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Developmental toxicity assessment of neonicotinoids and organophosphate esters with a human embryonic stem cell-and metabolism-based fast-screening model

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Journal of Environmental Sciences 2024年第3期137卷 370-381页

作者： Shuxian Zhang Miaomiao Zhao Shichang Li Renjun Yang Nuoya Yin Francesco Faiola State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China College of Resources and Environment University of Chinese Academy of SciencesBeijing 100049China

In recent years,neonicotinoids(NEOs)and organophosphate esters(OPEs)have been widely used as substitutes for traditional pesticides and brominated fame-retardants,respectively.Previous studies have shown that those compounds can be frequently detected in environmental and human samples,are able to penetrate the placental barrier,and are toxic to animals.Thus,it is reasonable to speculate that NEOs and OPEs may have potential adverse effects in humans,especially during development.We employed a human embryonic stem cell differentiation-and liver S9 fraction metabolism-based fast screening model to assess the potential embryonic toxicity of those two types of chemicals.We show that four NEO and five OPE prototypes targeted mostly ectoderm specification,as neural ectoderm and neural crest genes were down-regulated,and surface ectoderm and placode markers up-regulated.Human liver S9 fraction's treatment could generally reduce the effects of the chemicals,except in a few specific instances,indicating the liver may detoxify NEOs and OPEs.Our findings suggest that NEOs and OPEs interfere with human early embryonic development.

关键词： Neonicotinoids Organophosphate esters Human embryonic stem cells Fast screening model Developmental toxicity

The short-chain perfluorinated compounds PFBS,PFHxS, PFBA and PFHxA, disrupt human mesenchymal stem cell self-renewal and adipogenic differentiation

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Journal of Environmental Sciences 2020年第2期32卷 187-199页

作者： Shuyu Liu Renjun Yang Nuoya Yin Francesco Faiola State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China College of Resources and Environment University of Chinese Academy of SciencesBeijing 100049China Wellcome Trust/CRUK Gurdon Institute Department of PathologyUniversity of CambridgeCambridge CB21QNUK

Per-and polyfluorinated alkyl substances(PFASs) are commonly used in industrial processes and daily life products.Because they are persistent, they accumulate in the environment, wildlife and humans.Although many studies have focused on two of the most representative PFASs, PFOS and PFOA, the potential toxicity of short-chain PFASs has not yet been given sufficient attention.We used a battery of assays to evaluate the toxicity of several four-carbon and six-carbon perfluorinated sulfonates and carboxyl acids(PFBS,PFHxS, PFBA and PFHxA), with a human mesenchymal stem cell(hMSC) system.Our results demonstrate significant cyto-and potential developmental toxicity for all the compounds analyzed, with shared but also distinct mechanisms of toxicity.Moreover, the effects of PFBS and PFHxS were stronger than those of PFBA and PFHxA, but occurred at higher doses compared to PFOS or PFOA.

关键词： Short-chain perfluorinated compounds Human mesenchymal stem cells(hMSCs) Adipogenesis/osteogenesis Developmental toxicity PFBS/PFBA/PFHxS/PFHxA

干细胞毒理学在大气污染健康风险评估中的应用

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中国科学：化学 2018年第10期48卷 1269-1279页

作者：程战文殷诺雅 Francesco Faiola 中国科学院生态环境研究中心环境化学与生态毒理学国家重点实验室北京100085 中国科学院大学资源与环境学院北京100049

随着雾霾天气的频繁出现,大气污染问题已引起全社会的高度关注.流行病学研究证实,大气污染物对人体特别是婴幼儿健康可产生巨大影响.其中,持久性有毒污染物的健康危害不容忽视,但因其在大气中含量较低,常规的毒理学模型较难准确反映其... 详细信息

随着雾霾天气的频繁出现,大气污染问题已引起全社会的高度关注.流行病学研究证实,大气污染物对人体特别是婴幼儿健康可产生巨大影响.其中,持久性有毒污染物的健康危害不容忽视,但因其在大气中含量较低,常规的毒理学模型较难准确反映其毒性效应.本文从健康风险的角度出发,综述了目前干细胞毒理学在评价大气中持久性有毒污染物毒性效应时的应用,重点关注早期胚胎发育、心血管系统发育及神经系统发育过程中可能存在的健康风险及相关致毒机制.干细胞毒理学模型未来可发展为较全面的健康风险评估系统,用以深入且多角度阐释大气污染物的健康风险效应,尤其是在婴幼儿成长发育、多种器官系统机能评估等过程中起到关键作用.

