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Chemical exposure and local hypoxia caused by mask-wearing may result in skin physiology changes. The effects of methylparaben (MeP), a commonly used preservative in personal care products, and hypoxia on skin health were investigated by HaCaT cell and ICR mouse experiments. MeP exposure resulted in lipid peroxidation and interfered with cellular glutathione metabolism, while hypoxia treatment disturbed phenylalanine, tyrosine, and tryptophan biosynthesis pathways and energy metabolism to respond to oxidative stress. A hypoxic environment increased the perturbation of MeP on the purine metabolism in HaCaT cells, resulting in increased expression of proinflammatory cytokines. The synergistic effects were further validated in a mouse model with MeP dermal exposure and “mask-wearing” treatment. CAT, PPARG, and MMP2 were identified as possible key gene targets associated with skin health risks posed by MeP and hypoxia. Network toxicity analysis suggested a synergistic effect, indicating the risk of skin inflammation and skin barrier aging.

Dihydroxylated polybrominated diphenyl ethers (DiOH-PBDEs) could be the metabolites of PBDEs of some organisms or the natural products of certain marine bacteria and algae. OH-PBDEs may demonstrate binding affinity to thyroid hormone receptors (TRs) and can disrupt the functioning of the systems modulated by TRs. However, the thyroid hormone disruption mechanism of diOH-PBDEs remains elusive due to the absence of diOH-PBDEs standards. This investigation explores the potential disruptive effects of OH/diOH-PBDEs on thyroid hormones via competitive binding and coactivator recruitment with TRα and TRβ. At levels of 5000 nM and 25,000 nM, 6-OH-BDE-47 demonstrated significant recruitment of steroid receptor coactivator (SRC), whereas none of the diOH-PBDEs exhibited SRC recruitment within the range of 0.32–25,000 nM. AutoDock CrankPep (ADCP) simulations suggest that the conformation of SRC and TR–ligand complexes, particularly their interaction with Helix 12, rather than binding affinity, plays a pivotal role in ligand agonistic activity. 6,6′-diOH-BDE-47 displayed antagonistic activity towards both TRα and TRβ, while the antagonism of 3,5-diOH-BDE-100 for TRα and TRβ was concentration-dependent. 3,5-diOH-BDE-17 and 3,5-diOH-BDE-51 exhibited no discernible agonistic or antagonistic activities. Molecular docking analysis revealed that the binding energy of 3,3′,5-triiodo-L-thyronine (T3) surpassed that of OH/diOH-PBDEs. 3,5-diOH-BDE-100 exhibited the highest binding energy, whereas 6,6′-diOH-BDE-47 displayed the lowest. These findings suggest that the structural determinants influencing the agonistic and antagonistic activities of halogen phenols may be more intricate than previously proposed, involving factors beyond high-brominated PBDEs or hydroxyl group and bromine substitutions. It is likely that the agonistic or antagonistic propensities of OH/diOH-PBDEs are instigated by protein conformational changes rather than considerations of binding energy.

As one of the most important transportation hubs and industrial bases in China, Zhengzhou has suffered from serious PM2.5 pollution for a long time. However, the investigation of contamination status and possible exposure risks of environmentally persistent free radicals (EPFRs) in PM2.5 from Zhengzhou is rare. In this work, a comprehensive study of pollution levels, seasonal variations, sources, and potential health risks of PM2.5-bound EPFRs in Zhengzhou was conducted for the first time. The atmospheric concentrations of EPFRs in PM2.5 from Zhengzhou ranged from 1.732 × 1012 spin m−3 to 7.182 × 1014 spin m−3 between 2019 and 2020. Relatively serious contamination was noticed in winter and spring. Primary fossil fuel combustion and Fe-mediated secondary formation were apportioned as possible sources of PM2.5-bound EPFRs in Zhengzhou. Moreover, to avert the bias of the toxicity assessment induced by utilization of incompletely extracted EPFRs from sample filter, simulatively generated EPFRs were applied to toxicological evaluations (cell viability and reactive oxygen species assays). Corresponding experimental dosages were based on the estimated adults’ annual exposure amounts of EPFRs in real PM2.5 samples. The results elucidated that EPFRs might cause growth inhibition and oxidative stress of human lung cells, suggesting the possible exposure-induced health concerns for local people in Zhengzhou. This study provides practical information of real contamination status of PM2.5-bound EPFRs in Zhengzhou, which is favorable to local air pollution control and reduction of exposure risks on public health in central China.

Arabidopsis DXO1 is a member of the eukaryotic DXO family of decapping enzymes for NAD-capped RNAs. Here the authors show that DXO1 is an essential component in canonical m7G capping of mRNA and activates RNMT1 which methylates the guanosine cap to form the m7G cap.

Abstract Horseshoe bats host numerous SARS-related coronaviruses without overt disease signs. Bat intestinal organoids, a unique model of bat intestinal epithelium, allow direct comparison with human intestinal organoids. We sought to unravel the cellular mechanism(s) underlying bat tolerance of coronaviruses by comparing the innate immunity in bat and human organoids. We optimized the culture medium, which enabled a consecutive passage of bat intestinal organoids for over one year. Basal expression levels of IFNs and IFN-stimulated genes were higher in bat organoids than in their human counterparts. Notably, bat organoids mounted a more rapid, robust and prolonged antiviral defense than human organoids upon Poly(I:C) stimulation. TLR3 and RLR might be the conserved pathways mediating antiviral response in bat and human intestinal organoids. The susceptibility of bat organoids to a bat coronavirus CoV-HKU4, but resistance to EV-71, an enterovirus of exclusive human origin, indicated that bat organoids adequately recapitulated the authentic susceptibility of bats to certain viruses. Importantly, TLR3/RLR inhibition in bat organoids significantly boosted viral growth in the early phase after SARS-CoV-2 or CoV-HKU4 infection. Collectively, the higher basal expression of antiviral genes, especially more rapid and robust induction of innate immune response, empowered bat cells to curtail virus propagation in the early phase of infection.

Abstract Background Bioactive lipids play an important role in insulin secretion and sensitivity, contributing to the pathophysiology of type 2 diabetes (T2D). This study aimed to identify novel lipid species associated with incident T2D in a nested case–control study within a long-term prospective Chinese community-based cohort with a median follow-up of ~ 16 years. Methods Plasma samples from 196 incident T2D cases and 196 age- and sex-matched non-T2D controls recruited from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) were first analyzed using untargeted lipidomics. Potential predictive lipid species selected by the Boruta analysis were then verified by targeted lipidomics. The associations between these lipid species and incident T2D were assessed. Effects of novel lipid species on insulin secretion in mouse islets were investigated. Results Boruta analysis identified 16 potential lipid species. After adjustment for body mass index (BMI), triacylglycerol/high-density lipoprotein (TG/HDL) ratio and the presence of prediabetes, triacylglycerol (TG) 12:0_18:2_22:6, TG 16:0_11:1_18:2, TG 49:0, TG 51:1 and diacylglycerol (DG) 18:2_22:6 were independently associated with increased T2D risk, whereas lyso-phosphatidylcholine (LPC) O-16:0, LPC P-16:0, LPC O-18:0 and LPC 18:1 were independently associated with decreased T2D risk. Addition of the identified lipid species to the clinical prediction model, comprised of BMI, TG/HDL ratio and the presence of prediabetes, achieved a 3.8% improvement in the area under the receiver operating characteristics curve (AUROC) (p = 0.0026). Further functional study revealed that, LPC O-16:0 and LPC O-18:0 significantly potentiated glucose induced insulin secretion (GSIS) in a dose-dependent manner, whereas neither DG 18:2_22:6 nor TG 12:0_18:2_22:6 had any effect on GSIS. Conclusions Addition of the lipid species substantially improved the prediction of T2D beyond the model based on clinical risk factors. Decreased levels of LPC O-16:0 and LPC O-18:0 may contribute to the development of T2D via reduced insulin secretion.

