment) than those of controls (0.153 μg/L, 0.233 μg/g for creatinine adjustment). Furthermore, the serum levels of follicle-stimulating hormone and luteinizing hormone were positively associated with urinary thallium concentrations, whereas anti-Mullerian hormone and estradiol were negatively correlated with thallium. To the best of our knowledge, this is the first study to provide evidence that thallium exposure at currently environmental levels is the potential risk factor for POI in women.

Doubanjiang-meju has been used as an intermediate for producing Pixian Douban (PXDB) and contributes significantly to its flavor. In this study, a profiling analysis of volatile compounds in open fermented doubanjiang-meju (OFD) and closed fermented doubanjiang-meju (CFD) was performed with gas chromatography–mass spectrometry (GC–MS) and gas chromatography–olfactometry (GC–O). A total of 42 and 50 volatile compounds were identified in the OFD and CFD, respectively. Compared with the OFD, more diversity and higher concentrations of alcohols and esters were found in the CFD. Ten and 12 volatile compounds were finally identified as the major aroma-active compounds in the OFD and CFD, respectively, by the combined analysis of aroma intensity values and odor activity values (OAVs). The CFD had significantly stronger umami and soy sauce flavor but weaker beany when compared with the OFD (p

Cadmium, a toxic heavy metal that occurs in the environment in large quantities through human activities, has been shown to have adverse effects on female reproductive health. However, the association between cadmium exposure and primary ovarian insufficiency (POI), one of the most prevalent ovarian diseases in women, has not been examined yet. This case–control study involving 169 POI cases and 209 healthy controls was conducted in Zhejiang Province, China. The urinary concentrations of cadmium were determined by inductively coupled plasma mass spectrometry (ICP-MS). In addition, serum levels of reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol, were measured. The median concentration of urinary cadmium in POI cases (0.43 μg/L, 0.58 μg/g for creatinine adjustment) was significantly higher than that of controls (0.29 μg/L, 0.43 μg/g for creatinine adjustment). The results of binary logistic regression models showed that the concentrations of urinary cadmium were positively significantly correlated with the odds ratio (ORs) of POI before the adjustment of confounders. After the adjustment, a significantly positive association was still present between the increased concentrations of cadmium and the ORs of POI (2.50, 95% CIs: 1.34–4.65 for the third tertile, p for trend = 0.001). The serum levels of FSH and LH were positively associated with urinary cadmium, while AMH and estradiol levels were inversely correlated. To the best of our knowledge, this is the first reported positive association of cadmium exposure with the risk of POI in women.

Mixed Lineage Leukemia 1 (MLL1), an important member of Histone Methyltransferases (HMT) family, is capable of catalyzing mono-, di-, and trimethylation of Histone 3 lysine 4 (H3K4). The optimal catalytic activity of MLL1 requires the formation of a core complex consisting of MLL1, WDR5, RbBP5, and ASH2L. The Protein-Protein Interaction (PPI) between WDR5 and MLL1 plays an important role in abnormal gene expression during tumorigenesis, and disturbing this interaction may have a potential for the treatment of leukemia harboring MLL1 fusion proteins. In this review, we will summarize recent progress in the development of inhibitors targeting MLL1- WDR5 interaction.

The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.

Development of a fully functional dressing that can be applied throughout wound healing remains challenging. In this study, Bletilla striata polysaccharide (BSP) and the ethanol extract of B. striata (EEB) were physically blended and vacuum freeze-dried into a new medical dressing with various functions, such as hemostasis, anti-inflammatory, antibacterial and wound healing promotion. The in vivo and in vitro blood coagulation evaluation results showed that the most obvious hemostasis effects coming from the EEB25 sponge was probably due to good water absorption capacity. The drug sensitivity test results showed that the sponges presented a good antibacterial effect originated from the addition of EEB. In addition, the EEB25 sponge showed significant anti-inflammatory effects, as well as excellent biodegradability and biocompatibility. The full-thickness wound experiment illustrated the wound healing rates of EEB25 group on the 8th day and 16th day was 82.76 ± 2.78% and 95.36 ± 3.72%, respectively, which showed significant differences (p

