Publications by authors named "Junjie Ao"

27 Publications

  • Page 1 of 1

Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring Mutation in Early Clinical Experience.

J Cancer 2022 16;13(8):2656-2661. Epub 2022 May 16.

Department of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of locus. A total of eight patients (24.2%) exhibited at least one mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT was comparable to those patients with WT . These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by mutation.
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http://dx.doi.org/10.7150/jca.71494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174847PMC
May 2022

A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis.

Lab Invest 2022 May 28. Epub 2022 May 28.

Department of Gastroenterology, Chiba University, Graduate School of Medicine, Chiba, 260-8677, Japan.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-A mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-A mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD.
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http://dx.doi.org/10.1038/s41374-022-00807-6DOI Listing
May 2022

Association between triclosan exposure and obesity measures among 7-year-old children in northern China.

Ecotoxicol Environ Saf 2022 May 12;239:113610. Epub 2022 May 12.

MOE and Shanghai Key Laboratory of Children's Environmental Health, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address:

Background: Triclosan (TCS) is a widely used synthetic antibacterial compound with ubiquitous human exposure. Animal studies have suggested the obesogenic effect of TCS exposure, but knowledge regarding its impacts on childhood obesity was limited.

Objective: To investigate the associations of TCS exposure with childhood obesity in northern China.

Methods: This study included 423 children who participated in the 7-year-old follow-up visits of Laizhou Wan Birth Cohort in Shandong, northern China. Children's TCS exposure were determined in spot urine samples via high performance liquid chromatography-tandem mass. Their height, weight, waist circumference, body fat percentage, body mass index (BMI), and waist-to-height ratio (WHtR) were measured or calculated. BMI z-score ≥ 85th percentile was defined as overweight/obesity, and WHtR ≥ 0.5 was considered to be abdominal obesity. Multivariable linear regressions, generalized linear models (GLMs), and multivariable logistic regressions were performed to examine the associations between TCS exposure and obesity measures in children.

Results: Linear regressions showed that TCS concentrations, when treated as continuous variables, were positively associated with BMI z-score (β = 0.12, 95% CI: 0.01, 0.24) and body fat percentage (β = 0.82, 95% CI: 0.13, 1.52). When TCS concentrations were categorized as a four-level ordinal variable, the results of GLMs were similar those of continuous variables and both of the positive trends were significant (p-trend = 0.049 for BMI z-score; p-trend = 0.023 for body fat percentage). Moreover, the higher TCS levels versus reference group were associated with an approximate 2-3 fold increased risk of abdominal obesity (p-trend = 0.044).

Conclusion: Exposure to TCS was positively associated with obesity measures among 7-year-old children in northern, China. Given to the cross-sectional study design, a large prospective study is warranted to confirm our findings.
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http://dx.doi.org/10.1016/j.ecoenv.2022.113610DOI Listing
May 2022

Patterns of environmental exposure to phenols in couples who plan to become pregnant.

Sci Total Environ 2022 May 29;821:153520. Epub 2022 Jan 29.

Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; School of Public Health, Shanghai Jiao Tong University, Shanghai 200025, China. Electronic address:

Phenols are widely used in consumer products and known for their reproductive toxicities. Little is known regarding the environmental exposure to phenols in couples prior to conception, a key period affecting fertility. We measured the urinary concentrations of six parabens and seven bisphenols in 903 pre-conception couples in China. We investigated the occurrence, distribution, source and health risk of phenols in husbands and wives separately, and the correlation and difference in phenol concentrations between couples. Similar distribution profiles of urinary phenols were observed between females and males. Methyl 4-hydroxybenzoate (MeP) and bisphenol A (BPA) were the predominant compounds. The level of urinary phenols in our population was mostly lower than the global levels. Exposure to phenols was linked to processed food and personal care products. The correlations between phenols in males and females were moderate (0.218-0.686), while the correlation in phenols between husband and wife was low (0.009-0.215). Female had a significantly higher urinary phenol levels than male (P < 0.05). Urinary phenols in couples were associated with family income, type of drinking water and frequency of household cleaning. Household factors accounted for ≤1.5% of variance in phenol levels between couples, suggesting that individual variations may be the major factor. Risk assessment showed that exposure to phenols posed a low hazard to 17.5% of the couples in our population. Our findings provide important evidence of environmental exposure to phenols in couples of child-bearing age.
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http://dx.doi.org/10.1016/j.scitotenv.2022.153520DOI Listing
May 2022

Bisphenol S exposure induces intestinal inflammation: An integrated metabolomic and transcriptomic study.

Chemosphere 2022 Apr 31;292:133510. Epub 2021 Dec 31.

Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; School of Public Health, Shanghai Jiao Tong University, Shanghai, 200025, China.

As a typical substitute for bisphenol A (BPA), bisphenol S (BPS) is raising concerns due to the potential adverse effects on human health. Limit evidence is available to understand the toxicity of BPS to the digestive system, especially for intestine. In this study, we aimed to investigate the potential effects and underlying mechanisms of BPS exposure on human colon mucosal epithelial cells (NCM460). Our results showed that BPS exposure significantly increased the production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin-17A (IL-17A). The tight junctions of the cells has been destroyed by BPS exposure, which was characterized by a down-regulation of the tight junction proteins (Claudin1 and zonula occluden 1 (ZO1)). A multi-omics study explored the underlying mechanisms based on the metabolomic and transcriptomic responses. A variety of neurotransmitters increased significantly after exposure to BPS. The top enriched pathway was "glutamatergic synapse", which was activated by BPS exposure, resulting in the up-regulation of l-glutamine. Links were observed among the altered metabolites, genes and cytokines. Our results indicate that exposure to BPS may disturb the balance of gut-brain axis, leading to the production of inflammatory cytokines and the destruction of tight junction in NCM460 cells. It provides new clue for the development of intestinal inflammation in terms of the environmental pollutants.
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http://dx.doi.org/10.1016/j.chemosphere.2021.133510DOI Listing
April 2022

Transcriptomics integrated with metabolomics reveals the effect of Bisphenol F (BPF) exposure on intestinal inflammation.