Summary: Biomolecule regulation and communication between cells and organs show specific network and regional features and play an important role in disease progression. Here, we describe steps for in situ detection of biomolecules with detailed spatial distribution using imaging mass spectrometry (iMS). Using the information on inter-cells and inter-organs metabolic interactions provided by iMS, we detail the establishment of an iMS-dataset-sourced multiscale network strategy and present steps for exploring metabolic responses in environmental-exposure-induced disease model.For complete details on the use and execution of this protocol, please refer to Dong et al. (2022).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Recently, significant progress has been made in the development of microdevices for point-of-care infectious disease detection. However, most microdevices only allow limited steps, such as DNA amplification on the chip, while sample preparation, such as lysis and DNA extraction, is conducted off the chip using the traditional method. In this study, an all-in-one platform was developed, which incorporated all necessary procedures for nucleic acid detection. Our on-chip DNA extraction method utilized the magnetic bead-based technology on a hybrid channel-digital microfluidics (C-DMF) microdevice. It yielded high recovery rates, varying from 88.43% to 95.83%, with pathogen concentrations of 103–106 CFU/mL. In particular, the on-chip method exhibited significantly higher efficacy compared to the traditional off-chip manual method, for the DNA extraction of E. coli and S. aureus, representing Gram-negative and Gram-positive bacteria, respectively, at a sample concentration of 103 CFU/mL. To address the need for rapid and accessible diagnostics, colorimetric LAMP amplification was integrated into the proposed microdevice. The results were visually detectable with the naked eye, making it user-friendly for non-specialists. In addition, this platform demonstrated impressive sensitivity in simultaneously detecting common foodborne pathogens in spiked meat samples, achieving the LOD of 102–103 CFU/mL. The entire process, from sampling to result, was fully automated and only required approximately 60 min, offering promising applicability in resource-limited and on-site testing scenarios.

Looking for metabolic-associated vulnerabilities is a promising approach for therapeutic intervention in KRAS-mutant colorectal cancer. Here, the authors show that the cholesterol-uptake regulator PCSK9 drives tumourigenesis and is a therapeutic target in KRASmutant colorectal cancer.

Triclosan (TCS), an antimicrobial agent commonly found in consumer products, has been reported to exacerbates colitis in animal models. Here, using in vitro and in vivo approaches, the authors show that gut bacterial enzymes can drive the metabolic activation and gut toxicity of TCS, highlighting an important role of intestinal microbial factors in the complex etiology of colitis.

Abstract Background Diagnosing seronegative rheumatoid arthritis (RA) can be challenging due to complex diagnostic criteria. We sought to discover diagnostic biomarkers for seronegative RA cases by studying metabolomic and lipidomic changes in RA patient serum. Methods We performed comprehensive metabolomic and lipidomic profiling in serum of 225 RA patients and 100 normal controls. These samples were divided into a discovery set (n = 243) and a validation set (n = 82). A machine-learning-based multivariate classification model was constructed using distinctive metabolites and lipids signals. Results Twenty-six metabolites and lipids were identified from the discovery cohort to construct a RA diagnosis model. The model was subsequently tested on a validation set and achieved accuracy of 90.2%, with sensitivity of 89.7% and specificity of 90.6%. Both seropositive and seronegative patients were identified using this model. A co-occurrence network using serum omics profiles was built and parsed into six modules, showing significant association between the inflammation and immune activity markers and aberrant metabolism of energy metabolism, lipids metabolism and amino acid metabolism. Acyl carnitines (20:3), aspartyl-phenylalanine, pipecolic acid, phosphatidylethanolamine PE (18:1) and lysophosphatidylethanolamine LPE (20:3) were positively correlated with the RA disease activity, while histidine and phosphatidic acid PA (28:0) were negatively correlated with the RA disease activity. Conclusions A panel of 26 serum markers were selected from omics profiles to build a machine-learning-based prediction model that could aid in diagnosing seronegative RA patients. Potential markers were also identified in stratifying RA cases based on disease activity.

Summary: The metabolic responses of organism to external stimuli are characterized by the multicellular- and multiorgan-based synergistic regulation. Network analysis is a powerful tool to investigate this multiscale interaction. The imaging mass spectrometry (iMS)-based spatial omics provides multidimensional and multiscale information, thus offering the possibility of network analysis to investigate metabolic response of organism to environmental stimuli. We present iMS dataset-sourced multiscale network (iMS2Net) strategy to uncover prenatal environmental pollutant (PM2.5)-induced metabolic responses in the scales of cell and organ from metabolite abundances and metabolite-metabolite interaction using mouse fetal model, including metabotypic similarity, metabolic vulnerability, metabolic co-variability and metabolic diversity within and between organs. Furthermore, network-based analysis results confirm close associations between lipid metabolites and inflammatory cytokine release. This networking methodology elicits particular advantages for modeling the dynamic and adaptive processes of organism under environmental stresses or pathophysiology and provides molecular mechanism to guide the occurrence and development of systemic diseases.

The prevalence of diabetes mellitus has been increasing for decades worldwide. To develop safe and potent therapeutics, animal models contribute a lot to the studies of the mechanisms underlying its pathogenesis. Dietary induction using is a well-accepted protocol in generating insulin resistance and diabetes models. In the present study, we reported the multi-omics profiling of the liver and sera from both peripheral blood and hepatic portal vein blood from Macaca fascicularis that spontaneously developed Type-2 diabetes mellitus with a chow diet (sDM). The other two groups of the monkeys fed with chow diet and high-fat high-sugar (HFHS) diet, respectively, were included for comparison. Analyses of various omics datasets revealed the alterations of high consistency. Between the sDM and HFHS monkeys, both the similar and unique alterations in the lipid metabolism have been demonstrated from metabolomic, transcriptomic, and proteomic data repeatedly. The comparison of the proteome and transcriptome confirmed the involvement of fatty acid binding protein 4 (FABP4) in the diet-induced pathogenesis of diabetes in macaques. Furthermore, the commonly changed genes between spontaneous diabetes and HFHS diet-induced prediabetes suggested that the alterations in the intra- and extracellular structural proteins and cell migration in the liver might mediate the HFHS diet induction of diabetes mellitus.

Dioxins, environmentally stable and ubiquitous, have been found to induce metabolic changes especially in lipids and be related to multiple diseases. However, limited study is available on lipid alternations related to human exposure to dioxins. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of adverse health risks associated with dioxin exposure. A lipidomic study integrating nontargeted lipidomics, and targeted free fatty acid (FFA) and acyl-coenzyme A (acyl-CoA) analyses were conducted to investigate the 94 serum samples from two groups of male workers with remarkably different dioxin concentrations. The obtained results exhibited distinct lipidomic signatures between the high and low exposed groups. A total of 37 lipids were identified with the significant changes. The results revealed that dioxin exposure caused accumulations of triglyceride (TG), ceramide (Cer) and sphingoid (So), remodeling of glycerophospholipid (GP), imbalanced FFA metabolism, as well as upregulation of platelet-activating factor (PAF). These findings implied the associations between dioxin exposure and potential adverse health risks including inflammation, apoptosis, cardiovascular diseases (CVDs), and liver diseases. This study is the first to explain the associations between dioxin exposure and health effects at the level of lipid metabolism.