micro-RNAs (miRNAs) are non-coding RNAs which play important role in human diseases. Dysregulated miRNAs have been identified in asthma patient while their precise roles in asthma are not well elucidated. We compared the expression level of total 11 miRNAs between PMA/A23187-treated and control HMC-1 mast cells. We determined the effect of miR-20a on inflammation by overexpressing miR-20a mimic or its antagonist. We further predicted histone deacetylase 4 (HDAC4) as potential target of miR-20a and explored the effects of miR-20a on HDAC4 expression and histone modification. miR-20a was down-regulated in PMA/A23187-treated HMC-1 cells. miR-20a inhibited expression of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and Interferon gamma (IFN-γ) while promoted Interleukin 10 (IL-10) production. miR-20a targeted HDAC4 and suppressed its expression, which contributed to epigenetically regulation of IL-10 expression by miR-20a. hsa-miR-20a-5p attenuates allergic inflammation in HMC-1 cells by targeting HDAC4.

The protein-protein interaction between WDR5 (WD40 repeat protein 5) and MLL1 (mixed-lineage leukemia 1) is important for maintaining optimal H3K4 methyltransferase activity of MLL1. Dysregulation of MLL1 catalytic function is relevant to mixed-lineage leukemia, and targeting WDR5-MLL1 interaction could be a promising therapeutic strategy for leukemia harboring MLL1 fusion proteins. To date, several peptidomimetic and non-peptidomimetic small-molecule inhibitors targeting WDR5-MLL1 interaction have been reported, yet the discovery walk of new drugs inhibiting MLL1 methytransferase activity is still in its infancy. It’s urgent to find other small-molecule WDR5-MLL1 inhibitors with novel scaffolds. In this study, through fluorescence polarization (FP)-based high throughput screening, several small-molecule inhibitors with potent inhibitory activities in vitro against WDR5-MLL1 interaction were discovered. Nuclear Magnetic Resonance (NMR) assays were carried out to confirm the direct binding between hit compounds and WDR5. Subsequent similarity-based analog searching of the 4 hits led to several inhibitors with better activity, among them, DC_M5_2 displayed highest inhibitory activity with IC50 values of 9.63 ± 1.46 µM. Furthermore, a molecular docking study was performed and disclosed the binding modes and interaction mechanisms between two most potent inhibitors and WDR5.

As an essential flavor condiment in Sichuan cuisine, Pixian Douban (PXDB) is usually produced by open fermentation process in strip pools or ceramic vats. In this study, an experiment of PXDB fermentation was conducted for 90 days in a closed system of gradient steady‐state temperature field (GSTF). To investigate the characterization of volatile compounds of PXDB in the closed system, the volatiles in three kinds of samples including samples of GSTF (SGT), samples of constant temperature (SCT), and samples of traditional fermentation (STF) were analyzed. The results showed that 75, 67, and 68 volatile compounds were detected in SGT, SCT, and STF, respectively. Compared with the traditional fermentation, the process in the closed system of GSTF was conducive to produce more kinds of esters and alcohols. A total of 22 major aroma active compounds were identified in three samples by combination analyses of gas chromatography‐olfactometry (GC‐O) and odor activity value (OAV). The appearance, smell, texture, and taste of the three different samples had shown different changes, but the sensory characteristics of the SGT were more similar to those of the STF by quantitative descriptive analysis (QDA) and principal component analysis (PCA). This study indicated that the closed system of GSTF could be applied in PXDB fermentation to obtain higher quality products, which brought a bright prospect of replacing the traditional fermentation process to realize the controllable industrialized production of PXDB., The results showed that flavor characteristics of SGT were similar to those of the STF. This study indicated that the closed system of GSTF could be applied in PXDB fermentation to obtain higher quality products, which brought a bright prospect of replacing the traditional fermentation process to realize the controllable industrialized production of PXDB.