关键词：干细胞毒理学大气污染胚胎干细胞发育毒性

A human embryonic stem cell-based in vitro model revealed that ultrafine carbon particles may cause skin inflammation and psoriasis

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Journal of Environmental Sciences 2020年第1期32卷 194-204页

作者： Zhanwen Cheng Xiaoxing Liang Shaojun Liang Nuoya Yin Francesco Faiola State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Enuironmental SciencesChinese Academy of SciencesBeijing 100085China College of Resources and Environment University of Chinese Academy of SciencesBeijing 100049China

Air pollution has been linked to many health issues,including skin conditions,especially in children.Among all the atmospheric pollutants,ultrafine particles have been deemed very dangerous since they can readily penetrate the lungs and skin,and be absorbed into the bloodstream.Here,we employed a human embryonic stem cell(h ESC)-based differentiation system towards keratinocytes,to test the effects of ultrafine carbon particles,which mimic ambient ultrafine particles,at environment related concentrations.We found that10 ng/mL to 10μg/mL ultrafine carbon particles down-regulated the expression of the pluripotency marker SOX2 in h ESCs.Moreover,1μg/mL to 10μg/mL carbon particle treatments disrupted the keratinocyte differentiation,and up-regulated inflammationand psoriasis-related genes,such as IL-1β,IL-6,CXCL1,CXCL2,CXCL3,CCL20,CXCL8,and S100 A7 and S100 A9,respectively.Overall,our results provide a new insight into the potential developmental toxicity of atmospheric ultrafine particles.

关键词： Human embryonic stem cells(hESCs) Keratinocytes Ultrafine carbon particles Inflammation Psoriasis Developmental toxicity

Stem cell toxicology:a powerful tool to assess pollution effects on human health

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National Science Review 2016年第4期3卷 430-450页

作者： Xinglei Yao Nuoya Yin Francesco Faiola Stake Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental SciencesChinese Academy of Sciences College of Resources and Environment University of Chinese Academy of Sciences

Environmental pollution is a global problem;the lack of comprehensive toxicological assessments may lead to increased health risks.To fully understand the health efects of pollution,it is paramount to implement fast,eicient and speciic toxicity screening that relies on human models rather than on time-consuming,expensive and oten inaccurate tests involving live animals.Human stem cell toxicology represents a valid alternative to traditional toxicity assays because it takes advantage of the ability of stem cells to diferentiate into multiple cell types and tissues of the human body.hus,this branch of toxicology provides a possibility to assess cellular,embryonic,developmental,reproductive and functional toxicity in vitro within a single system highly relevant to human physiology.In this review,we describe the development,performance and future perspectives of stem cell toxicology,with an emphasis on how it can meet the increasing challenges posed by environmental pollution in the modern world.

关键词： stem cell toxicology embryonic stem cells mesenchymal stem cells environmental pollution environmental toxicology health efects

Perfluorinated iodine alkanes promote the differentiation of mouse embryonic stem cells by regulating estrogen receptor signaling

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Journal of Environmental Sciences 2024年第3期137卷 443-454页

作者： Zhihua Ren Xiaoxi Yang Tingting Ku Qian S.Liu Jiefeng Liang Qunfang Zhou Francesco Faiola Guibin Jiang State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijing 100085China College of Resources and Environment University of Chinese Academy of SciencesBeijing 100049China College of Environment and Resource Research Center of Environment and HealthShanxi UniversityTaiyuan 030006China College of Sino-Danish University of Chinese Academy of SciencesBeijing 100049China