Sci Total Environ 2022 Apr 11;816:151644. Epub 2021 Nov 11.

Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Institute of Early Life Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, USA. Electronic address:

As a viable alternative to Bisphenol A (BPA), Bisphenol F (BPF) has been detected in humans at comparable concentrations and detection frequencies. Emerging evidence reveals that BPF induces intestinal toxicity. However, less information is available concerning BPF and its potential effects on intestinal inflammation, which has been associated with numerous disorders. The results from the present study showed that BPF exposure triggered lipopolysaccharide (LPS)-induced explosion of pro-inflammatory cytokines interleukin-17A (IL-17A), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) and impairment of the intestinal epithelial barrier by downregulating the expression of tight junction proteins Zonula Occludens-1 (ZO-1) and Claudin-1 (CLDN1) in normal colonic epithelial cells (NCM460). A multi-omics analysis integrating the transcriptomics with metabolomics revealed an altered transcripts and metabolites profile following BPF exposure. Correlation analysis indicated that RAS Guanyl Releasing Protein 2 (RASGRP2) and Phospholipase A2 Group IVE (PLA2G4E) were positively associated with the increased serotonin which was positively associated with the stimulated IFN-γ in BPF-treated NCM460 cells. Pyrogallol, pyridoxine, and N-acetylputrescine were positively associated with IL-17A levels. Collectively, the integrative analyses demonstrated an orchestrated coordination between the inflammatory response, transcriptomic, and metabolomics changes. Data presented herein provide evidence for the possible roles of BPF in the pathogenesis of intestinal inflammation. These results illustrate the advantages of using integrative analyses of high throughput datasets for characterizing the effects and mechanisms of toxicants.
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http://dx.doi.org/10.1016/j.scitotenv.2021.151644DOI Listing
April 2022

Environmental exposure to bisphenol analogues and unexplained recurrent miscarriage: A case-control study.

Environ Res 2022 03 30;204(Pt C):112293. Epub 2021 Oct 30.

Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China; School of Public Health, Shanghai Jiao Tong University, Shanghai, 200025, China. Electronic address:

The use of bisphenol A (BPA) has been substantially limited since 2010 due to its toxicity to human health. A group of bisphenol analogues that are structurally similar to BPA have been developed as the alternatives and used widely. The reproductive toxicity of these emerging chemicals has caused substantial concerns in recent years. Whether bisphenol analogues affect miscarriage, especially unexplained recurrent miscarriage (URM), remains to be explored. We conducted a hospital-based, case-control study with 1180 URM cases and 571 controls in China from 2014 to 2016. Concentrations of six bisphenol analogues (BPA, BPAF, BPAP, BPB, BPP and BPS) were measured in the urine samples collected at median intervals of 7.6 months after last miscarriage (interquartile ranges: 4.8, 14.7 months). Multiple logistic regression, Bayesian kernel machine regression (BKMR) and quantile g-computation (q-gcomp) were used to assess the relationship of bisphenol analogues with URM risk. We observed significantly higher levels of all urinary bisphenols in the cases than the controls. After controlling for potential confounders, bisphenol analogues were significantly associated with increased odds of URM in varying degrees. A dose-response pattern was observed for the associations of BPAF, BPAP and BPB quartiles with URM. The mixed exposure of six bisphenol analogues was positively associated with the risk of URM (adjusted odds ratio (aOR) = 1.25; 1.11-1.42), which was mainly driven by BPAP (60.1%), BPAF (25.1%) and BPA (14.8%). After age stratification, the risks tended to be higher in women aged 30 years or older, compared to women <30 years. Our large case-control study indicates that environmental exposure to bisphenol analogues is associated with an increased risk of URM. Older women may be more vulnerable to the insult.
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http://dx.doi.org/10.1016/j.envres.2021.112293DOI Listing
March 2022

EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma.

Sci Rep 2021 11 1;11(1):21396. Epub 2021 Nov 1.

Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2H3K27me3 cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.
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http://dx.doi.org/10.1038/s41598-021-00889-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560765PMC
November 2021

Serum Angiopoietin 2 acts as a diagnostic and prognostic biomarker in hepatocellular carcinoma.