A closed system of gradient steady-state temperature field (GSTF) was constructed to ferment Pixian broad bean paste (PBP). The contents of physicochemical factors and organic acids in the fermentation under GSTF (FG) were closer to those in the traditional fermentation (TF). The taste intensities of 8 free amino acids in the FG were higher than those in the constant temperature fermentation (CTF), but 14 in the TF showed the highest among the processes of FG, CTF and TF. The FG product had the most volatiles with 87, and its flavor properties were more stable. The FG produced great effects on the microbe evolutions especially improved the fungal diversity. Bacillus were identified as the core microbes in the FG while the roles of Staphylococcus, Lactobacillus and Pantoea were strengthened. The results indicated that the fermentation characteristics in the FG had been further improved compared with the CTF.

As one of the medicine homologous foods in China, Atractylodis Macrocephalae Rhizoma (AMR) is usually distributed after thermal processing, which raised the possibility of acrylamide pollution and a potential carcinogenic risk. In this study, a method was developed for the determination of the acrylamide in AMR using graphited multiwalled carbon nanotubes as the dispersive solid phase extraction sorbent and liquid chromatography tandem mass spectrometry. The concentration of acrylamide was investigated at processing conditions of 80℃-210℃ and 5 min–100 min. Method validation results demonstrated the reliability of the method with good linearity, accuracy and precision. Significant increment of acrylamide was found in AMR after thermal processing with the highest concentration at 9826 μg/kg, which led to a margin of exposure at 90.83–181.7 according to the BMDL10 of carcinogenicity at 0.17 mg/kg, indicating a high health risk of taking thermally processed AMR, and monitoring and controlling should be considered.

A few epidemiological investigations and animal studies have demonstrated that bisphenol A (BPA) may affect female reproductive health. However, no epidemiologic study has investigated the relationship between BPA exposure and the risk of premature ovarian insufficiency (POI). In this case–control study, urinary concentrations of BPA and serum levels of reproductive hormone were measured. Associations between BPA concentrations and the risk of POI and POI-related hormone levels were estimated. Among BPA quartiles, no obvious association was found between BPA levels and the risk of POI (p = 0.603). Although the adjusted odds ratio (OR) of POI was slightly increased for participants in the highest BPA concentration quartile, the association was not statistically significant (OR = 1.282, 95% confidence interval [CI] 0.615–2.049 for the highest vs. lowest quartile, p = 0.508). Although follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH) levels showed no tendency of an association with BPA (p = 0.941 and p = 0.876 for FSH and AMH, respectively), the highest quartile of luteinizing hormone was significantly positively associated with BPA levels (OR = 1.333, 95% CI 0.986–1.803, p = 0.042). The urinary concentrations of BPA determined in this study were consistent with the range of exposure currently observed in Chinese women. However, BPA exposure at a relatively low level is not associated with POI in Chinese women. Further epidemiological studies are needed to confirm our findings.

In the search for biocompatible composite microspheres to be used as a hemostatic agent, in a previous study, we designed a novel biomaterial, consisting of composite microspheres containing three natural biological ingredients, carboxymethyl chitosan, sodium alginate and collagen (CSCM). Furthermore, the chemical and physical properties, hemostatic ability, biocompatibility and cytotoxicity were investigated in vitro. In this work, the in vivo hemostatic performance, wound healing, hemocompatibility, histocompatibility, and biodegradability were evaluated by a series of experiments. The results showed that CSCM could both stop bleeding and enhance healing efficiency by accelerating the clotting and the wound closure rate, suggesting that CSCM acts as a hemostat, and enhances wound healing. In addition, the CSCM material had negligible intracutaneous stimulation reactions and no obvious hemolytic reactions. More importantly, CSCM can be degraded in vivo without significant impacts on physiology, biochemistry, and organization. Thus, CSCM may be a useful tool to stop bleeding in emergency conditions in both military and civilian settings.