Investigating the development toxicity of perfuorinated iodine alkanes(PFIs)is critical,given their estrogenic effects through binding with estrogen receptors(ERs).In the present study,two PFIs,including dodecafuoro-1,6-diiodohexane(PFHx DI)and tridecafuorohexyl iodide(PFHx I),with binding preference to ERαand ERβ,respectively,were selected to evaluate their effects on proliferation and differentiation of the mouse embryonic stem cells(m ESCs).The results revealed that,similar to E_(2),50μmol/L PFHx DI accelerated the cell proliferation of the m ESCs.The PFI stimulation at the exposure concentrations of 2–50μmol/L promoted the differentiation of the m ESCs as characterized by the upregulation of differentiation-related biomarkers(i.e.,Otx2 and Dnmt3β)and downregulation of pluripotency genes(i.e.,Oct4,Nanog,Sox2,Prdm14 and Rex1).Comparatively,PFHx DI exhibited higher induction effect on the differentiation of the m ESCs than did PFHx I.The tests on ER signaling indicated that both PFI compounds induced exposure concentration-dependent expressions of ER signaling-related biomarkers(i.e.,ERα,ERβand Caveolin-1)in the m ESCs,and the downstream ER responsive genes(i.e.,c-fos,c-myc and c-jun)well responded to PFHx I stimulation.The role of ER in PFI-induced effects on the m ESCs was further validated by the antagonistic experiments using an ER inhibitor(ICI).The findings demonstrated that PFIs triggered ER signaling,and perturbed the differentiation program of the m ESCs,causing the potential health risk during early stage of development.

关键词： Perfuorinated iodine alkanes(PFIs) Embryonic stem cells(ESCs) Developmental toxicity Cell differentiation Estrogen receptor-related signaling

皮肤中原代黑色素细胞和角质形成细胞同时分离法及其在超细颗粒物毒性效应评价中的应用

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生态毒理学报 2020年第6期15卷 158-166页

作者：程战文殷诺雅郑卫 Francesco Faiola 中国科学院生态环境研究中心环境化学与生态毒理学国家重点实验室北京100085 中国科学院大学资源与环境学院北京100049 重庆医科大学附属第三医院泌尿外科重庆401120

大气污染及大气中的超细颗粒物,会对人体健康造成一定的危害。皮肤作为人体最大的器官,是保护人体不受外源性物质损害的第一道防线。为探究超细颗粒物对人体皮肤特别是表皮的潜在风险,从人体皮肤中分离得到了原代黑色素细胞和角质形成细... 详细信息

大气污染及大气中的超细颗粒物,会对人体健康造成一定的危害。皮肤作为人体最大的器官,是保护人体不受外源性物质损害的第一道防线。为探究超细颗粒物对人体皮肤特别是表皮的潜在风险,从人体皮肤中分离得到了原代黑色素细胞和角质形成细胞,使用1~10000μg·L^(-1)商业化超细碳颗粒物模拟大气中的超细颗粒物,探究了其潜在的皮肤毒性。研究结果表明,从皮肤中分离的原代黑色素细胞和角质形成细胞能在体外扩增,具有相应的功能。超细碳颗粒物粒径<100 nm,处于纳米尺度,且72 h急性暴露不会影响黑色素细胞的细胞活性。qRT-PCR结果显示,超细碳颗粒物暴露会上调黑色素细胞功能基因MITF、MITF-M、c-KIT、SILV、PAX3、SLUG、TYR和TYRP1的表达,干扰其基因表达。以上研究结果为大气颗粒物的毒性评价,提供了重要的数据和模型。

关键词：超细碳颗粒物超细颗粒物黑色素细胞角质形成细胞急性毒性功能基因表皮

干细胞毒理学在环境污染物毒性效应和机制评估中的应用

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干细胞毒理学在环境污染物毒性效应和机制评估中的应用

Assessment of Bisphenol A(BPA) neurotoxicity in vitro with mouse embryonic stem cells

中国毒理学会第十次全国毒理学大会

作者： Francesco Faiola 杨仁君殷诺雅环境化学与生态毒理学国家重点实验室中国科学院生态环境研究中心中国科学院大学资源与环境学院

随着世界经济的发展、科技的进步和人类物质需求的日益增长,许多新型化学品被合成、制造和应用,2023年,在美国CAS登记注册的化学品已经超过2亿,并且以每年约0.12亿的速度持续增长,这些化学品的随意使用和排放造成了日益严重的污染问题...