J Cancer 2021 5;12(9):2694-2701. Epub 2021 Mar 5.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Hepatocellular carcinoma (HCC) is typically accompanied by abundant arterial blood flow. Although angiogenic growth factors such as Angiopoietin 2 (Ang2) play a central role in tumor angiogenesis in HCC, the role of serum Ang2 as a biomarker in HCC remains unclear. In this study, we aimed to investigate the potential of Ang2 as a diagnostic and prognostic biomarker in HCC using a sandwich enzyme-linked immunosorbent assay (ELISA). The median Ang2 levels in controls (n=20), chronic liver disease patients (n=98), and HCC patients (n=275) were 1.58, 2.33, and 3.53 ng/mL, respectively. The optimal cut-off value of Ang2 was determined as 3.5 ng/mL by receiver operating curve analysis. The sensitivity, specificity, and accuracy of Ang2 for HCC detection were 50.9, 83.7, and 59.5%, respectively. Spearman's rank correlation coefficient analysis demonstrated only a weak correlation between Ang2 serum levels and alpha-fetoprotein (AFP) or des-gamma-carboxy prothrombin (DCP) serum levels. The diagnostic value of Ang2 was comparable to those of other existing markers. In addition, 24 out of 73 patients with normal AFP and DCP levels (32.9%) demonstrated abnormally high Ang2 levels (≥3.5 ng/mL). Although no significant difference in overall survival was found between Ang2 and Ang2 patients with curative ablation therapy, recurrence-free survival (RFS) in Ang2 patients was observed to be significantly shorter than those in Ang2 patients. Multivariate analysis demonstrated that high serum Ang2 levels (≥3.5 ng/mL) and the presence of multiple tumors were poor prognostic factors. In conclusion, our findings indicate that serum Ang2 is a potential novel biomarker for both diagnosis and prognosis in HCC.
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http://dx.doi.org/10.7150/jca.56436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040723PMC
March 2021

A simple, rapid and sensitive method for the simultaneous determination of eighteen environmental phenols in human urine.

Chemosphere 2021 Sep 5;278:130494. Epub 2021 Apr 5.

Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. Electronic address:

Environmental phenols are a typical group of endocrine disrupting compounds (EDCs) and have caused growing concerns upon the potential adverse effects on humans. Urinary concentrations of phenols can be used as valid biomarkers for the assessment of human exposure. A method was developed for the simultaneous determination of eighteen environmental phenols (six parabens, seven bisphenols, four benzophenones and triclosan) in human urine using liquid-liquid extraction (LLE) coupled to high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The optimized LLE was time saving and required low volumes of organic solvents. A volume of only 0.2 mL urine sample was extracted and analyzed. The method yielded good linearity (0.9925-0.9994) and satisfactory limit of detection (LOD) (≤0.08 ng mL). The relative recoveries ranged between 76.7% and 116% at three spiked levels, with intra- and inter-day precision less than 8.04% and 13.5%, respectively. Our method has been proved to be simple, rapid and sensitive by a comprehensive comparison between methods. This proposed method provides a large-scale biomonitoring tool for exposure assessment of human population to environmental phenols.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130494DOI Listing
September 2021

Acquisition of mesenchymal-like phenotypes and overproduction of angiogenic factors in lenvatinib-resistant hepatocellular carcinoma cells.

Biochem Biophys Res Commun 2021 04 3;549:171-178. Epub 2021 Mar 3.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Lenvatinib is one of the first-line drugs for patients with advanced hepatocellular carcinoma (HCC) and widely used around the world. However, the mechanisms underlying resistance to lenvatinib remain unclear. In this study, we conducted characteristic analyses of lenvatinib-resistant HCC cells. Lenvatinib-resistant HCC cell lines were established by exposure to serially escalated doses of lenvatinib over 2 months. The biological characteristics of these cells were examined by in vitro assays. To investigate the cytokine profile of lenvatinib-resistant HCC cells, the supernatant derived from lenvatinib-resistant Huh7 cells was subjected to nitrocellulose membrane-based sandwich immunoassay. Both activation of the MAPK/MEK/ERK signaling pathway and upregulation of epithelial mesenchymal transition markers were observed in lenvatinib-resistant cells. Concordant with these findings, proliferation and invasion abilities were enhanced in these cells compared with control cells. Screening of a cytokine array spotted with 105 different antibodies to human cytokines enabled us to identify 16 upregulated cytokines in lenvatinib-resistant cells. Among them, 3 angiogenic cytokines: vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and angiogenin, were increased significantly. Conditioned medium from lenvatinib-resistant cells accelerated tube formation of human umbilical vein cells. In conclusion, lenvatinib-resistant HCC cells were characterized by enhanced proliferation and invasion abilities. These findings might contribute to the establishment of new combination therapies with lenvatinib.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.097DOI Listing
April 2021

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.

Sci Rep 2021 03 5;11(1):5303. Epub 2021 Mar 5.

Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19 (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 (n = 105) patients, there were no significant differences between FGF19 (n = 21) and FGF19 (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.
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http://dx.doi.org/10.1038/s41598-021-84117-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935880PMC
March 2021

Prenatal Exposure to Specific PM Chemical Constituents and Preterm Birth in China: A Nationwide Cohort Study.

Environ Sci Technol 2020 11 4;54(22):14494-14501. Epub 2020 Nov 4.

Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.

Exposure to fine particulate matter (PM) during pregnancy has been associated with preterm birth (PTB). However, the existing evidence is inconsistent, and the roles of specific PM chemical constituents remain unclear. Based on the China Labor and Delivery Survey, we included birth data from 89 hospitals in 25 provinces in mainland China, and conducted a national multicenter cohort study to examine the associations of PM and its chemical constituents with PTB risk in China. We applied satellite-based models to predict prenatal PM mass and six main component exposure. Multilevel logistic regression analysis was used to examine the associations, controlling for sociodemographic characteristics, seasonality, and spatial variation. We observe an increased PTB risk with an increase in PM mass and the most significant association is found during the third trimester when the adjusted odds ratio (OR) per interquartile range increases in PM total mass is 1.12 (95% confidence Interval, CI: 1.05-1.20). Infants conceived by assisted reproductive technology (ART) show greater PTB risk associated with PM exposure (OR = 1.33, 95% CI: 1.05-1.69) than those conceived naturally (OR = 1.11, 95% CI: 1.03-1.19). We also find black carbon, sulfate, ammonium and nitrate, often linked to fossil combustion, have comparable or larger estimates of the effect (OR = 1.07-1.14) than PM. Our findings provide evidence that components mainly from fossil fuel combustion may have a perceptible influence on increased PTB risk associated with PM exposure in China. Additionally, compared to natural conception, conception through ART may be more susceptible to PM exposure.
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http://dx.doi.org/10.1021/acs.est.0c02373DOI Listing
November 2020

Interferon-γ induced PD-L1 expression and soluble PD-L1 production in gastric cancer.