Cadmium is a well-known hazardous pollutant that mainly comes from dietary, tobacco and occupational exposure, posing threat to kidney. However, there is still a lack of systematic study on metabolic pathways and urinary biomarkers related to its nephrotoxicity under cadmium exposure for both females and males. In this study, a mass spectrometry-based metabolomics investigation of a cohort of 144 volunteers was conducted to explore sex-specific metabolic alteration and to screen biomarkers related to cadmium-induced nephrotoxicity. When the concentration of urinary cadmium increased, creatine pathway, amino acid metabolism especially the tryptophan metabolism, aminoacyl-tRNA biosynthesis, and purine metabolism were primarily influenced regardless of the gender. Also, the most specific biomarkers linked with nephrotoxicity based on the statistical analysis were detected including creatine, creatinine, l-tryptophan, adenine and uric acid. The study outcome might provide information to reflect the body burden and help improve health policy for risk assessment.

Angiotensin II (Ang II) plays an important role in regulating various physiological processes. However, little is known about the existence of intracellular Ang II (iAng II), whether iAng II would regulate the automaticity of early differentiating cardiomyocytes, and the underlying mechanism involved. Here, iAng II was detected by immunocytochemistry and ultra-high performance liquid chromatography combined with electrospray ionization triple quadrupole tandem mass spectrometry in mouse embryonic stem cell–derived cardiomyocytes (mESC-CMs) and neonatal rat ventricular myocytes. Expression of AT1R-YFP in mESC-CMs revealed that Ang II type 1 receptors were located on the surface membrane, while immunostaining of Ang II type 2 receptors (AT2R) revealed that AT2R were predominately located on the nucleus and the sarcoplasmic reticulum. While extracellular Ang II increased spontaneous action potentials (APs), dual patch clamping revealed that intracellular delivery of Ang II or AT2R activator C21 decreased spontaneous APs. Interestingly, iAng II was found to decrease the caffeine-induced increase in spontaneous APs and caffeine-induced calcium release, suggesting that iAng II decreased spontaneous APs via the AT2R- and ryanodine receptor–mediated pathways. This is the first study that provides evidence of the presence and function of iAng II in regulating the automaticity behavior of ESC-CMs and may therefore shed light on the role of iAng II in fate determination.

Perfluorooctanoic acid (PFOA) is one of the most commonly used perfluorinated chemicals in industry. Wide concerns of PFOA toxicity are increased in recent years. However, report on immunotoxicity of PFOA was quite limited. This study aimed to investigate the immunotoxicity of PFOA exposure on macrophage RAW264.7. We assessed the effects of PFOA exposure on macrophage cell viability, cell apoptosis and cellular ROS level, and detected prominent cytokines release by RAW264.7. The results indicated that the cell viability of macrophage RAW264.7 was decreased by PFOA in dose- and time-dependent manners. Specifically, the exposure of 200 μM PFOA significantly increased apoptosis and ROS generation in macrophage, and thus caused cell damage. The ELISA results displayed that 100 μM PFOA exposure induced macrophage activation and enhanced cytokines secretion, including TNF-α, IL-1, IL-6, and IL-12. We also conducted nontargeted metabolomics based on LC-MS/MS and unveiled the perturbed metabolic pathways in macrophages induced by sublethal doses of PFOA (10 μM and 100 μM). Remarkably, global metabolomics results displayed that 10 μM PFOA exposure affected glutamine related pathways and the exposure at 100 μM conspicuously changed glutathione and fatty acid oxidation metabolism. These findings showed that 10 μM PFOA exposure could impel metabolic reprogramming of macrophage to trigger inflammatory response, although such dose displayed no obvious effect on cell viability, cellular ROS or apoptosis events of macrophage RAW264.7.

Background: Widespread exposure to parabens has been a concern, especially among pregnant women. Only one study reported that parabens are associated with glucose levels among pregnant women. However, studies on parabens exposure and gestational diabetes mellitus (GDM) are lacking. Objectives: This study investigated whether exposure to parabens in early pregnancy is related to GDM. Methods: We conducted a prospective study of 1087 pregnant women from a single tertiary medical center between 2014 and 2015 in Wuhan, China. Parabens [methyl paraben (MeP), ethylparaben (EtP), propylparaben (PrP), butylparaben (BuP), and benzylparaben (BzP)] concentrations were measured in spot urine samples collected between 8 and 16 gestational weeks. GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Groups Consensus Panel (IADPSG) recommendations. We used the Poisson regression with a robust error variance with generalized estimating equations (GEE) estimation analyses to evaluate associations between parabens exposure and GDM risk. Results: A total of 103 (9.5%) women were diagnosed with GDM. We evaluated the associations of GDM risk with urinary MeP, EtP, and PrP (detection rate: >90%), but not with BuP and BzP due to the relatively low detection rate (

Background: Benzophenones (BPs), parabens, and triclosan (TCS) are widely used in personal care products and may be neurotoxic to children, but limited studies have estimated the associations between exposure to these potential endocrine disrupting chemicals during pregnancy and child neurocognitive development. Objective: Our aim was to evaluate the relationships of prenatal exposure to BPs, parabens and TCS with child neurocognitive development at age 2. Methods: From 2014 to 2015, 478 mother-child pairs from a longitudinal prenatal cohort in China were included in present study. We quantified BPs, parabens and TCS in three spot urine samples during pregnancy (in the first, second, and third trimester). The Bayley Scales of Infant Development (BSID) test to children was performed at 2 years. Multivariate linear regression models and generalized estimating equations were used to examine changes in mental developmental index (MDI) and psychomotor development index (PDI) per 2-fold increase in averaged and trimester-specific maternal urinary phenols, respectively. Results: In the adjusted models, each 2-fold increase in average prenatal paraben concentration was associated with lower MDI scores among girls [−1.08 (95% CI: −2.10, −0.06) and − 1.51 (95% CI: −2.69, −0.32) for methyl paraben (Mep) and Σparabens, respectively], but the association was not statistically significant among boys [−0.24 (95% CI: −1.46, 0.99), Psex-int = 0.37 and 0.18 (95% CI: −1.28, 1.64), Psex-int = 0.10 for Mep and Σparabens, respectively]. Increasing urinary 4-hydroxybenzophenone (4-OH-BP) concentration was associated with lower PDI scores among boys [−2.96 (95% CI: −4.48, −1.45)], not girls [−0.07 (95% CI: −1.57, 1.43)] and the association was significantly different in boys and girls (Psex-int = 0.01). No significant associations were observed between the average prenatal TCS exposure and BSID results. In trimester-specific analyses, increasing parabens was associated with lower girls' MDI only in the second trimester, while increasing 4-OH-BP was associated with lower boys' PDI in each trimester. Conclusion: Our results suggest that prenatal exposure to BPs and parabens may be associated with impairment in child cognitive abilities at 2 years. Further human and animal studies are needed to verify our results and elucidate the biological mechanisms involved in these associations. Keywords: Benzophenones, Parabens, Triclosan, Child neurocognitive development

Previous studies have proven the endocrine-disrupting properties and health hazards of parabens, triclosan, and benzophenones, but their relationship with blood pressure during pregnancy remains unknown. Therefore, we investigated the associations of repeated measures of urinary parabens, triclosan, and benzophenones with blood pressure during pregnancy and evaluated whether the associations were modified by fetal sex. From a prospective birth cohort in Wuhan, China, we collected urine samples from 644 pregnant women in the first, second, and third trimesters between 2014 and 2015. Five parabens, triclosan, and three benzophenones were quantified in all urine samples. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in each trimester after urine sampling. Mixed linear models were used to estimate the associations between urinary chemical levels and blood pressure during pregnancy among all pregnant women and subgroups stratified by fetal sex. In the women carrying male fetuses, urinary triclosan and selected benzophenone concentrations were associated with a slight change of SBP during pregnancy. In the women carrying female fetuses, no chemical was associated with SBP, while urinary concentration of triclosan was inversely associated with DBP, though the magnitude was small. Urinary paraben levels weren't associated with blood pressure during pregnancy. Our results suggest that triclosan and selected benzophenone exposure might be associated with blood pressure during pregnancy in a potential fetal sex-different manner. Replicated research studies in pregnant women with higher triclosan and benzophenone exposure levels are needed in the future.

