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检索条件"任意字段=2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会"

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Kidney-on-a-chip for evaluating Cadmium-induced nephrotoxicity

Kidney-on-a-chip for evaluating Cadmium-induced nephrotoxici...

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者： Zhongyu Li Yaqiong Guo Jianhua Qin Division of Biotechnology Dalian Institute of Chemical PhysicsChinese Academy of Sciences University of Chinese Academy of Sciences

Cadmium(Cd) is a common environmental pollutant,which has caused great attention in public *** kidney is the organ that is the most affected by Cd *** this work,we present a kidney-on-a-chip with three compartmentalized culture chambers to examine Cd-induced *** culture and collection channels represent the capillary and the glomerular capsule sides of the glomerular filtration barrier,*** primary rat glomerular endothelial cells(GECs) were cultured on the side surface of the middle gel *** integrated GEC layer demonstrated the selective permeability of the renal barrier against small molecules and large *** device was utilized to study Cd-induced nephrotoxicity in *** result shown that Cd induced significant cytotoxicity and disrupted the expression of tight junction protein ZO-1 in a dose-dependent ***,Cd exposure increased the permeability of the endothelial layer to large molecules,immunoglobulin G and albumin,which was agreement with Cd-induced responses in *** results facilitate the evaluation of nephrotoxicity testing in a physiologically relevant *** proposed approach enables the direct visualization and quantitative analysis of the biological processes of the glomerular endothelial barrier in ways that have not been achieved in traditional cell culture or animal *** proposed kidney-on-a-chip model may provide a useful and cost-effective platform for the study of renal pharmacology,nephrotoxicity and glomerular disease under various pathological conditions and environmental exposures.

关键词： Microfluidics Glomerulus-filtration-barrier Cadmium Nephrotoxicity Organ-on-a-chip

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TT21C non-animal toxicity testing strategy:ten years of inspiration to application

TT21C non-animal toxicity testing strategy:ten years of insp...

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者： Paul Carmichael Unilever Safety and Environmental Assurance Center

What is a Next Generation Risk Assessment（NGRA）? Since the publication in 2007 of the inspirational book 'Toxicity Testing in the 21 Century（TT21 C）:a Vision and a Strategy'many scientists from multiple disciplines,have been working to realise the challenge of how new technological advances in molecular biology and computational modelling can be brought together to make safety decisions without the need for animal *** extensive collaboration and evaluation of case study chemicals,we have arrived at a tiered approach that can constantly *** silico-first approaches with informatics data-mining are initially used to identify pathways of concern and to formulate hypotheses for ***,lead molecular initiating events（MIEs） and on/off-target pathways are evaluated with respect to relevant exposures through in vitro experimental data generation（transcriptomics,screening panels,high content imaging） teamed with computational ***,a final tier employing organotypic human cell models or more complex toxicokinetic/toxicodynamic computational models may be utilised to provide additional confidence for decision *** years ago the National Research Council was asked by the *** Protection Agency to review the state of the science and create a far-reaching vision for the future of toxicity ***,through the application of these novel approaches,an NGRA becomes an exposure-led risk assessment solution to biological pathway-indicated hazard concerns.

关键词： TT21C non-animal toxicity testing strategy:ten years of inspiration to application

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Non testing method TTC and DST approach during safety assessment on natural extracts in cosmetics

Non testing method TTC and DST approach during safety assess...

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者： John YANG Francoise GAUTIER Jacques CLOUZEAU L'Oreal preclinical safety

Today,there isa growing consumer demand for personal care products containing natural ingredients especially on the Asian ***,the safety assessment of plant-derived ingredients is sometimes complicated with very limited toxicological data on complex *** systemic toxicity and skin sensitization are critical safety endpoints should be assessed,which are always difficult with limited toxicological data and too much rely on animal *** ensure natural ingredients are safe to consumers by avoiding unnecessary animal studies,the Threshold of Toxicological Concern(TTC) and Dermal Sensitization Threshold(DST) can be applied during safety assessment on natural extract *** botanical ingredient can be phytochemical characterized into several chemical fractions,and TTC approach is applied on each this separated chemical categories to ensure non systemic toxicity in exposure *** can be applied for chemical category by excluding chemicals with non-sensitizing potential,and to be performed in sensitization risk assessment according to exposure *** exposure is above DST threshold,the use of in vitro alternative methods could address sensitizing potential of natural ingredients and therefore to avoid unnecessary animal *** we present safety assessment strategy on natural extract in L'Oreal and how TTC and DST approaches are applied in the safety assessment with examples.