Oncol Lett 2020 Sep 19;20(3):2161-2168. Epub 2020 Jun 19.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan.

Programmed death-ligand 1 (PD-L1) plays an essential role in tumor cell escape from anti-tumor immunity in various types of cancer, including gastric cancer (GC). The present study investigated the intracellular and membrane-bound expression of PD-L1 in the GC cell lines MKN1, MKN74, KATO III and OCUM-1. Furthermore, soluble PD-L1 (sPD-L1) level in the supernatant of GC cells and the serum of patients with GC and healthy controls was determined by ELISA. Interferon (IFN)-γ treatment of cells resulted in increased cytoplasmic expression of PD-L1 in GC cells in a dose-dependent manner, except for MKN74 cells; however, there was no association between tumor necrosis factor-α treatment and enhanced PD-L1 expression. Concordant with these findings, results from flow cytometry analysis demonstrated that membrane-bound PD-L1 expression was also increased following GC cell treatment with IFN-γ in a dose-dependent manner. In addition, significant sPD-L1 overproduction was observed only in the culture supernatant of OCUM-1 cells. Serum level of sPD-L1 was significantly increased in patients with GC, in particular in stage IV patients, compared with healthy controls. In conclusion, the present study demonstrated that IFN-γ treatment increased the intracellular and membrane-bound PD-L1 expression in GC cells. In addition, sPD-L1 was detected not only in the supernatant of GC cells but also in the serum of patients with GC. Further investigation on the underlying mechanism of regulation of PD-L1 expression and sPD-L1 production is required.
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http://dx.doi.org/10.3892/ol.2020.11757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400993PMC
September 2020

Fine particular matter and its constituents in air pollution and gestational diabetes mellitus.

Environ Int 2020 09 25;142:105880. Epub 2020 Jun 25.

Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200092, China; School of Public Health, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China. Electronic address:

Background: Ambient air pollution has been linked to the development of gestational diabetes mellitus (GDM). However, previous studies provided inconsistent findings and no study has examined the effects of complex chemical constituents of the particular matter on GDM, especially in developing countries. Therefore, we aim to investigate the associations of exposure to PM (particular matter ≤ 2.5 μm) and its constituents with GDM, and to identify susceptible exposure window in a large survey in China.

Methods: The China Labor and Delivery Survey was a cross-sectional investigation conducted in 24 provinces in China between 2015 and 2016. A random sample of all deliveries in each participating hospital was selected and detailed obstetric and newborn information was extracted from medical records. Average concentrations of PM and six constituents (organic matter, black carbon, sulfate, nitrate, ammonium and soil dust) were estimated (1 km × 1 km) using a combined geoscience-statistical model. GDM was diagnosed based on an oral glucose tolerance test (OGTT) between 24 to 28 weeks of gestation and according to IADPSG criteria. Generalized linear mixed models were used to adjust for potential confounders.

Results: A total of 54,517 subjects from 55 hospitals were included. The incidence of GDM was 10.8%. An interquartile range (IQR) increase in PM exposure in the 2nd trimester of pregnancy was associated with an increased GDM risk in the single pollutant model, [adjusted odds ratio (aOR) = 1.11 and 95% confidence interval (CI): 1.01-1.22]. Exposure to organic matter (aOR = 1.14; 95%CI: 1.05-1.23), black carbon (aOR = 1.15; 95%CI: 1.07-1.25) and nitrate (aOR = 1.13; 95%CI: 1.02-1.24) during 2nd trimester were associated with increased risks of GDM. Associations between constituents and GDM were robust after controlling for total PM mass and accounting for multi-collinearity.

Conclusions: Exposure to PM in 2 trimester of pregnancy was associated with an increased risk of GDM. Organic matter, black carbon and nitrate may be the main culprits for the association.
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http://dx.doi.org/10.1016/j.envint.2020.105880DOI Listing
September 2020

Perfluoroalkyl substances in early pregnancy and risk of hypertensive disorders of pregnancy: A prospective cohort study.

Environ Int 2020 05 27;138:105656. Epub 2020 Mar 27.

MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. 1665 Kong Jiang Road, Shanghai 200092, China; School of Public Health, Shanghai Jiao Tong University School of Medicine, 227 South Chongqing Road, Shanghai 200052, China. Electronic address:

Background: Perfluoroalkyl substances (PFASs) were reported to be associated with hypertensive disorders of pregnancy (HDP) but the results were inconsistent and prospective data are scarce. We aimed to examine these associations in a large prospective birth cohort study in Shanghai, China.

Methods: A total of 10 PFASs were measured by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples from 3220 women who were enrolled during early pregnancy and gave birth to a singleton live birth between 2013 and 2016. The outcomes included gestational hypertension (GH), preeclampsia (PE) and overall HDP. Associations of these outcomes with each PFASs were estimated by multivariable logistic regression and expressed as odd ratios (ORs) and 95% confidence intervals (95% CIs). Potential non-linear association between PFASs and HDP was examined with restricted cubic spline model. To handle the potential confounding by correlated PFASs, we applied elastic net regression (ENR) to identify independent PFASs components of outcomes.