An aqueous protocol was developed for nattokinase purification under scalable conditions using a combination of salting out, anion exchange chromatography and ultra-filtration. The enzyme was firstly washed off from the fermented soybeans. The whole proteins were precipitated by ammonium sulfate and purified by anion exchange chromatography. The purified enzyme was finally refined by size exclusion chromatography and ultra-filtration at laboratory and industry-compatible level, respectively. There was a 476.18-fold increase in enzymatic activity with a 48.3% yield at the laboratory level and 429.75-fold increase in enzymatic activity with a 42.7% yield at the industrial-compatible scale. The protocol was universally adaptive for purifying the fibrinolytic enzymes produced by bacillus tequilensis, bacillus amyloliquefaciens, and bacillus cereus, showing a purification efficiency of 329.76-fold with 42.7% yield, 221.78-fold with 32.5% yield, and 288.56-fold with 38.7% yield, respectively. All procedures are scalable, aqueous, simple, cost-effective, and suitable for fibrinolytic enzymes industrial production.

Background: Previous studies have suggested that phthalates might disrupt fetal steroidogenesis. However, the evidence of the effects of prenatal phthalate exposure across pregnancy on fetal glucocorticoids was insufficient. Objective: We investigated the associations between urinary phthalate metabolites across pregnancy and cord blood glucocorticoids in a prospective birth cohort. Methods: Our study included 553 mother-infant pairs from a prospective birth cohort conducted in Wuhan, China. Maternal urine samples were collected at 14, 24 and 36 weeks of gestation (mean). Urinary phthalate metabolites and cord blood glucocorticoids (cortisol and cortisone) were measured. Generalized estimating equation models were conducted to explore the relationships of phthalate metabolite concentrations at each trimester and glucocorticoid levels. Results: Among the participants, mono‑benzyl phthalate (MBzP) in the first trimester was associated with higher cortisol/cortisone ratio concentrations, and mono‑(2‑ethyl‑5‑carboxypentyl) phthalate (MECPP) and mono‑(2‑ethyl‑5‑oxohexyl) phthalate (MEOHP) measured in the third trimester were associated with decreased cortisone. Moreover, the associations between phthalates and glucocorticoids varied by sex. Among the female infants, each 10-fold increase in several maternal urinary phthalate metabolite concentrations in 1st and 3rd trimester was associated with the increased glucocorticoid levels with percent changes ranged from 16.2%–55.9%. However, among male infants, each 10-fold increase in maternal urinary MECPP, mono‑(2‑ethyl‑5‑hydroxyhexyl) phthalate (MEHHP) and MEOHP in 3rd trimester was associated with 20.8%–36.3% decreased cortisol and cortisone levels, respectively. Conclusion: We have shown that prenatal phthalate exposure during early and late trimester disrupted the infant steroidogenesis and these associations might be modified by infant sex. To the best of our knowledge, this is the first study to evaluate phthalate exposure at three trimesters during pregnancy in relation to infant glucocorticoids. Keywords: Phthalate, Glucocorticoid, Prenatal exposure, Trimester-specific

Background: Benzotriazoles (BTRs) and benzothiazoles (BTHs) are emerging contaminants with high production volume worldwide, which exhibit potential health risk to human. To date, little is known about the exposure of BTRs and BTHs (BTs) on human, especially in the context of pregnancy. Objectives: We aimed to characterize the exposure profiles, temporal variability, and potential predictors of urinary BTs during pregnancy. Methods: Between 2014 and 2015, we recruited 856 pregnant women in Wuhan who provided urine samples at three trimesters (13.1 ± 1.1, 23.7 ± 3.2, and 35.7 ± 3.4 gestational weeks). We measured the urinary concentrations of five BTRs (1‑H‑benzotriazole, 1‑hydroxy‑benzotriazole, xylyltriazole, tolyltriazole, 5‑chloro‑1‑H‑benzotriazole) and five BTHs (benzothiazole, 2‑hydroxy‑benzothiazole, 2‑methylthio‑benzothiazole, 2‑amino‑benzothiazole, 2‑thiocyanomethylthio‑benzothiazole) to characterize the exposure profiles of BTs. We calculated the intra-class correlation coefficients (ICCs) to assess the temporal variability and investigated potential predictors of urinary BTs by using the mixed models. Results: Most of the targeted BTs were detected in over 50% of urine samples, except for 5‑chloro‑1‑H‑benzotriazole (9.3%) and 2‑thiocyanomethylthio-benzothiazole (1.4%). The predominant BTRs in urine was 1‑hydroxy‑benzotriazole [Geometric Mean (GM): 0.77 ng/mL]. Benzothiazole was the major derivative in urine samples with a GM concentration of 1.6 ng/mL. Correlations among BTHs (r = 0.04–0.39) were higher than that among BTRs (r = 0.02–0.14). The exposure pattern was constant at low level and co-exposure to all the targeted compounds was infrequent during pregnancy. Urinary concentrations of BTRs exhibited considerable within-subject variation (ICCs: 0.12–0.56) during pregnancy. Relatively high temporal reliability was observed for urinary concentrations of BTHs with ICCs ranging from 0.42 to 0.85. It was found that parity, household income, pregnancy occupational status, sampling season and menstrual cycle were associated with urinary concentrations of BTs in pregnant women (P

Increasing prevalence of childhood obesity poses threats to the global health burden. Because this rising prevalence cannot be fully explained by traditional risk factors such as unhealthy diet and physical inactivity, early-life exposure to endocrine disrupting chemicals (EDCs) is recognized as emerging novel risk factors for childhood obesity. EDCs can disrupt the hormone-mediated metabolic pathways, affect children’s growth and mediate the development of childhood obesity. Many organic pollutants are recently classified to be EDCs. In this review, we summarized the epidemiological and laboratory evidence related to EDCs and childhood obesity, and discussed the possible mechanisms underpinning childhood obesity and early-life exposure to non-persistent organic pollutants (phthalates, bisphenol A, triclosan) and persistent organic pollutants (dichlorodiphenyltrichloroethane, polychlorinated biphenyls, polybrominated diphenyl ethers, per- and polyfluoroalkyl substances). Understanding the relationship between EDCs and childhood obesity helps to raise public awareness and formulate public health policy to protect the youth from exposure to the harmful effects of EDCs.