关键词： DST Non testing method TTC and DST approach during safety assessment on natural extracts in cosmetics TTC

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Novel Aerosol exposure devices for in vitro toxicity testing of airborne pollutants at the air/liquid interface

Novel Aerosol exposure devices for in vitro toxicity testing...

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者： Tobias Krebs VITROCELL Systems GmbH

In state-of-the-art health risk assessment,it is becoming increasingly important to accurately characterize the biological activities of active airborne substances,gases and complex mixtures in the human respiratory *** can be achieved by using in vitro exposure technologies for mammalian cellular systems from the respiratory *** exposure of mammalian cells or tissues to airborne substances is frequently performed under submerged *** doing so,the test substances are dosed into the culture *** procedure results in an undesired interaction of the formerly airborne substances with the medium,causing limitations for authentic ***,assessment of the applied dose proves to be difficult using this *** response to the scientific need to expose in physiologically relevant conditions,cutting-edge exposure systems have been specifically designed and engineered to enable direct exposure of mammalian cells or tissue at the air/liquid *** this purpose the cell systems are cultivated on microporous membranes and later exposed while not being covered with culture *** approach allows for more credible and authentic results than achieved by submerged exposure due to a closer replication of the human physiology.A typical in vitro exposure system for in vitro testing of airborne pollutants consists of 4 major component groups:aerosol source,dilution system,exposure modules and dosimetry *** a reliable product assessment it is essential that all components match the requirements of exposure the air/liquid interface.

关键词： air/liquid interface in vitro exposure systems airborne pollutants in vitro toxicity testing

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Studies on Genetic Toxicity of Different Component in Particulate Matter in Shanghai during Winter and Summer

Studies on Genetic Toxicity of Different Component in Partic...

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者： Zhang Ying Yang Jing Chen Xiaoqian Yang Hexing Yin Haowen Shanghai Academy of Public Measurement

As a leading environmental indicator of air pollution in Shanghai,Particulate Matter 2.5(PM) show highest in winter,lowest in summer in the terms of change *** SOS chromotest was used to analyze the genetic toxicity on the total-pellet extract,the organic extract and the water soluble fraction of PMin vitro at Huinan and Pudong station,Shanghai during winter and summer in light of its relatively higher standards,simple operations and low false positive *** study results of the SOS chromotest showed good agreement with the existing achievements in the study of specific component in atmospheric particulate matter and it'ssuitable for periodic,rapid and effective evaluation to the genetic toxicity of particulates in the *** of the genetic toxicity on the total-pellet extract at two stations during winter and summer were all positive and the genetic toxicity increased when the concentrations increased,showing good dose-response *** of the genetic toxicity on the water soluble fraction were positive at the highest concentration of 2000 mg·L and negative on the the organic *** the same particle concentration,the genotoxicity effect on the total-pellet extract and the water soluble fraction of PM in winter is higher than that in summer at same *** genotoxicity effect at Pudong station is higher than that at Huinan station at same *** toxic substances of PM are probably different between Pudong station and Huinan station during winter and summer.

关键词： SOS chromotest PM2.5 genotoxicity

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CXCR3-mediated toxicity pathway contributes to inflammatory microenvironment shapping in esophageal carcinogenesis and targeted by tocopherols

CXCR3-mediated toxicity pathway contributes to inflammatory ...