Although an acceleration of male pubertal development has been observed, precisely which endocrine-disrupting chemicals (EDCs) might contribute to the advancing onset of puberty in boys remains unclear. Here, pyrethroids, a class of widely used insecticides that have been considered as EDCs, are proposed as new environmental risk factors. In this study, 463 boys at the age of 9-16 years old were recruited in Hangzhou, Zhejiang, China. The common metabolites of pyrethroids, 3-phenoxybenzoic acid (3-PBA), and 4-fluoro-3-phenoxybenzoic acid (4-F-3-PBA), as well as gonadotropins, including luteinizing hormone (LH) and follicle-stimulating hormone (FSH), were analyzed in urine samples. Pubertal development was assessed based on Tanner stages and testicular volume (TV). A positive association between 3-PBA and gonadotropins was found (p0.001), in which a 10% increase in 3-PBA was associated with a 2.4% and 2.9% increase in LH and FSH, respectively. Higher urinary levels of 3-PBA in boys were associated with 275% and 280% increase in the risk of being genitalia stage 3 (G3) and G4, respectively (p0.05). There was a significant (132%) induction in odd of being TV 12-19 mL with increasing 3-PBA concentration compared to being in TV4 mL (p0.05). For the first time to our knowledge, this work reports on an association of increased pyrethroid exposure with elevated gonadotropins levels and earlier pubertal development in boys.

Arsenic, a well-known toxic metalloid, is ubiquitously existed in environment. Arsenic exposure has been associated with female reproductive health. However, a potential association between arsenic exposure and primary ovarian insufficiency (POI) in women has not been recognized yet. In this case-control study, a total of 169 POI cases and 209 healthy controls were recruited to determine urinary concentrations of arsenic and serum levels of reproductive hormones (follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol). The median concentration of urinary arsenic in cases (21.5 μg/L, 28.0 μg/g for creatinine adjustment) was significantly higher than that of controls (13.8 μg/L, 19.3 μg/g for creatinine adjustment). Urinary arsenic concentrations were significantly positively associated with the risk of POI (adjusted odds ratio (OR) = 2.66, 95% CI: 1.43–4.95 for the highest vs lowest tertile of arsenic, p = 0.002; p for trend = 0.004). We also assessed the associations between arsenic exposure and reproductive hormones that are important for ovarian functions. FSH and LH levels were positively associated with urinary arsenic, whereas AMH and estradiol levels were negatively correlated with this element. This study provided evidence that arsenic exposure could be the potential risk factor for POI in women.

Protein tyrosine phosphatase 1B (PTP1B) plays an important role in the negative regulation of insulin and leptin signaling. The development of small molecular inhibitors targeting PTP1B has been validated as a potential therapeutic strategy for Type 2 diabetes (T2D). In this work, we have identified a series of compounds containing dihydropyridine thione and particular chiral structure as novel PTP1B inhibitors. Among those, compound 4b showed moderate activity with IC50 value of 3.33 μM and meanwhile with good selectivity (>30-fold) against TCPTP. The further MOA study of PTP1B demonstrated that compounds 4b is a substrate-competitive inhibitor. The binding mode analysis suggested that compound 4b simultaneously occupies the active site and the second phosphotyrosine (pTyr) binding site of PTP1B. Furthermore, the cell viability assay of compound 4b showed tolerable cytotoxicity in L02 cells, thus 4b may be prospectively used to further in vivo study.