Background: The association between exposure to organochlorine pesticides (OCPs) and infant growth has been reported contradictorily in previous studies. Few studies have investigated the effects of prenatal exposure to OCPs on infant growth assessed longitudinally at multiple time points. Objectives: The purpose of the study was to examine the associations between prenatal exposure to OCPs and infant growth at birth, 6, 12 and 24 months of age, and further to explore the potential sex-specific effects. Methods: The study population included 1039 mother-infant pairs who participated in a birth cohort study in Wuhan, China. The weight, length and body mass index (BMI) z-score of infants were measured and calculated at birth, 6, 12 and 24 months of age. The overweight status was defined as BMI z-score ≥ 85th percentile according to the standard of World Health Organization. The concentrations of OCPs were measured in cord serum, including hexachlorocyclohexanes (HCHs, consisted of α-HCH, β-HCH, and γ-HCH), p,p′-dichlorodiphenyltrichloroethane (p,p′-DDT) and its metabolites: p,p′-dichlorodiphenyldichloroethane (p,p′-DDD), and p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE). Generalized linear models were applied to estimate the associations of cord OCPs with infant growth parameters. A group-based semiparametric mixture model was used to estimate growth patterns of infants. Linear-mixed growth curve models were used to examine relationships between predicted growth trajectories and prenatal exposure to OCPs. Weighted quantile sum regression (WQSR) analyses were used to estimate the mixture effects of OCPs on infant growth. Results: Higher cord serum β-HCH concentrations were associated with higher BMI z-score at 12 [β = 0.07, 95%CI: 0.01, 0.13] and 24 months of age [β = 0.08, 95% CI: 0.02, 0.14]. Similar patterns were observed for relationships of γ-HCH [β = 0.04, 95%CI: 0.01, 0.07] and p,p′-DDT [β = 0.03, 95% CI: 0.00, 0.06] with BMI z-score at 6 and 12 months of age, respectively. However, higher cord serum p,p′-DDE concentrations were associated with a reduction of BMI z-score at 6 months of age [β = −0.07, 95% CI: −0.12, −0.01]. Cord serum β-HCH was also positively associated with the risk of overweight at 12 months of age [RR = 1.16, 95% CI (1.02, 1.33), for the medium vs the lowest tertile]. Among girls, the effects of β-HCH on BMI z-score and overweight status were stronger than boys at 12 and 24 months of age. No statistically significant relationships of other OCPs with infant growth were observed. Conclusions: Prenatal exposure to β-HCH was associated with increased BMI z-score and higher risk of overweight status in infants especially at 12 and 24 months of age, which seemed to be stronger in girls.

Bufalin (BFL) and cinobufagin (CBF) are the principal bioactive constituents of Chansu, a widely used traditional Chinese medicine (TCM). The synergistic effects of potential active components are responsible for the bioactivities of TCM. Our results showed that the cotreatment with BFL and CBF confers superior anticancer efficacy compared to monotreatment. To reveal the underlying mechanisms of their cotreatment, an integrated method composed of mass spectrometry-based lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging was used to delineate the responses of tumor-bearing mice treated with BFL and CBF individually or in combination. The cotreatment with BFL and CBF modulated the sphingolipid metabolism and glycerophospholipid metabolism, and subsequently led to mitochondria-driven apoptosis and systemic disruption of biomembranes in tumor cells. Furthermore, we found that the disturbed lipid markers were mainly located in the non-necrotic tumor areas, the essential parts for the formation of solid tumor framework. Together, our findings revealed what occurred in tumor in response to the treatment of BFL and CBF, from lipids to enzymes, and thus provide insights into the critical role of lipid reprogramming in the satisfactory anticancer effect of BFL in combination with CBF.

Cadmium has been widely detected in the environment and various foods. The association between cadmium burden and osteoporosis has been studied in cohorts. However, the effects and mechanisms of environmental cadmium exposure on bone metabolism is poorly understood. This study aims to investigate the altered metabolites in bone cells affected by low-level cadmium by metabolomics analysis. Specifically, we used the dosage of cadmium that do not decrease the cell viability (determined by MTT assay) to treat Saos-2 cells for 24 h. ICP-MS was applied to quantify the cadmium in culture medium and cell precipitate. The cellular metabolites were extracted and analyzed by liquid chromatography-mass spectrometry. The pathway analysis based on the identified differential metabolites showed that 1 μM cadmium significantly affected citric acid cycle and malate-aspartate shuttle, while 10 μM cadmium treatment affected citric acid cycle, alanine metabolism, glucose-alanine cycle, pyrimidine metabolism and glutamate metabolism. Taken together, 1 μM cadmium exposure could suppress the electrons transportation from the cytosol to mitochondrial matrix in Saos-2, and the impediment of the electron transport chain further inhibited downstream activities in citric acid cycle, which resulted in the accumulation of pyruvic acid. In addition, the suppressed pyrimidine degradation resulted in senescent nucleic acid accumulation and the decrease of mRNA transcription in Saos-2 cells. In general, our studies unveil the cadmium-induced metabolic perturbations in Saos-2 cells and demonstrate the feasibility of our established metabolomics pipeline to understand cadmium-induced effects on bone.

Endocrine-disrupting chemicals (EDCs) are widespread environmental chemicals that are often considered as risk factors with weak activity on the hormone-dependent process of pregnancy. However, the adverse effects of EDCs in the body of pregnant women were underestimated. The interaction between dynamic concentration of EDCs and endogenous hormones (EHs) on gestational age and delivery time remains unclear. To define a temporal interaction between the EDCs and EHs during pregnancy, comprehensive, unbiased, and quantitative analyses of 33 EDCs and 14 EHs were performed for a longitudinal cohort with 2317 pregnant women. We developed a machine learning model with the dynamic concentration information of EDCs and EHs to predict gestational age with high accuracy in the longitudinal cohort of pregnant women. The optimal combination of EHs and EDCs can identify when labor occurs (time to delivery within two and four weeks, AUROC of 0.82). Our results revealed that the bisphenols and phthalates are more potent than partial EHs for gestational age or delivery time. This study represents the use of machine learning methods for quantitative analysis of pregnancy-related EDCs and EHs for understanding the EDCs’ mixture effect on pregnancy with potential clinical utilities.

Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) is linked to abnormal lipid metabolism, but evidence regarding PAHs as risk factors for dyslipidemia is lacking. Objective: To investigate the respective role and interaction of PAH exposure and antioxidant consumption in the risk for pediatric dyslipidemia. Methods: We measured the concentrations of serum lipids, superoxide dismutase (SOD) and urinary hydroxylated PAHs (OH-PAHs) in 403 children, of which 203 were from an e-waste-exposed area (Guiyu) and 200 were from a reference area (Haojiang). Biological interactions were calculated by additive models. Results: Guiyu children had higher serum triglyceride concentration and dyslipidemia incidence, and lower serum concentration of high-density lipoprotein (HDL) than Haojiang children. Elevated OH-PAH concentration, and concomitant SOD reduction, were both associated with lower HDL concentration and higher hypo-HDL risk (∑3OH-Phes: B for lgHDL = −0.048, P

Polygonum perfoliatum L. has a long history of medicinal and edible applications. Studies have shown that it can significantly protect liver injury, but the mechanism is unclear. The purpose of this study was to explore the protective mechanism of P. perfoliatum on chronic alcoholic liver injury from the perspective of lipid metabolism. After 8 weeks of alcohol exposure in male Wister mice, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in serum were significantly increased, and the activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in liver were significantly decreased. Meanwhile, pathological changes of liver tissue in mice were observed by histopathology. Then, Ultra-High Performance Liquid Chromatography (UHPLC) QExactive Plus Mass Spectrometer lipidomics and matrix-assisted laser desorption/ionization time-of-flight/time -of-flight (MALDI-TOF/TOF) mass spectrometry imaging methods were established to analyze lipid metabolism in mice. Ten different lipids were identified by statistical analysis, including Fatty Acyls, Glycerophospholipids, Prenol lipids and Sphingomyelins. After intervention with P. perfoliatum extracts at different doses (25 to 100 mg/kg), levels of AST, ALT, ALP in serum, and activities of ADH and ALDH in liver were significantly corrected. The hepatic cord structure was clear, and the liver cells were closely arranged without other obvious abnormalities. Non-target lipidomics analysis showed that P. perfoliatum extract could regulate the metabolic disorders of the 10 different lipids caused by continuous alcohol exposure. Pathway analysis suggested that the mechanism of P. perfoliatum extract on chronic alcoholic liver injury may be related to the regulation of linoleic acid and α-linolenic acid.

