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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.

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.

Polycyclic aromatic hydrocarbons (PAHs) are a typical class of persistent organic pollutants that is ubiquitous worldwide. Previous animal studies suggested that PAHs had adverse effects on female reproduction. However, the human data regarding relationship of PAHs exposure with women reproductive health, such as ovarian dysfunction, are scarce. In this case-control study, the associations of serum levels of PAHs with the risk of premature ovarian failure (POF) and reproductive hormones in Chinese women were investigated, with recruiting 157 POF patients and 217 healthy women. The serum levels of 12 types of PAHs, as well as reproductive hormones, including follicle-stimulating hormone, luteinizing hormone and anti-mullerian hormone, were determined. In the logistic regression models, most individual PAH congeners showed significantly positive correlations with the risk of POF (p 0.05), except for fluorine and pyrene. Benzo(a)pyrene (BaP), as the most carcinogenic PAH congener, was observed to be significantly positively associated with the risk of POF. After adjustment for age, body mass index, educational levels and household income, per one-unit increase in the log-transformed BaP concentration was significantly correlated with 2.191-fold increased risk of POF (OR = 2.191, 95%CI: 1.634-2.938, p 0.05). To the best of our knowledge, this is the first study to report an association between internal exposure levels of PAHs and the increased risk of POF in women.

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

Although some persistent organic pollutants (POPs) may not be currently in production, many of these chemicals still exist ubiquitously in the environment and continue to represent significant environmental health concern. One of the important concerns of POPs exposure may lead to the adverse reproductive consequences including primary ovarian insufficiency (POI), but the limited evidence has been reported so far. Our case-control study was performed to explore the association between serum levels of selected POPs and risk for POI in a Chinese female population, including 157 cases and 217 healthy controls. Serum concentrations of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and serum levels of reproductive hormones [follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol] were measured. The medians of dioxin-like PCBs (DL-PCBs) and p,p′-dichlorodiphenyltrichloroethane (p,p′-DDT) were significantly higher in case sera than in controls. Higher concentrations of DL-PCBs and p,p’-DDT were significantly associated with elevated risk of POI. A dose-response relationship was observed between the sum of DL-PCBs (Σ6 DL-PCBs) and the risk of POI (p for trend = 0.003), with odds ratios for the second and third tertiles, compared with the first, of 1.31- (95% CIs: 0.67–2.57) and 3.15-fold (95% CIs: 1.63–6.10), respectively. Similar results were observed for the sum of p,p′-DDT and its metabolites (Σ2 p,p′-DDTs). In control women, FSH levels were negatively associated with PCBs exposure, while LH had a positive association with OCPs. In patients with POI, exposure to PCBs was correlated with higher levels of LH, whereas exposure to OCPs was associated with lower levels of AMH. To the best of our knowledge, this study for the first provided evidence that exposure to PCBs and DDT could be the potential risk factors for POI in women. Keywords: Persistent organic pollutants, Polychlorinated biphenyls, Organochlorine pesticides, Primary ovarian insufficiency, Reproductive health, Women

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.

This paper presents a semantic-guided interpolation scheme (SemFlow) to handle motion boundaries and occlusions in large displacement optical flow. The basic idea is to segment images into superpixels and estimate their homographies for interpolation. In order to ensure each superpixel can be approximated as a plane, a semantic-guided refinement method is introduced. Moreover, we put forward a homography estimation model weighted by the distance between each superpixel and its K -nearest neighbors. Our newly-proposed distance metric combines the texture and semantic information to find proper neighbors. Our homography model performs better than the original affine model, since it accords with the real world projection relationship. The experiments on KITTI dataset demonstrate that SemFlow outperforms other state-of-the-art methods, especially in solving the problem of large scale motions and occlusions.