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者： Hui Yang Qiannan Zhang Yongquan Feng Xudong Jia Key Laboratory of Food Safety Risk Assessment of Ministry of Health National Center for Food Safety Risk Assessment

Esophageal cancer is one of the major causes of cancer mortality in the *** predominant histological subtype esophageal squamous cell carcinoma(ESCC) often results in poor prognosis due to the lack of approaches for the early diagnosis and treatment,which highlights the need for preventive interventions against this *** we showed that the interaction of chemokine CXCL9/10/11 with their receptor CXCR3 was specifically elevated in ESCC carcinogenesis murine models induced by N-nitrosomethylbenzylamine(NMBA).The production of pro-inflammatory cytokines as well as the induction and infiltration of CXCR3+effector T cells(CD4+ Th1 and CD8+ CTLs) were markedly increased in the inflammatory *** supplementation with 0.15%α-Tocopherol(P-T),δ-Tocopherol(δ-T),or γ-Tocopherol enriched mixture(γ-TmT) markedly suppressed CXCR3-mediated inflammation especially at early stage of *** vivo and in vitro experiments indicated that these outcomes were tightly correlated with the blockade of NF-κB *** data demonstrate that CXCR3-mediated toxicity pathway contributes to inflammatory microenvironment shapping in esophageal carcinogenesis and can be targeted by tocopherols at early premaligant lesions,offering a novel target and approach for chemoprevention of esophageal cancer.

关键词： vitamin E tocopherols esophageal cancer CXCR3 inflammation

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Preliminary Study on the Toxic Effects of Atmospheric Fine Particulate Matter on Caenorhabditis elegans in Beijing

Preliminary Study on the Toxic Effects of Atmospheric Fine P...

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者： Ling Kong Junyu Ning Nan Zhang Haiming Jing Shan Gao Yong Zhang Jin Tao Xinyu Wang Li Wei He Lijuan Qi Guojun Li Beijing Center for Disease Prevention and Control/Beijing Research Center for Preventive Medicine Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning

In recent years,the haze or smog episodes characterized by fine particulate matter has occurred in many regions of ***-term or long-term exposure to atmospheric fine particulate matter(also known as PM) could cause adverse effects on *** this study,Caenorhabditis elegans were used as experimental models in ***-soluble components of outdoor PM samples collected in Beijing in winter were combined for the study of acute and chronic toxic *** this basis,longevity-related genes specific mutants and real-time PCR technology were utilized to explore the mechanism of toxic *** groups were set up according to different exposure doses including blank control group（ddH O）,PM aqueous solution group A（air mass index AQI≤100） and group B（100

关键词： PM2.5 Caenorhabditis elegans Escherichia coli OP50 heat tolerance lifespan development pharyngeal pump motion

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多环芳烃诱导支气管上皮细胞恶性转化以及关键生物学事件的分析

多环芳烃诱导支气管上皮细胞恶性转化以及关键生物学事件的分析

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者：王婷马俊香郑玉新段化伟中国疾病预防控制中心职业卫生与中毒控制所中国疾病预防控制中心化学污染与健康安全重点实验室

目的:建立混合多环芳烃诱导的支气管上皮细胞(16HBE)恶性转化模型,并观察细胞恶性转化过程中的关键生物学事件的改变,为理解多环芳烃致癌过程中的早期生物学事件的关系,进一步指导混合多环芳烃暴露人群的生物标志物监测提供依据。方法:... 详细信息

目的:建立混合多环芳烃诱导的支气管上皮细胞(16HBE)恶性转化模型,并观察细胞恶性转化过程中的关键生物学事件的改变,为理解多环芳烃致癌过程中的早期生物学事件的关系,进一步指导混合多环芳烃暴露人群的生物标志物监测提供依据。方法:采集焦炉厂炉顶处的焦炉逸散颗粒物,提取有机物后进行细胞染毒处理,采用5、10、20、40μg/ml的有机提取物诱导16HBE发生恶性转化。结合流式细胞仪检测细胞周期改变,运用彗星试验和胞质分裂阻滞实验试验来观察支气管细胞株的DNA损伤、微核、核桥、核质芽等指标的改变,运用磷酸测序法观察MGMT启动子区甲基化改变;同时观察DNA加合物的变化。期间通过刀豆蛋白A凝集试验、软琼脂试验以及裸鼠试验观察和验证细胞的成瘤特征。结果:研究发现焦炉逸散物颗粒相有机提取物主要为多环芳烃。细胞接受这类混合多环芳烃染毒处理后,随着染毒剂量的增加,16HBE的细胞生存率呈明显下降趋势,40μg/ml剂量组细胞活性下降为56.2%。诱导75d后,细胞形态明显异常,细胞周期发生紊乱,G1期缩短,S期和G2期延长;处理100d后,20μg/ml和40μg/ml剂量组细胞在低浓度(6.25μg/ml)的刀豆蛋白A中短时间(<30min)内发生凝集现象。在处理120d时,软琼脂培养基中出现明显集落,该时期的细胞其裸鼠致瘤率为41.67%。诱导120天的细胞中BPDE-DNA加合物的浓度最高。遗传损伤标志物检测中发现,在诱导50d、100d、120d的细胞组中,核分裂指数分别为对照组的1、1.5和2倍,核芽率为对照组的7倍、核质桥率分别为对照组的8、3.5和2倍,微核率分别为对照组的20、22.5和25倍,Olive TM分别为对照组的3、3.5和4倍,差异具有统计学意义(P<0.05)。DNA甲基化标志物观察发现,恶性转化后细胞的MGMT启动子区呈现明显的低甲基化改变,同时也表现为MGMT的mRNA和蛋白表达水平的改变。结论:我们成功建立混合多环芳烃的支气管恶性转化模型,不同时期中标志物的分析,有助于理解多环芳烃致肺癌中关键生物学事件的作用。BPDE-DNA加合物是多环芳烃致癌的关键起始事件,细胞周期改变、DNA和染色体损伤以及MGMT基因甲基化的改变,可以作为多环芳烃暴露的早期效应标志物。但是,该类细胞中的标志物改变也需要暴露人群的验证。