This article studies the enhancement of methyl orange (MO) adsorption by Mongolian montmorillonite (MMt) modified by the intercalation of the Keggin Al13 complex, followed by calcination during the pillaring process. The properties of MMt, Al-intercalated MMt (P-MMt), and Al-pillared MMt (P-MMt-C) were determined using X-ray diffraction (XRD), thermogravimetric analysis (TGA), surface-area analysis, and a field emission scanning electron microscope (FE-SEM). The MO adsorption by modified MMt was subsequently evaluated. The XRD basal distance (d001) and the specific surface area (SSA) increased after the modification of MMt. The TGA results revealed that P-MMt and P-MMt-C had better thermal stability than MMt. The Al-pillared MMt obtained after calcination (e.g., P-MMt-C400) showed a larger basal distance and surface area than that without pillaring. The MO adsorption process of P-MMt-C400 was supposed to be dominated by chemisorption and heterogeneous multilayer adsorption, according to the kinetic and isotherm studies. The maximum adsorption capacity of P-MMt-C400 is 6.23 mg/g. The MO adsorption ability of Al-pillared MMt was contributed by the Keggin Al13 complex attracting MO and the increase in the surface area of macro-, meso- and micro-pores (>1.2 nm). The Al-pillared MMt in this study could be applied as an adsorbent in a water purification system to remove MO or other dye elements.

Background: Mitochondria are sensitive to environmental toxicants due to the limited repair capacity. Exposure to benzotriazoles (BTRs) and benzothiazoles (BTHs) may contribute to adverse health outcomes through oxidative stress, which may interfere with mitochondrial function. However, the mitochondrial effects of exposure to BTs (BTRs and BTHs) have not yet been elucidated, particularly in human investigations. Objectives: We examined the associations between trimester-specific urinary BTRs and BTHs concentrations and cord blood mitochondrial DNA copy number (mtDNAcn) in a prospective birth cohort. Methods: The present study included 742 mother-infant pairs who participated in a birth cohort between 2014 and 2015 in Wuhan and had data on urinary concentrations of BTRs and BTHs and mtDNAcn in cord blood. Concentrations of BTs were repeatedly measured in maternal urine samples at different trimesters using high performance liquid chromatography-tandem mass spectrometry. Relative mtDNAcn in umbilical cord blood was analyzed by quantitative real-time polymerase chain reaction. Generalized estimating equations were used to evaluate the associations between BTs exposure across gestation and mtDNAcn in cord blood. Results: In the present study, we observed a positive association between urinary 2-methylthio-benzothiazole (2-MeS-BTH) concentrations in the first trimester and cord blood mtDNAcn, with marginal significance [percent changes (%Δ) = 3.97, 95% confidence interval (CI): −0.05, 8.16, p = 0.05], while urinary 2-amino-benzothiazole concentrations in the third trimester were significantly negatively associated with cord blood mtDNAcn (%Δ = −5.89, 95% CI: −10.32, −1.24). Similar patterns of associations were demonstrated between urinary 1-H-benzotriazole (1-H-BTR) and xylyltriazole concentrations in the third trimester and cord blood mtDNAcn (%Δ = −4.18 to −3.23). In sex-specific analysis, we identified that maternal urinary 1-H-BTR in the first trimester and 2-MeS-BTH in the third trimester were positively associated with cord blood mtDNAcn among male infants but not female (P for interaction = 0.05 for 1-H-BTR, P for interaction = 0.05 for 2-MeS-BTH, respectively). Conclusions: We found evidence that prenatal exposure to BTRs and BTHs were associated with cord blood mtDNAcn alternation, and these associations were modified by infant gender. Further investigations are needed to corroborate these findings.

Dioxins, a group of persistent organic pollutants, have been proved to correlate with ranges of diseases by activating the aryl hydrocarbon receptor (AhR). However, previous dioxin toxicity studies primarily focused on the activation of AhR with signaling pathways at gene and protein levels. The investigation of underlying mechanisms at the metabolic level is still necessary. In this study, serum samples of 48 and 47 healthy participants with the highest and lowest dioxin levels based on quartile distribution of the serum dioxin concentrations of 215 male adults were selected for metabolomics analysis by using liquid chromatography coupled with orbitrap high-resolution mass spectrometry to investigate dioxin-related metabolic responses. The identified potential biomarkers included acylcarnitines, fatty acids and derivatives, glycerophospholipids, etc. suggested that metabolic pathways such as fatty acid β-oxidation, essential fatty acid metabolism, arachidonic acid metabolism, glycerophospholipid and sphingolipid metabolism and purine metabolism were disturbed by dioxin exposure. The results indicated that people with high dioxin exposure levels were at the potential health risks of inflammation, liver and cardiovascular diseases. The metabolic findings may help understand the link between dioxin exposure and the diseases.

The ever-increasing prevalence of microplastics and different bisphenols made the presence of bisphenol-attached microplastics a critical concern. In this study, experiments were performed to examine desorption behaviors and cytotoxicity performance of contaminated microplastics in aquatic surroundings and intestinal environment after ingestion by organisms (cold-/warm-blooded). The kinetic study shows that the rate of desorption for bisphenols can be enhanced threefold under simulated warm intestinal conditions. The Freundlich isotherms indicate multiple-layer desorption of the bisphenols on the heterogeneous surfaces of polyvinyl chloride (PVC) microplastics. Hysteresis was detected in the adsorption/desorption of bisphenols in a water environment, but no adsorption/desorption hysteresis was observed in the simulated intestinal conditions of warm-blooded organisms. Due to enhanced bioaccessibility, the desorption results imply that the environmental risk of contaminated PVC microplastics may be significantly increased after ingestion at a high bisphenols dosage. Although with different IC50, the five bisphenols released under the intestinal conditions of warm-blooded organisms can cause higher proliferation reduction in fish and human cell lines than the bisphenols released in water. This study helps elucidate the consequential fate and potential cytotoxicity of contaminated microplastics and the possible implications of the microplastics as a critical vector for bisphenols to increase the potential health risks.