随着世界经济的发展、科技的进步和人类物质需求的日益增长,许多新型化学品被合成、制造和应用,2023年,在美国CAS登记注册的化学品已经超过2亿,并且以每年约0.12亿的速度持续增长,这些化学品的随意使用和排放造成了日益严重的污染问题。环境污染是造成新生儿缺陷的重要原因,WHO报道显示,2022年,世界范围内具有先天缺陷的新生儿比例高达6%,当年约有41万新生儿在5岁之内死于先天缺陷,因此亟需建立高效、精准的环境污染物发育毒性效应与机制研究方法。毒理学的研究长期以来非常依赖动物模型。然而动物实验存在着通量低、成本高、发育毒性研究难度高的缺点,并且由于物种间的差异,基于动物实验得到的结果并不都适用于人类。为弥补这些不足,人们开发了体外细胞实验作为动物实验的补充,这些体外细胞实验大多基于人体癌细胞,条件简单可控、成本低、并且可实时检测,能够很好的作为毒性初筛模型,不过由于癌细胞本身存在大量的突变,生理功能异常,越来越多的研究显示其不能很好的反应人体真实情况,也不适用于发育毒性研究。近年来干细胞毒理学的兴起为补齐现有毒理学模型的短板提供了条件,由于相关模型使用的人多能干细胞可以在体外近乎无限增殖并维持正常核型,因此容易满足大规模毒性筛查的需要,并且相关细胞均为正常细胞,能够贴切反应人体真实情况。此外,这些细胞还具有多向分化潜能,可分化为成体所有类型细胞,不仅适合人体早期发育毒性研究,还能用于特定类型细胞的发育/功能毒性研究。基于人多能干细胞的优势,我们致力于搭建一个以干细胞相关模型为基础的研究平台,用于评估环境污染物的毒性效应和机制。我们在研究中建立了多种模拟人体胚胎发育过程、脏器发育过程以及生理功能的毒理学研究模型,开发了发育毒性数据库和相关分析方法、研发了高通量发育毒性检测手段,建立了毒理学大数据可视化分析方法,形成了集细胞培养、不同脏器分化、多种毒性检测和毒性数据处理为一体的成套分析平台。基于干细胞毒理学研究平台,揭示了纳米颗粒物、多溴联苯醚类、双酚类、零苯二甲酸酯类、新烟碱类和有机磷类化合物对人体不同细胞或发育过程的毒性效应,为相关化合物的安全使用提供了参考。

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Journal of Environmental Sciences 2015年第10期27卷 181-187页

作者： Nuoya Yin Xinglei Yao Zhanfen Qin Yuan-Liang Wang Francesco Faiola State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental SciencesChinese Academy of Sciences Section of Molecular Biology University of California at San Diego

The adverse effects of environmental pollution on our well-being have been intensively studied with many in vitro and in vivo systems. In our group, we focus on stem cell toxicology due to the multitude of embryonic stem cell（ESC） properties which can be exerted in toxicity assays. In fact, ESCs can differentiate in culture to mimic embryonic development in vivo, or specifically to virtually any kind of somatic cells. Here, we used the toxicant Bisphenol A（BPA）, a chemical known as a hazard to infants and children, and showed that our stem cell toxicology system was able to efficiently recapitulate most of the toxic effects of BPA previously detected by in vitro system or animal tests. More precisely, we demonstrated that BPA affected the proper specification of germ layers during our in vitro mimicking of the embryonic development, as well as the establishment of neural ectoderm and neural progenitor cells.

关键词： Bisphenol A（BPA） Stem cell toxicology Neurotoxicity Embryonic stem cells（ESCs） Developmental toxicity Neural ectoderm