In this article, we consider time-series, ordinary least-squares, and instrumental-variable regressions and introduce a new pair of commands, har and hart, that implement more accurate heteroskedasticity- and autocorrelation-robust (HAR) F and t tests. These tests represent part of the recent progress on HAR inference. The F and t tests are based on the convenient F and t approximations and are more accurate than the conventional chi-squared and normal approximations. The underlying smoothing parameters are selected to target the type I and type II errors, which are the two fundamental objects in every hypothesis testing problem. The estimation command har and the postestimation test command hart allow for both kernel HAR variance estimators and orthonormal-series HAR variance estimators. In addition, we introduce another pair of new commands, gmmhar and gmmhart, that implement the recently developed F and t tests in a two-step generalized method of moments framework. For these commands, we opt for the orthonormal-series HAR variance estimator based on the Fourier bases because it allows us to develop convenient F and t approximations as in the first-step generalized method of moments framework. Finally, we present several examples to demonstrate these commands.

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.

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.

Neural networks have recently achieved impressive success in semantic and instance segmentation on 2D images. However, their capabilities have not been fully explored to address semantic instance segmentation on unstructured 3D point cloud data. Digging into the regional feature representation to boost point cloud comprehension, we propose a region-feature-enhanced structure consisting of adaptive regional feature complementary (ARFC) module and affinity-based regional relational reasoning (AR3) module. The ARFC module aims to complement low-level features of sparse regions adaptively. The AR3 module emphasizes on mining the potential reasoning relationships between high-level features based on affinity. Both the ARFC and AR3 modules are plug-and-play. Besides, a novel dual spatial-aware discriminative loss is proposed to improve the discrimination of instance embedding. Our proposal-free point cloud instance segmentation network (RegionNet) equipped with the region-feature-enhanced structure and dual spatial-aware discriminative loss achieves state-of-the-art performance on S3DIS dataset and ScanNet-v2 dataset.

Monocular 3D object detection is a challenging task due to unreliable depth, resulting in a distinct performance gap between monocular and LiDAR-based approaches. In this paper, we propose a novel domain adaptation based monocular 3D object detection framework named DA-3Ddet, which adapts the feature from unsound image-based pseudo-LiDAR domain to the accurate real LiDAR domain for performance boosting. In order to solve the overlooked problem of inconsistency between the foreground mask of pseudo and real LiDAR caused by inaccurately estimated depth, we also introduce a context-aware foreground segmentation module which helps to involve relevant points for foreground masking. Extensive experiments on KITTI dataset demonstrate that our simple yet effective framework outperforms other state-of-the-arts by a large margin.

Unbalanced panel data or panel data with missing observations are common in empirical research. In this paper, we consider an unbalanced panel data Tobit model with interactive effects, and provide an estimator based on the iteration of Tobit factor analysis and maximum likelihood estimation. Monte Carlo studies are carried out to investigate the finite sample performance of the proposed method in comparison with other candidate methods. The results show that the finite sample performance of the proposed method is satisfactory under different Mont Carlo designs. We also apply our method to study female labor supply using an unbalanced panel data set from the Chinese Family Panel Studies (CFPS).

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.

Despite the great success achieved by supervised fully convolutional models in semantic segmentation, training the models requires a large amount of labor-intensive work to generate pixel-level annotations. Recent works exploit synthetic data to train the model for semantic segmentation, but the domain adaptation between real and synthetic images remains a challenging problem. In this work, we propose a Separated Semantic Feature based domain adaptation network, named SSF-DAN, for semantic segmentation. First, a Semantic-wise Separable Discriminator (SS-D) is designed to independently adapt semantic features across the target and source domains, which addresses the inconsistent adaptation issue in the class-wise adversarial learning. In SS-D, a progressive confidence strategy is included to achieve a more reliable separation. Then, an efficient Class-wise Adversarial loss Reweighting module (CA-R) is introduced to balance the class-wise adversarial learning process, which leads the generator to focus more on poorly adapted classes. The presented framework demonstrates robust performance, superior to state-of-the-art methods on benchmark datasets.