More attention is being paid to the enantioselective toxicity of chiral pesticides. However, limited investigations have been done to assess the ecological risks of chiral pesticides to soil community. Fenvalerate (FV), an extensively used synthetic pyrethroid, is a typical chiral pesticide. The most insecticidally active enantiomer of FV, esfenvalerate (ESFV), also has been marketed and widely used. In this study, the toxicological sensitivity and bioaccumulation of FV and ESFV in earthworms were assessed. The results showed that FV was less toxic than ESFV, but more accumulated in earthworms. ESFV was at least 4 times more toxic to earthworms than FV according to the filter paper contact toxicity test and the artificial soil test. Enantiospecific induction in oxidative stress was observed in earthworms exposed to FV and ESFV. The bioaccumulation of FV and ESFV in earthworm tissues was also enantioselective, preferentially accumulating FV. The uptake of ESFV by earthworms was lower than that of FV, so that the biota to soil accumulation factor (BSAF) value of ESFV was lower than that of FV. Our findings suggest that the enantioselective toxicity and bioaccumulation of chiral pesticides should be considered for evaluating ecological risks of these compounds to non-target organisms.

Co-occurrence of pesticides such as synthetic pyrethroids and metals in aquatic ecosystems raises concerns over their combined ecological effects. Cypermethrin, 1 of the top 5 synthetic pyrethroids in use, has been extensively detected in surface water. Cadmium (Cd) has been recognized as 1 of the most toxic metals and is a common contaminant in the aquatic system. However, little information is available regarding their joint toxicity. In the present study, combined toxicity of cypermethrin and Cd and the underlying mechanisms were investigated. Zebrafish embryos and adults were exposed to the individual contaminant or binary mixtures. Co-exposure to cypermethrin and Cd produced synergistic effects on the occurrence of crooked body, pericardial edema, and noninflation of swim bladder. The addition of Cd significantly potentiated cypermethrin-induced spasms and caused more oxidative stress in zebrafish larvae. Cypermethrin-mediated induction of transcription levels and catalytic activities of cytochrome P450 (CYP) enzyme were significantly down-regulated by Cd in both zebrafish larvae and adults. Chemical analytical data showed that in vitro elimination of cypermethrin by CYP1A1 was inhibited by Cd. The addition of Cd caused an elevation of in vivo cypermethrin residue levels in the mixture-exposed adult zebrafish. These results suggest that the enhanced toxicity of cypermethrin in the presence of Cd results from the inhibitory effects of Cd on CYP-mediated biotransformation of this pesticide. The authors' findings provide a deeper understanding of the mechanistic basis accounting for the joint toxicity of cypermethrin and Cd.

Pyrethroids, a class of ubiquitous insecticides, have been recognized as endocrine-disrupting chemicals (EDCs). A lot of studies have implied the endocrine-disrupting effects of pyrethroids on the hypothalamic-pituitary-gonadal (HPG) axis. However, there are few review articles regarding the effects of pyrethroids on the HPG axis of mammal and human, especially new research progress made in this area. The present review sums up the effects of pyrethroids on the HPG axis-related reproductive outcomes, including epidemiological investigations based on human biomonitoring, animal studies and in vitro tests. Mechanisms have described that the endocrine-disrupting effects of pyrethroids on mammal can be mediated via the interaction with steroid receptors, the direct action on ion channels and signaling molecules. Finally, we summarize the current research gaps and suggest future directions in this topic.

Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ± 19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.

Ten urinary biomarkers of organophosphate esters (OPEs) from six parent OPEs were analyzed in urine from adolescents students in Eastern China. Bis (1,3-dichloro-2-propyl) phosphate, urinary biomarker of tris (1,3-dichloro-2-propyl) phosphate (TDCIPP), was detected in all urine samples with the highest residual concentration of 6.2 ng/mL (median). Bis (1-chloro-propyl) hydroxyl-2-propyl phosphate, dibutyl phosphate, biomarkers of tris (1-chloro-2-propyl) phosphate (TCIPP), tri-n-butyl phosphate (TNBP), respectively, and tris (2-chloroethyl) phosphate (TCEP), were also frequently detected with median concentrations of 1.5, 2.6 and 0.3 ng/mL, respectively. Results indicate that exposure to OPEs, in particular to TDCIPP, TNBP, TCIPP and TCEP, was highly prevalent for adolescent students. The exposure pathways of OPEs were then evaluated according to the OPE internal body burdens (IBBs). Three pathways were identified as the main pathways for adolescents exposed to OPEs including dermal absorption, oral intake of food and dust and inhalation. (c) 2019 Elsevier B.V. All rights reserved.