关键词：多环芳烃细胞恶性转化加合物 MGMT甲基化

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线粒体钙离子通道在MnCl2诱导胚胎期斑马鱼的神经毒性中的作用

线粒体钙离子通道在MnCl2诱导胚胎期斑马鱼的神经毒性中的作用

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者：彭涛屠鸿薇柳家贤廖耿泽孟晓静南方医科大学公共卫生学院职业卫生与职业医学系

目的:锰（manganese,Mn）是机体必需的微量金属元素,对于维持正常的细胞功能和新陈代谢起着关键的作用,过度锰暴露可导致急慢性锰中毒,并诱发不可逆的精神和锥体外系运动功能障碍,出现类似于帕金森氏病的临床表现。锰中毒主要累及中枢... 详细信息

目的:锰（manganese,Mn）是机体必需的微量金属元素,对于维持正常的细胞功能和新陈代谢起着关键的作用,过度锰暴露可导致急慢性锰中毒,并诱发不可逆的精神和锥体外系运动功能障碍,出现类似于帕金森氏病的临床表现。锰中毒主要累及中枢神经系统,造成基底神经节的局灶性损伤,其特征是该区域内耗氧量的剧烈增加和多巴胺的耗竭,并最终导致线粒体功能障碍,而线粒体钙离子通道在锰的神经毒性中的作用及机制尚不明确。本研究旨在探索锰对胚胎期斑马鱼神经毒性以及对线粒体钙离子通道在其中的作用。方法:将斑马鱼胚胎暴露于MnCl,检测其生存率、畸形表现以及孵化状况;采用ICP-MS法测定锰在胚胎/幼鱼体内的蓄积;通过行为学检测,观察锰暴露6d后对其幼鱼自发运动的改变;通过吖啶橙染色,观察锰暴露对其诱导的凋亡状况,并运用激光共聚焦显微镜观察锰对标记神经元的Tg（nbt:dsRed）转基因斑马鱼的神经系统凋亡的影响;通过荧光定量PCR（q-PCR）分析锰暴露对线粒体钙转运相关分子vdac1、mcu、pink1、nclx、letm1、micu1、micu2、mcur1和emre等基因的mRNA表达的影响。结果:在胚胎1hpf内开始进行锰暴露,50μM锰处理组于96hpf时开始出现大量死亡,并随暴露时间和浓度的增加,死亡率显著增加（P<0.05）;在96hpf,50μM锰处理组开始出现大量畸形,随时间和浓度增加,畸形率出现明显升高（P<0.01）;锰处理至120hpf后发现,幼鱼主要表现为心包水肿、卵黄囊水肿、脊柱弯曲三种畸形。斑马鱼胚胎/幼鱼体内锰吸收量与暴露剂量之间有着剂量-反应关系（P<0.01）,同时随着时间的增加,其吸收量也逐渐上升（P<0.01）。锰暴露至6dpf后,进行幼鱼自主运动能力实验发现,在25μM和50μM的MnCl暴露时,幼鱼的运动次数、运动时间、运动距离均低于对照组（P<0.01）。根据吖啶橙染色显示100uM锰暴露在72hpf引起明显的全鱼凋亡生成,在脑和脊柱部位出现凋亡位点,对斑马鱼幼鱼线粒体钙转运蛋白的相关基因转录水平检测发现,mcu基因表达降低至0.6（P<0.05）,nclx略升高,其他轻微下调;进一步对mcu四个剪接体检测发现均下调（P<0.05）。结论:在低剂量不影响形态改变浓度下锰暴露即可造成斑马鱼幼鱼的神经行为损伤和神经元凋亡,而此损伤可能与线粒体钙单向转运体改变有关。