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.

To combine the advantages of long detection range and small antenna array, the newly designed Wuhan Ionospheric Oblique Backscattering Sounding System (WIOBSS) transmits radio waves by ionospheric reflection and receives oceanic backscattered ground waves. To combine the functions of operating frequency selection and sea-state detection, WIOBSS can transmit the interpulse coding wave and frequency-modulated continuous wave waveforms in one hardware platform. The hardware and software of the radio system are introduced. A sky-wave over-the-horizon sea-state detection experiment was carried out in Chongyang and Longhai, China, on January 28, 2015. The observations of the oceanic surface echoes 130–300 km from the coastline are also presented.

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.

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.

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.

Diesel exhaust (DE) is one of the main sources of urban air pollution. An increasing number of evidence showed the association of air pollution with cardiovascular diseases. Pulmonary arterial hypertension (PAH) is one of the most disastrous vascular diseases, which results in right ventricular failure and death. However, the relationship of DE inhalation exposure with PAH is still unknown. In this study, male adult mice were exposed by inhalation to filtered ambient air (negative control), 10% O2 hypoxia (PAH-phenotype positive control), 350 μg/m3 particulate matter whole DE, or the combination of DE and hypoxic condition. DE inhalation induced PAH-phenotype accompanied with increased right ventricular systolic pressure (RVSP), right ventricle hypertrophy and pulmonary arterial thickening in a mouse model. DE exposure induced the proliferation of vascular smooth muscle cells (VSMCs) and apoptosis of endothelial cells in pulmonary artery. DE inhalation exposure induced an accumulation of CD45+ lymphocytes and CD68+ macrophages surrounding and infiltrating pulmonary arteriole. The levels of pro-inflammatory cytokines tumor necrosis factor (TNF-α), interleukin-6 (IL-6) and IL-13 produced by T helper 17 (Th17) and Th2 cells were markedly elevated in lung tissues of mice after DE inhalation exposure. Our findings suggest DE exposure induces PAH by activating Th17-skewed and Th2-droved responses, stimulating VSMCs proliferation and inducing endothelial cell apoptosis by the production of multifunctional pro-inflammatory cytokines, especially IL-6 and TNF-α. Considering the adverse impact of air pollution on health care, it is imperative to understand air pollution-induced susceptibility of progressive cardiopulmonary disease, such as PAH, and also elucidate critical mechanistic pathways which mediate pulmonary artery vascular remodeling and may serve as targets for preventive measures.

Pyrethroids, a class of ubiquitous insecticides, have been considered as endocrine-disrupting chemicals (EDCs). Female animal studies suggested that early-life pyrethroids exposure might delay puberty onset. However, it remains unclear whether this association applies to human populations. A total of 305 girls at the ages of 9–15 years old were recruited in Hangzhou, China in this study. The concentration of the common metabolite of pyrethroids, 3-phenoxybenzoic acid (3-PBA), was analyzed in urine samples to reflect the exposure level of pyrethroids. The associations of 3-PBA with pubertal stages were evaluated using a multinomial logistic regression model. The geometric mean level of 3-PBA was 1.11 μg/L (1.42 μg/g for creatinine-adjusted concentration). There was a significant 45% reduction in odds of being in breast stage 3 (B3) per one-unit increase in the log-transformed 3-PBA levels [OR = 0.55 (95%CI: 0.31–0.98), p = 0.042]. A similar negative association was found between urinary 3-PBA levels with later onset by pubic hair stage 2 (P2) [OR = 0.56 (95%CI: 0.36–0.90), p = 0.015]. Similar negative association was also observed between urinary 3-PBA levels and pubertal onset indicated by menarche [OR = 0.51 (95%CI: 0.28–0.93), p = 0.029]. For the first time to our knowledge, this work reveals that pyrethroids exposure may increase the risk of delayed pubertal onset in girls.