Protein arginine methyltransferase 5 (PRMT5), a type II PRMT enzyme, is reported as an important therapeutic target in leukemia and lymphoma. In the present study, based on the combination of virtual screening and biochemical validations, we discovered a series of small-molecule inhibitors targeting PRMT5. Among those, DC_Y134 exhibited the most potent activity with IC50 value of 1.7 μM and displayed good selectivity against other methyltransferases. Further treatment with DC_Y134 inhibited the proliferation of several hematological malignancy cell lines by causing cell cycle arrest and apoptosis. Western blot assays indicated that DC_Y134 reduced the cellular symmetrically dimethylated levels. In addition, we analyzed the binding mode of DC_Y134 through molecular docking, which revealed that DC_Y134 occupies the binding site of substrate arginine and explained the selectivity of this inhibitor. Taken together, compound DC_Y134 could be used to elucidate the biological roles of PRMT5 and serve as a lead c...

Pyrethroids are a class of widely used insecticides. Female animal studies suggested that pyrethroid exposure impaired ovarian function, which resulted in similar symptoms of primary ovarian insufficiency (POI). However, it is still unknown whether this association applies to women. In this case-control study, a total of 172 POI patients and 247 control women were recruited in Zhejiang, China. The urinary concentrations of metabolites of pyrethroids, 3-phenoxybenzoic acid (3-PBA) and 4-fluoro-3-phenoxybenzoic acid (4-F-3-PBA), as well as the serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and anti-Mullerian hormone (AMH) were determined. The associations of pyrethroid metabolites with POI and POI-related hormones were accessed using unconditional logistic regression. Higher urinary levels of 3-PBA were significantly associated with increased risk of POI [adjusted odds ratio (OR) = 2.344, 95% CI: 1.193-4.607 for the highest vs lowest quartile of 3-PBA, p = 0.013]. Stratified analyses showed that each log increase in urinary 3-PBA concentration was significantly associated with an induction in odds of 51.0% being in the highest quartile of FSH and 28.6% being in the highest quartile of LH levels, whereas a 25.9% reduction in odds of being in the highest quartile of AMH levels (All p for trend0.05). To our knowledge, this is the first case-control study to report an association of pyrethroid exposure with increased risk of POI in women.

Benomyl and carbendazim are benzimidazole fungicides that are used throughout the world against a wide range of fungal diseases of agricultural products. There is as yet little information regarding the toxicity of benzimidazole fungicides to human placenta. In this study, we utilized human placental trophoblast cell line HTR-8/SVneo (HTR-8) to access the toxic effects of benomyl and carbendazim. Our data showed that these two fungicides decreased cell viability and the percentages of cells in G0/G1 phase, as well as induced apoptosis of HTR-8 cells. The invasion and migration of HTR-8 cells were significantly inhibited by benomyl and carbendazim. We further found that benomyl and carbendazim altered the expression of protease systems (MMPs/TIPMs and uPA/PAI-1) and adhesion molecules (integrin α5 and β1) in HTR-8 cells. Our present study firstly shows the deleterious effects of benomyl and carbendazim on placental cells and suggests a potential risk of benzimidazole fungicides to human reproduction.