Results: Among all singleton live births, the incidence rates of GH and PE were 2.0% and 2.2%, respectively. Overall, PFASs did not show a significant and consistent pattern of the associations with GH, PE or overall HDP, both before and after controlling for potential confounders. ENR model confirmed the results that there was no independently predictive role of PFASs on GH, PE or overall HDP.

Conclusions: In this large prospective cohort study, maternal plasma concentration of PFASs in early pregnancy were not associated with GH, PE or overall HDP in singleton livebirths.
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http://dx.doi.org/10.1016/j.envint.2020.105656DOI Listing
May 2020

Associations between organophosphate esters and sex hormones among 6-19-year old children and adolescents in NHANES 2013-2014.

Environ Int 2020 03 10;136:105461. Epub 2020 Jan 10.

School of Public Health, Shanghai Jiao Tong University, Shanghai 200025, China; Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200092, China. Electronic address:

Background: Organophosphate esters (OPEs) are a class of alternative replacements for polybrominated diphenyl ethers. In vitro and in vivo studies suggested that OPEs may disrupt the homeostasis of sex steroid hormones. However, human evidence in children and adolescents is limited.

Objectives: We conducted a cross-sectional analysis of the associations between OPE biomarkers and sex steroid hormones among children (6-11 years) and adolescents (12-19 years) in the U.S. National Health and Nutrition Examination Survey, 2013-2014.

Methods: Participants aged 6-19 years who had available data on urinary OPE metabolites, serum sex hormones [total testosterone (TT), estradiol (E)] and sex hormone binding globulin (SHBG) were included (n = 544). Free androgen index (FAI) calculated as TT divided by SHBG and a ratio of TT to E (TT/E) were generated. Five urinary OPE metabolites were examined. A constructed puberty status was defined as either high steroid hormone levels (TT ≥ 50 ng/dL in males and E ≥ 20 pg/ml in females) or onset of menarche. Multiple linear regression and weighted quantile sum (WQS) regression analyses stratified by sex-age and sex-puberty-status groups were conducted to examine the associations of OPE metabolites and its mixture with sex hormone levels.

Results: After adjusting for covariates, dibutyl phosphate (DBUP) and dibutyl phosphate (DPHP) were significantly inversely associated with TT (or FAI) and E; DBUP was negatively associated with SHBG; and DPHP was positively associated with SHBG and TT/E in female adolescents. In male adolescents, we observed monotonic negative associations of bis(1,3-dichloro-2-propyl) phosphate (BDCPP), DBUP or DPHP with TT (or FAI) and E, and positive associations of BDCPP and DPHP with SHBG. Among adolescents, the OPEs index was negatively associated with TT [WQS beta = -0.29 (95% confidence interval: -0.51, -0.07) in males and -0.15 (-0.28, -0.01) in females ], FAI [-0.46 (-0.71, -0.2) in males and -0.23 (-0.41, -0.05) in females] and E [-0.25 (-0.41, -0.1) in males and -0.33 (-0.59, -0.08) in females], with stronger associations with TT and FAI in males and a slightly stronger association with E in females. In addition, the OPEs index presented a comparable positive association with SHBG in both sexes of adolescents. In contrast, significant associations of individual OPE metabolites or OPEs index with sex hormones were sparse in children. Results by sex-puberty status in single pollutant and WQS regression analyses presented a similar pattern, where most of the significant associations were limited to the pubertal individuals. Of note, stronger inverse associations of the OPEs index with TT and FAI remained in pubertal boys. But the association between the OPEs index and E was non-significant in pubertal girls, and only in pubertal boys did the OPEs index show a significant and stronger inverse association with E.

Conclusions: Exposure to OPEs, either individually or as a mixture, was associated with decreased levels of certain sex steroid hormones (TT, FAI, and E) and increased levels of SHBG in adolescents or pubertal individuals, with the associations presenting somewhat sex-dependent pattern. However, there is little evidence of the significant associations in children or prepubescent ones. Given the cross-sectional nature of the analysis, our findings need further confirmation.
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http://dx.doi.org/10.1016/j.envint.2020.105461DOI Listing
March 2020

Serum fibroblast growth factor 19 serves as a potential novel biomarker for hepatocellular carcinoma.

BMC Cancer 2019 Nov 12;19(1):1088. Epub 2019 Nov 12.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background: Abnormal autocrine fibroblast growth factor 19 (FGF19) production has been observed in several types of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the potential of serum FGF19 as a novel tumor marker of HCC based on a sandwich enzyme-linked immunosorbent assay (ELISA).

Methods: The serum FGF19 levels of 304 patients with HCC was measured by ELISA. The serum levels of existing markers, including alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) were determined by chemiluminescence enzyme immunoassay. Both diagnostic value of FGF19 and its changes after curative ablation therapy was further examined.

Results: The median FGF19 levels in controls, chronic liver disease patients, and primary HCC patients, were 78.8 pg/mL, 100.1 pg/mL, and 214.5 pg/mL, respectively. The subsequent receiver operating characteristic curves (ROC) successfully determined an optimal cut-off value of 200.0 pg/mL. The area under the ROC curve (AUC) of FGF19 for HCC detection was comparable to those of AFP and DCP. Of importance, FGF19 showed higher sensitivity for the detection of small HCC (solitary cancer with diameter < 20 mm) than those of existing markers. In addition, 43 out of 79 cases (54.4%) with normal AFP and DCP (so-called "double negative HCC") exhibited serum FGF19 level ≥ 200 pg/mL. In 45 HCC patients treated with curative ablation therapy, serum FGF19 levels changed from 257.4 pg/mL to 112.0 pg/mL after the treatment.