Background: Benzotriazoles (BTRs) and benzothiazoles (BTHs) are emerging contaminants with potential insulin modulation activities. Pregnancy exposure to BTs (BTRs and BTHs) may be a risk factor for the development of gestational diabetes mellitus (GDM). However, epidemiological studies are limited. Objectives: We prospectively investigated the associations of exposure to BTs at early pregnancy with the blood glucose levels and the risks of GDM. Methods: A prospective cohort of 1770 pregnant women who were free of diabetes at baseline was established between 2013 and 2015 in Wuhan, China. Urine samples collected at 13.1 ± 1.1 weeks of gestation were analyzed to estimate the exposure level of BTs. The diagnosis of GDM was based on a 75 g oral glucose tolerance test (OGTT) conducted at 26.4 ± 2.4 weeks of gestation. We examined the associations between urinary concentration of BTs and blood glucose levels by linear regression models. The associations of urinary BTs concentrations with the relative risk (RR) of GDM were evaluated by generalized estimating equations with Poisson regression. Effect modifications by fetus sex and pre-pregnancy body mass index (BMI) were further evaluated in the sensitivity analysis. Results:A total of 147 (8.31%) pregnant women were diagnosed with GDM. Median concentrations of urinary BTs did not differ significantly between pregnant women with and without GDM. It was found that urinary levels of benzothiazole and 2-hydroxy-benzothiazole (2-OH-BTH) were positively associated with 2-hour blood glucose (p for trend

Background: The widespread use of bisphenol A (BPA) substitutes has aroused great attention towards their toxicological evaluation in vivo and in vitro. Considering the intimate correlation between BPA and metabolic diseases, we explored whether bisphenol S (BPS), a major substitute to BPA, could cause the splenic toxicity by disturbing the lipid metabolism in mouse model. Methods: We investigated the splenic injury by combing the mass spectrometry (MS)-based lipidomics and imaging analysis, as well as molecular biological methods. Mice were divided into three groups (control-olive oil, 10 and 100 μg-BPS/kg body weight/day group) and treated by BPS in 56 days. Results: Two of BPS-treated concentrations induced the splenic morphological alterations and inflammation, including the decreased numbers and cellularity in the periarteriolar lymphoid sheath (T cell zone) and paucicellular primary lymphoid follicles (B cell zone) in splenic white pulp. Lipidome profiling of spleen after BPS treatment was also changed with up-regulated sphingosine [So], neutral glycosphingolipids [CerG], cholesteryl ester [ChE], diacylglycerols [DAG], lysophosphatidylcholine [LPC], lysophosphatidylethanolamine [LPE], phosphatidylglycerols [PG], phosphatidylinositols [PI] and phosphatidylserine [PS] as well as down-regulated ceramide [Cer], phosphatidylethanolamines [PE] and sphingomyelin [SM] compared to the control group. More importantly, significant different lipids in abundance and spatial distribution also implicated that white pulp were more sensitive to BPS treatment than other splenic sub-structures. Signaling lipids such as So (d18:0), Cer (d18:1/24:0), Cer (d18:1/22:0), SM (d18:1/22:1) and SM (d18:1/24:2) associated with inflammation were remarkable changed and co-localized in the splenic white pulp. Conclusions: Our finding indicated that BPS exposure promoted the splenomegaly, pro-inflammatory activation and morphological alterations, as well as induced the lipidome perturbation in the immune cells of white pulp, which might be expected to contribute a new perspective of bisphenol-induced organ injury. Keywords: Bisphenol S, Splenic injury, Mass spectrometry imaging, Lipidomics, Splenic white pulp

Organophosphate flame retardants (OPFRs) are emerging contaminants in recent years. They can be present in the atmospheric fine particle (PM2.5), leading to potential adverse effects on humans. In this study, the concentrations and in vitro toxicities of OPFRs in PM2.5 samples were investigated for one year at Guangzhou and Taiyuan in China. Eleven OPFRs, including chloro-, aryl-, and alkyl-substituted OPFRs, were detected at total concentrations ranging from 3.10 to 544 ng m−3. Chloro-substituted OPFRs were the dominant contaminants. Based on the statistical analysis, the same contamination sources of all OPFRs were found except for tris(butoxyethyl) phosphate (TBOEP) and triethyl phosphate (TEP), which may come from traffic emission. The results of cell viability and dithiothreitol assays indicated that OPFRs and PM2.5 could induce the death of normal lung epithelial cells and the production of reactive oxygen species (ROS), respectively. According to the redundancy analysis, the distribution of OPFRs was significantly related to the PM2.5 concentrations and indirectly associated with ROS production induced by PM2.5 from Taiyuan. Exposure to PM2.5-bound OPFRs in Guangzhou and Taiyuan only posed minimum health risks to both toddlers and adults. These findings could provide important evidence to better clarify the contamination profiles and human health risks of OPFRs in atmospheric fine particles. Keywords: Organophosphate flame retardants, PM2.5, Contamination profile, In vitro assay, Health risk assessment

Background: Bisphenol A (BPA) may cause some adverse effects on human health by mimicking estrogen activities. In vitro and animal studies have observed the non-monotonic associations between BPA and natural estrogens, but the evidence in human study is lacking, particularly at multiple points in time during pregnancy. Objective: We aimed to examine the relationships between BPA and estrogens in the three trimesters among Chinese pregnant women and their gender variations. Methods: This study included 851 participants from a birth cohort conducted in Wuhan, China between 2014 and 2015. We measured concentrations of BPA and three estrogens (estrone (E1), 17β-estradiol (E2) and estriol (E3)) in urine samples collected in the three trimesters of pregnancy (mean for each visit: 13.0, 23.6, and 35.9 weeks’ gestation). We calculated the estimated daily intakes using urinary BPA concentrations and compared them with the tolerable intake value to assess potential health risks. We used multivariate linear regression models stratified by trimester and gender to explore trimester-specific and gender-specific associations of BPA with E1, E2, and E3. Results: We found the decreased levels of estrogens (β

The complexity of rotaxane dendrimers poses a great synthetic challenge and the synthesis of higher generation rotaxane dendrimers has therefore rarely been reported. Here the authors report the synthesis of acid-base switchable rotaxane dendrimers up to generation 4 and demonstrate the uptake and release of guest molecules.

Abstract Background Bioactive activities of adzuki bean have been widely reported, however, the phytochemical information of adzuki bean is incomplete. The aim of this study was to characterize and quantify flavonoids and saponins in adzuki bean. High performance liquid chromatography with diode array detection and electro spray ionization-tandem multi-stage mass spectrometry (HPLC–DAD–ESI–MSn) were applied to do qualitative and quantitative analyses. Results A total of 15 compounds from adzuki bean were identified by HPLC–DAD–ESI–MSn. Among 15 compounds identified, four flavonoids (catechin, vitexin-4″-O-glucoside, quercetin-3-O-glucoside, and quercetin-3-O-rutinoside) and six saponins (azukisaponin I, II, III, IV, V, and VI) in adzuki bean were further quantified by external calibration method using HPLC–MS with the program of time segment and extract ion chromatogram (EIC) analysis. Conclusions Current qualitative and quantitative method based on HPLC and MS technique provides a scientific basis for in vitro and in vivo pharmacological study in the future. Graphical abstract Isolation and characterization of flavonoids and saponins from adzuki bean.