关键词：锰神经毒性斑马鱼线粒体钙离子通道

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线粒体动力相关蛋白1调节铂类药物肝细胞癌化疗敏感性的机制研究

线粒体动力相关蛋白1调节铂类药物肝细胞癌化疗敏感性的机制研究

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2017（第三届）毒性测试替代方法与转化毒理学（国际）学术研讨会

作者：车琳周腾建张仕利何承勇林育纯林忠宁分子疫苗学和分子诊断学国家重点实验室厦门大学公共卫生学院

目的:线粒体动力相关蛋白1(Drp1)通过调控线粒体分裂对维持线粒体质量控制(MQC)、稳态和功能等起重要作用,与致癌作用的发生发展和肿瘤的诊断治疗密切相关。本研究旨在探讨Drp1介导线粒体分裂对细胞周期的调控在铂类药物诱导肝细胞癌(H... 详细信息

目的:线粒体动力相关蛋白1(Drp1)通过调控线粒体分裂对维持线粒体质量控制(MQC)、稳态和功能等起重要作用,与致癌作用的发生发展和肿瘤的诊断治疗密切相关。本研究旨在探讨Drp1介导线粒体分裂对细胞周期的调控在铂类药物诱导肝细胞癌(HCC)转归中的作用,为肝致癌作用靶向干预的转化毒理学研究提供实验依据。方法:采用GEO组学数据分析HCC病例中Drp1编码基因(DNM1L)与细胞周期蛋白依赖性激酶2(CDK2)基因转录的相关性。肝癌HepG2细胞分别给予顺铂(CDDP)、卡铂(CBP)和奥沙利铂(L-OHP)处理建立模型,以及采用Drp1抑制剂Mdivi-1(20μM)药物干预、DNM1L小干扰RNA(siDNM1L)转染构建Drp1活性抑制和敲低表达细胞模型;qRT-PCR和免疫印迹法检测Drp1、CDK2等mRNA和蛋白水平,激光共聚焦观察线粒体形态及蛋白亚细胞定位,流式细胞术检测细胞周期和凋亡,噻唑蓝(MTT)法检测细胞增殖活性。结果:(1)GEO数据库中基因转录组芯片检测HCC病例肿瘤组织中、且检测发现HCC细胞株中CDK2和DNM1L mRNA水平显著增高,二者呈正相关(P<0.05)。(2)铂类药物处理组HepG2细胞Drp1表达呈浓度依赖性增高(P<0.05)。(3)Mdivi-1干预使铂类药物处理组HepG2细胞Drp1、CDK2和Cyclin E1均降低(P<0.05);细胞周期G1期比例增高(P<0.05)。(4)siDNM1三使铂类药物处理HepG2细胞Drp1表达降低,验证了对CDK2、Cyclin E1表达降低和G1期比例增高(P<0.05)的影响。(5)铂类药物处理组HepG2细胞p53与Drp1线粒体转位和定位增多;Mdivi-1干预的铂类药物处理组HepG2细胞p53与Drp1线粒体共定位降低,线粒体分裂抑制。结论:HCC中存在DNM1L和CDK2基因高表达的潜在关联性;Drp1靶向干预可通过CDK2介导细胞周期G1/S期阻滞调节参与铂类药物诱导HCC抗肿瘤作用敏感性,与经由线粒体p53的转录非依赖性调控机制有关。

关键词：线粒体动力相关蛋白1 细胞周期蛋白依赖性激酶2 肝细胞癌铂类药物抗肿瘤作用敏感性

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