Conclusion: Our findings reveal that FGF19 can be a potential novel biomarker for HCC. Although FGF19 is not necessarily a substitute for existing markers, it may help improve the prognosis in HCC patients owing to its resourceful use in various aspects of HCC management and treatment.
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http://dx.doi.org/10.1186/s12885-019-6322-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849282PMC
November 2019

Characteristic and human exposure risk assessment of per- and polyfluoroalkyl substances: A study based on indoor dust and drinking water in China.

Environ Pollut 2019 Nov 18;254(Pt A):112873. Epub 2019 Jul 18.

Department of Developmental and Behavioral Pediatrics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.

Per- and polyfluoroalkyl Substances (PFAS) are ubiquitous in the environmental matrix, and their eco-toxicity on wide life and health risks on humans arising concerns. Due to the information gap, current risk assessments of PFAS ignore the indoor exposure pathway such as indoor dust and the different sources of drinking water. We collected and analyzed 168 indoor dust and 27 drinking water samples (including tap water, filtered water and bottled water). The mean concentrations of six typical PFAS measured in indoor dust and drinking water are in the range of 15.13-491.07 ng g and 0.31-4.14 ng L, respectively. For drinking water, PFOA and PFOS were the dominant compounds, while PFHxS was the most abundant in indoor dust. Short-chain PFAS concentrations were higher than long-chain PFAS in both drinking water and indoor dust. Higher concentration of PFAS was observed in tap water and filtered water than bottled water. The total daily intake (TDI) of six PFAS are 20.67-52.97 ng kg d for infants, children, teenagers, and adults. As to children, teenagers, and adults, perfluorooctanoate (PFOA) is the major compound, accounting for 72.9-74.7% of the total daily intake. And PFOA (38.7%) and perfluorooctane sulfonate (PFOS, 42.2%) are the dominant PFAS for infants. The quantitative proportions of exposure sources are firstly revealed in this study, which in the order of foodstuff > indoor dust > drinking water > indoor air. Although the contribution to the PFAS intake of drinking water and indoor dust was not predominant (<9%), the health risks caused by long-term exposure need our attention. The hazard quotient (HQ) values of total PFAS were in the range of 0.154-0.498, which suggesting the relatively lower exposure risk in Chinese population. This study provides important reference to understand PFAS exposure status other than foodstuff.
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http://dx.doi.org/10.1016/j.envpol.2019.07.041DOI Listing
November 2019

Organic UV filters in indoor dust and human urine: A study of characteristics, sources, associations and human exposure.

Sci Total Environ 2018 Nov 7;640-641:1157-1164. Epub 2018 Jun 7.

MOE and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.

Organic ultraviolet (UV) filters are emerging contaminants that may pose health risks to humans. We measured the concentrations of four commonly used organic UV filters (2-hydroxy-4-methoxybenzophenone (BP-3), 4-methylbenzylidene camphor (4-MBC), homosalate (HMS), and octocrylene (OC)) in 203 indoor dust samples and 98 human urine samples from households in eastern China. The total concentrations of the four organic UV filters ranged from 66.6-56,123.0 ng g in indoor dust and 1.17-52.15 μg g (creatinine-adjusted concentration (Cr)) in urine. BP-3 was the most abundant organic UV filter in the urine samples (median concentration: 1.89 μg g Cr), while OC was the most abundant in the indoor dust samples (median concentration: 325.7 ng g). No significant correlations were found between organic UV filter concentrations in paired urine and dust samples, but the concentrations of UV filters in the indoor dust samples were positively correlated with family income and sunscreen use. The sources of the organic UV filters in the indoor dust samples differed based on the geographical location of the tested household. The fraction of human exposure to organic UV filters that resulted from ingestion or dermal absorption of indoor dust was close to 8%.
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http://dx.doi.org/10.1016/j.scitotenv.2018.05.367DOI Listing
November 2018

Organic UV filters exposure induces the production of inflammatory cytokines in human macrophages.

Sci Total Environ 2018 Sep 24;635:926-935. Epub 2018 Apr 24.

School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.

Organic ultraviolet (UV) filters, found in many personal care products, are considered emerging contaminants due to growing concerns about potential long-term deleterious effects. We investigated the immunomodulatory effects of four commonly used organic UV filters (2-hydroxy-4-methoxybenzophenone, BP-3; 4-methylbenzylidene camphor, 4-MBC; 2-ethylhexyl 4-methoxycinnamate, EHMC; and butyl-methoxydibenzoylmethane, BDM) on human macrophages. Our results indicated that exposure to these four UV filters significantly increased the production of various inflammatory cytokines in macrophages, particular tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). After exposure to the UV filters, a significant 1.1-1.5 fold increase were found in TNF-α and IL-6 mRNA expression. In addition, both the p38 MAPK and the NF-κB signaling pathways were enhanced 2 to 10 times in terms of phosphorylation after exposure to the UV filters, suggesting that these pathways are involved in the release of TNF-α and IL-6. Molecular docking analysis predicted that all four UV filter molecules would efficiently bind transforming growth factor beta-activated kinase 1 (TAK1), which is responsible for the activation of the p38 MAPK and NF-κB pathways. Our results therefore demonstrate that exposure to the four organic UV filters investigated may alter human immune system function. It provides new clue for the development of asthma or allergic diseases in terms of the environmental pollutants.
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http://dx.doi.org/10.1016/j.scitotenv.2018.04.217DOI Listing
September 2018

Applying molecular modelling and experimental studies to develop molecularly imprinted polymer for domoic acid enrichment from both seawater and shellfish.