Background: Phthalates are a family of endocrine disruptors with short elimination half-lives in the human body. To date, few epidemiological studies have examined repeated measures of maternal urinary phthalates and the combined effects of prenatal exposure to multiple phthalates on children's neurocognitive development. Objectives: We aimed to investigate the association between children's neurocognitive development at 2 years of age and prenatal phthalate exposure, as assessed by repeated measurements during pregnancy, and to further examine the effects of co-exposure to multiple phthalates using cumulative risk assessment. Method: Within a prenatal cohort in Wuhan, China, we measured five high-molecular-weight (HMW) phthalates and three low-molecular-weight (LMW) phthalate metabolites' concentrations in three urine samples collected in the 1st, 2nd, and 3rd trimester of pregnancy from each mother. We assessed neurocognitive development by Bayley Scales of Infant and Toddler Development (BSID) at 2 years of age (n = 476) to obtain the children's mental development index (MDI) and psychomotor development index (PDI). Results: Higher exposure levels to LMW phthalates compared to HMW phthalates were observed in our population. Ln-transformed averaged concentration of mono-n-butyl phthalate (MnBP), a metabolite of the LMW phthalate di-n-butyl phthalate (DnBP) during pregnancy, was associated with decreased PDI scores in all children (β = −1.90, 95% CI: −3.43, −0.37). Similarly, the averaged sum concentration of ∑dibutyl phthalate (∑DBP) was associated with decreased PDI scores in all children (β = −1.89, 95% CI: −3.63, −0.15). A negative trend of association between exposure to HMW phthalates and PDI scores was observed in girls, while a positive association was found in boys. In cumulative risk assessment analyses, we consistently observed that the hazard quotient of DnBP (the parent compound of MnBP) was inversely associated with PDI scores in all children, whereas the hazard quotient of di-2-ethylhexyl phthalate (DEHP), an HMW phthalate, was positively associated with PDI scores in boys only. Conclusions: This study is the first to use repeated measurement of maternal urinary phthalates in all three trimesters to assess prenatal exposure in relation to children's neurodevelopment. Our study suggested a negative association between prenatal exposure to MnBP and children's psychomotor development, and potentially sex-specific associations between HMW phthalates and neurocognitive development among boys and girls. These findings warrant further confirmation. Keywords: Phthalate metabolites, Child neurodevelopment, Prenatal exposure, Trimester-specific, Cumulative risk assessment

Background: The association of bisphenol A (BPA) and gestational diabetes mellitus (GDM) has been investigated in only a small number of studies, and research on the associations between BPA substitutes and GDM is scarce.Objective: We aimed to investigate the associations of four bisphenols [bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF)] levels in urine sample with the risk of gestational diabetes mellitus (GDM) and plasma glucose levels.Methods: A total of 1,841 pregnant women from a cohort study were recruited at their first prenatal examination between 2013 and 2015 in Wuhan, China. Concentrations of four bisphenols (BPA, BPS, BPF, BPAF) were measured in first-trimester urine samples using Ultra-high performance liquid chromatography system coupled to a Triple Quadrupole mass spectrometer (UHPLC-TQMS). An oral glucose tolerance test (OGTT) was performed at 24–28 gestational weeks and GDM was diagnosed post hoc using International Association of Diabetes and Pregnancy Study Groups criteria. We used multivariable logistic regression models to examine the associations of urinary bisphenols with the risk of GDM, and multiple linear regression models to determine the associations between bisphenols exposure and plasma glucose levels.Results: Urinary BPAF was associated with increased odds of GDM among women with normal pre-pregnancy BMI [adjusted odds ratio (aOR) = 1.70 (95% CI: 1.08, 2.67) for the highest group compared to the lowest group], and the association remained significant after additional adjustment for other bisphenols [aOR = 1.68 (95% CI: 1.03, 2.72)]. No significant associations were observed for other bisphenols and GDM. Consistent with the result of GDM, women in the highest BPAF category had a mean of 0.05 mmol/L (95% CI: 0.01, 0.09) higher fasting plasma glucose (FPG) levels than women in the lowest category. For BPA and plasma glucose, non-linear associations were observed between urinary BPA and FPG and the sum of the PG z-score among women who were overweight (p for non-linear association < 0.05). We also found that the per-unit increase in natural log transformed specific gravity adjusted BPS [ln (SG-adj BPS)] was associated with a 0.03 mmol/L (95% CI: 0.01, 0.04) increase in FPG levels and the associations might be modified by fetal sex (p for interaction < 0.05). Among women with female fetus, a per-unit increase in ln (SG-adj BPS) was associated with a 0.04 mmol/L (95% CI: 0.02, 0.06) increase in FPG, a 0.11 mmol/L (95% CI: 0.04, 0.17) increase in 1 h-PG and a 0.19 mmol/L (95% CI: 0.08, 0.30) increase in the sum of PG z-score.Conclusions: Our results provide evidence that BPAF and BPS might be potential risk factors of GDM, which require to be studied further.

Cancer cells under stress use acetate to maintain the acetyl-CoA pool and fuel lipid biosynthesis. Here, the authors show that acetate also promotes de novo lipid synthesis by increasing histone acetylation at the promoters of lipogenic enzymes ACACA and FASN, thus inducing their expression.

Tetrodotoxin (TTX) is a potent neurotoxin isolated mainly from toxic puffer fish. To date, the TTX biosynthetic mechanism inside its hosts remains unresolved. Here, we hypothesize the TTX synthesis relies on the host gut microbiota, including the neglected non-culturable bacteria. In these studies, we collected the gut contents from 5 puffer fish species of the genus Takifugu including one suspected hybrid species for gut microbiota study by 16S rRNA amplicon metagenomics approach. Their gut samples were divided into toxic and non-toxic groups based on the TTX concentrations in the livers detected by LC-MS/MS. Bacterial diversity studies showed that gut microbiota structures were significantly different between toxic and non-toxic species. Vibrio and Cyanobacteria centered at the gut bacterial co-occurrence network, suggesting their importance in TTX biosynthesis. The results of PICRUSt2 metagenomic prediction and gene set enrichment analysis provided new support of arginine-precursor required in TTX biosynthesis. This is the first study to profile the gut microbiota in toxic and non-toxic puffer fish species by 16S rRNA amplicon metagenomic approach, defining significant microbial co-occurrence patterns in their gut environment. Our data supported the proposed biosynthesis of TTX inside the hosts by their gut bacterial symbionts using arginine as a precursor.

Background and purpose: As an herbal medicine, adzuki bean has been practiced since the Tang Dynasty of China to maintain health and control weight; this practice is still very popular in China nowadays. However, it is still lack of sufficient scientific basis to explain scientific principle of this popular civil practice in weight control using adzuki bean. The purpose of this study was to verify and explain the anti-obesity effects of adzuki bean through in vitro enzymatic assays, in vitro lipolysis and in vivo study of obese mice model.Methods: Inhibitory effects of flavonoids and saponins from adzuki bean (Vigna angularis) on pancreatic lipase, α-glucosidase activities, and noradrenaline-induced lipolysis were assessed. High-fat diet-induced obesity model was created to study anti-obesity effects of adzuki bean. Both serum and liver lipid parameters were determined after 8 weeks intervention.Results: Adzuki bean extracts enhanced lipolysis. Compared to the final body weight of high-fat diet group, oral administration of adzuki bean significantly (p < 0.05) reduced the final body weight of mice and adipose tissue accumulation. The adzuki bean intervention also significantly reduced the levels of serum triglyceride, total cholesterol, low density lipoprotein-cholesterol, and liver lipid.Conclusion: Adzuki bean demonstrated the anti-obesity effects on mice, such effects may mediated through the inhibitory effects of flavonoids and saponins from adzuki bean on α-glucosidase and pancreatic lipase activities, and lipolysis enhancement effect of active components from adzuki bean.

Matrix-assisted laser desorption/ionization (MALDI), a soft ionization method, coupling with time-of-flight mass spectrometry (TOF MS) has become an indispensible tool for analyzing macromolecules, such as peptides, proteins, nucleic acids and polymers. However, the application of MALDI for the analysis of small molecules (