Pyrethroids, a class of insecticides that are widely used worldwide, have been identified as endocrine-disrupting chemicals (EDCs). Our recent epidemiological study reported on an association of increased pyrethroids exposure with elevated gonadotropins levels and earlier pubertal development in Chinese boys. In this study, we further investigated the effects of cypermethrin (CP), one of the most ubiquitous pyrethroid insecticides, on hypothalamic-pituitary-gonadal (HPG) axis and pubertal onset in male animal models. Early postnatal exposure to CP at environmentally relevant doses (0.5, 5, and 50 μg/kg CP) significantly accelerated the age of puberty onset in male mice. Administration of CP induced a dose-dependent increase in serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone in male mice. CP did not affect gonadotropin-releasing hormone (GnRH) gene expression in the hypothalamus, but CP at higher concentrations stimulated GnRH pulse frequency. CP could induce the secretion of LH and FSH, as well as the expression of gonadotropin subunit genes [chorionic gonadotropin α (CGα), LHβ, and FSHβ] in pituitary gonadotropes. CP stimulated testosterone production and the expression of steroidogenesis-related genes [steroidogenic acute regulatory (StAR) and Cytochrome p 450, family 11, subfamily A, polypeptide 1 (CYP11A1)] in testicular Leydig cells. The interference with hypothalamic sodium channels as well as calcium channels in pituitary gonadotropes and testicular Leydig cells was responsible for CP-induced HPG axis maturation. Our findings established in animal models provide further evidence for the biological plausibility of pyrethroid exposure as a potentially environmental contributor to earlier puberty in males.

Background: In biological systems, the individual stereoisomers of chiral substances possess significantly different biochemical properties because the specific structure-activity relationships are required for a common site on biomolecules. In the past decade, there has been increasing concern over the enantioselective toxicity of environmental chiral pollutants, especially chiral pesticides. Different responses and activities of a pair of enantiomers of chiral pesticides were often observed. Therefore, assessment of the enantioselective toxicological properties of chiral pesticides is a prerequisite in application of single-isomer products and particularly important for environmental protection. The development of biomarkers that can predict enantioselective effects from chiral pesticides has recently been gained more and more attention. The biomarkers of oxidative stress have become a topic of significant interest for toxic assessments. Methods: In this review, we summarized current knowledge and advances in the understanding of enantiomeric oxidative processes in biological systems in response to chiral pesticides. Results: The consistent results in two types of chiral insecticides (synthetic pyrethroids and organochlorine pesticides) showed the significant difference in cytotoxicity of enantiomers, suggesting the antioxidant enzymes are reliable biomarkers for the assessment of toxicity of chiral chemicals. Results indicate that antioxidant enzymes are sensitive and valid biomarkers to assess the oxidative damage caused by chiral herbicides. In addition, it can be inferred that the enantioselectivity of chiral herbicides on antioxidant enzymes exists in other species. Compared with insecticides and herbicides, researches about the enantioselectivity of oxidative stress caused by chiral fungicides are quite limited. Only two kinds of chiral fungicides has been used to study the enantioselectivity of oxidative stress by now. Conclusion: The current knowledge that enantioselective processes of oxidative damage occur in organisms or cells extends toxicological studies of environmental contamination by chiral chemicals. These studies indicate that oxidative biomarkers can be useful for monitoring enantioselective toxicity of chiral contaminates, while comparing enantiomer-induced responses in different species should be approached with caution because of differences in uptake, target sites, biotransformation and pharmacokinetics of the enantiomers.

Bromadiolone, a potent second-generation anticoagulant rodenticide, has been extensively used worldwide for the field control of rodents. Invertebrates may be at risk from primary poisoning as a result of bromadiolone bait applications. However, there are few data regarding the toxicity and bioaccumulation of bromadiolone to earthworms. In this study, we reported that bromadiolone was toxic to earthworms at 1mg/kg soil, which is a likely concentration in the field following application of bromadiolone baits. Exposure to bromadiolone resulted in a significant inhibition of earthworm growth. The antioxidant activities of superoxide dismutase and catalase were slightly increased in earthworms, while malondialdehyde content (as a molecular marker indicative of the damage to lipid peroxidation) was dominantly elevated over the duration of exposure. Bromadiolone in soil is bioaccumulative to earthworms. The biota to soil accumulation factors (BSAFs) of bromadiolone were concentration dependent and BSAFs decreased as the level of bromadiolone in soil increased. These results suggest earthworms are not only the potential subject to primary poisoning but also the source of secondary exposure for insectivores and scavengers following application of bromadiolone.