Chemosphere 2018 May 3;199:98-106. Epub 2018 Feb 3.

School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.

A highly selective sample cleanup method using molecularly imprinted polymers (MIP) was developed for the enrichment of domoic acid (DA, an amnesic shellfish toxin) from both seawater and shellfish samples. Molecular modelling was firstly applied to screening a suitable functional monomer and optimize the polymer preparation. Theoretical results were in a good agreement with those of the experimental studies. MIP was prepared by precipitation polymerization using 1, 3, 5-pentanetricarboxylic acid and 2-(Trifluoromethyl)acrylic acid as the template molecule and functional monomer, respectively. The morphology and molecular structure of MIP were revealed by scanning electron microscope (SEM) and fourier transform infrared spectroscopy (FTIR), respectively. The obtained MIP showed high affinity and selectivity for DA with binding site numbers of 0.875 mg g and an average association constant of 0.219 L mg evaluated by adsorption experiments. The developed molecularly imprinted solid-phase extraction (MISPE) column achieved satisfied adsorption rate (99.2%) and recovery (71.2%) with relative standard deviation (RSD) less than 1.0%, which is more stable and precise than the C, SAX, and HLB columns. Finally, the determination method for DA in both seawater and shellfish samples was then successfully established and validated using MISPE coupled with high-performance liquid chromatography-ultraviolet detection (HPLC-UV). The method limit of detection was 20 μg L and 50 μg kg for seawater and shellfish, respectively. This study demonstrates that molecular modelling is a useful tool to screening functional monomer and optimize polymer preparation. It provides an innovative polymer for trace DA monitoring in both seawater and shellfish.
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http://dx.doi.org/10.1016/j.chemosphere.2018.02.005DOI Listing
May 2018

Identification, characteristics and human exposure assessments of triclosan, bisphenol-A, and four commonly used organic UV filters in indoor dust collected from Shanghai, China.

Chemosphere 2017 Oct 9;184:575-583. Epub 2017 Jun 9.

School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.

Indoor dust is a very significant medium to understand human exposure of emerging contaminants. A novel and robust analytical method to measure the amounts of six personal care products (PCPs) (triclosan, bisphenol-A and four commonly used organic ultraviolet (UV) filters) simultaneously in indoor dust is developed in this paper. Target analytes were extracted using accelerated solvent extraction. After sample cleanup by solid-phase extraction (SPE), the extracts were derivatized and analyzed using gas chromatography-tandem mass spectrometry. The method detection limits achieves 0.16-0.62 pg g (except for 4-methylbenzylidene camphor with 3800 pg g). The method was successfully applied to the analysis of 110 indoor dust samples from Shanghai, China. Results showed that the PCPs were found in most of the samples analyzed. The concentrations of the most analytes are relatively lower than those reported in USA, Japan, and European countries. The median concentration of octocrylene (OC) (1170.4 ng g) was found to be nearly 5-10 times higher than those of other analytes. The significantly higher concentration of ∑PCPs was observed in indoor dusts from residences than from offices (P < 0.05). The human exposure was analyzed by calculate the estimated daily intakes (EDI) of PCPs through dust ingestion for various age groups. The EDI of the target analytes for infants ranged from 0.85 to 6.18 ng kg -bw day and 0.07-0.49 ng kg -bw day for adults, respectively. This is the first study to report the doses of human exposure to UV filters in China.
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http://dx.doi.org/10.1016/j.chemosphere.2017.06.033DOI Listing
October 2017

Organic UV filters inhibit multixenobiotic resistance (MXR) activity in Tetrahymena thermophila: investigations by the Rhodamine 123 accumulation assay and molecular docking.

Ecotoxicology 2016 Sep 17;25(7):1318-26. Epub 2016 Jun 17.

School of Life Science, Hubei University, Wuhan, 430062, China.

Multixenobiotic resistance (MXR) transporters, which belong to ATP-binding cassette (ABC) family proteins, are present in living organisms as a first line of defense system against xenobiotics and environmental contaminants. The effects of six organic UV filters (4-methyl -benzylidene camphor, 4-MBC; benzophenone-3, BP-3; butyl methoxydibenzoyl-methane, BM-DBM; ethylhexyl methoxy cinnamate, EHMC; octocrylene, OC and homosalate, HMS) on multixenobiotic resistance (MXR) in Tetrahymena thermophila were investigated in this study. It was found that 4-MBC, BP-3 and BM-DBM could significantly inhibit activity of the MXR system, causing concentration dependent accumulation of rhodamine 123; while EHMC, OC and HMS had weak MXR inhibition. The IC50 (50 % inhibition concentration) values of 4-MBC, BP-3 and BM-DBM were 23.54, 40.59 and 26.37 μM, respectively, with inhibitory potentials of 23.1, 13.4 and 20.6 % relative to verapamil (VER, a model inhibitor of P-glycoprotein). Our results firstly provide the evidence for UV filters inhibition effect on MXR in aquatic organisms. In addition, it was revealed by molecular docking analysis that the selected six UV filters can occupy the same binding site on T. thermophila P-gp as VER does; and form H-bonds with residues Ser 328 and/or Asn 281. This study raises the awareness of aquatic ecological risk from the organic UV filters exposure, as they would be involved in potentiating toxic effects by chemosensitizing.
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http://dx.doi.org/10.1007/s10646-016-1684-0DOI Listing
September 2016

Effects of triclosan and triclocarban on the growth inhibition, cell viability, genotoxicity and multixenobiotic resistance responses of Tetrahymena thermophila.

Chemosphere 2015 Nov 3;139:434-40. Epub 2015 Aug 3.

School of Life Science, Hubei University, Wuhan 430062, China.

The information about adverse effects of emerging contaminants on aquatic protozoa is very scarce. The growth inhibition effect, cell viability, genotoxicity and multixenobiotic resistance (MXR) responses of two commonly used antimicrobial agents, triclosan (TCS) and triclocarban (TCC) to protozoan Tetrahymena thermophila were investigated in this study. The results revealed that TCS and TCC can inhibit the growth of T. thermophila with 24h EC50 values of 1063 and 295μgL(-1), respectively. The impairment of plasma membrane was observed after 2h exposure of TCS or TCC at the level of mg/L. Furthermore, it is noticeable that at environmentally relevant concentration (1.0μgL(-1)), both TCS and TCC can lead to statistically significant DNA damage in T. thermophila, while the inhibition of growth and change of cell viability cannot be observed. Our results firstly provide the evidence for genotoxic effects of TCS and TCC on the freshwater protozoan. Additionally, both TCS and TCC were found to inhibit the efflux transporter activities, with the inhibitory potencies of 39% and 40% (using verapamil as a model inhibitor), respectively. Particularly, TCC could significantly down-regulate the expression of MXR related gene Abcb15, which encodes the membrane efflux protein that acting as P-gp in T. thermophila. The results raise the awareness of potential aquatic ecological and human health risks from the exposure of TCS and TCC, as they might potentiate the toxic effects by chemosensitizing with co-existing toxicants.
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http://dx.doi.org/10.1016/j.chemosphere.2015.07.059DOI Listing
November 2015

Interaction mechanisms between organic UV filters and bovine serum albumin as determined by comprehensive spectroscopy exploration and molecular docking.

Chemosphere 2015 Jan 14;119:590-600. Epub 2014 Aug 14.

School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan, Hubei 430065, China.

Organic UV filters are a group of emerging PPCP (pharmaceuticals and personal care products) contaminants. Current information is insufficient to understand the in vivo processes and health risks of organic UV filters in humans. The interaction mechanism of UV filters with serum albumin provides critical information for the health risk assessment of these active ingredients in sunscreen products. This study investigates the interaction mechanisms of five commonly used UV filters (2-hydroxy-4-methoxybenzophenone, BP-3; 2-ethylhexyl 4-methoxycinnamate, EHMC; 4-methylbenzylidene camphor, 4-MBC; methoxydibenzoylmethane, BDM; homosalate, HMS) with bovine serum albumin (BSA) by spectroscopic measurements of fluorescence, circular dichroism (CD), competitive binding experiments and molecular docking. Our results indicated that the fluorescence of BSA was quenched by these UV filters through a static quenching mechanism. The values of the binding constant (Ka) ranged from (0.78±0.02)×10(3) to (1.29±0.01)×10(5) L mol(-1). Further exploration by synchronous fluorescence and CD showed that the conformation of BSA was demonstrably changed in the presence of these organic UV filters. It was confirmed that the UV filters can disrupt the α-helical stability of BSA. Moreover, the results of molecular docking revealed that the UV filter molecule is located in site II (sub-domain IIIA) of BSA, which was further confirmed by the results of competitive binding experiments. In addition, binding occurred mainly through hydrogen bonding and hydrophobic interaction. This study raises critical concerns regarding the transportation, distribution and toxicity effects of organic UV filters in human body.
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http://dx.doi.org/10.1016/j.chemosphere.2014.07.019DOI Listing
January 2015

Effects of four commonly used UV filters on the growth, cell viability and oxidative stress responses of the Tetrahymena thermophila.

Chemosphere 2013 Nov 13;93(10):2507-13. Epub 2013 Oct 13.

School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China; School of Resource and Environment, Ningxia University, Yinchuan 750021, China.

UV filters are increasingly used in sunscreens and other personal care products. Although their residues have been widely identified in aquatic environment, little is known about the influences of UV filters to protozoan. The growth inhibition effects, cell viability and oxidative stress responses of four commonly used UV filters, 2-ethylhexyl 4-methoxycinnamate (EHMC), benzophenone-3 (BP-3), 4-methyl-benzylidene camphor (4-MBC) and octocrylene (OC), to protozoan Tetrahymena thermophila were investigated in this study. The 24-h EC50 values with 95% confidence intervals for BP-3 and 4-MBC were 7.544 (6.561-8.675) mg L(-1) and 5.125 (4.874-5.388) mg L(-1), respectively. EHMC and OC did not inhibit the growth of T. thermophila after 24h exposure at the tested concentrations. The results of cell viability assays with propidium iodide (PI) staining were consistent with that of the growth inhibition tests. As for BP-3 and 4-MBC, the relatively higher concentrations, i.e. of 10.0 and 15.0 mg L(-1), could lead to the cell membranes impairment after 4h exposure. With the increase of the exposure time to 6h, their adverse effects on cell viability of T. thermophila were observed at the relatively lower concentration groups (1.0 mg L(-1) and 5.0 mg L(-1)). In addition, it is noticeable that at environmentally relevant concentration (1.0 μg L(-1)), BP-3 and 4-MBC could lead to the significant increase of catalase (CAT) activities of the T. thermophila cells. Especially for the BP-3, the oxidative injuries were further confirmed by the reduction of glutathione (GSH) content. It is imperative to further investigate the additive action of UV filters and seek other sensitive endpoint, especially at environmentally relevant concentration.
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http://dx.doi.org/10.1016/j.chemosphere.2013.09.041DOI Listing
November 2013
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