人多能干细胞在环境污染物风险评估中的应用与展望

在环境污染问题日益严峻的今天,人们亟需一套高效的毒理学评价体系来全面评估各类环境污染物的毒性效应和致毒机制,并阐明化合物结构与毒性效应之间的关系,进而指导安全化合物的合成。人多能干细胞(hPSCs)具有近乎无限的增殖能力和分化成所有成体细胞的潜能,近年来在毒理学的应用中崭露头角,显现出极大的应用潜力。由hPSCs分化而来的细胞可以代替原代细胞进行高通量的毒理学研究;hPSCs分化模型便于在体外研究环境污染物暴露对人体胚胎发育过程的毒性;基于hPSCs构建的类器官技术也使环境污染物的器官毒性研究成为可能。hPSCs在环境污染物风险评估中有很高的应用价值。

基于美国FAERS数据库的拉米夫定妊娠相关不良反应信号挖掘研究

目的:利用美国FDA不良事件报告系统(FAERS)挖掘拉米夫定妊娠相关不良反应的风险信号,为该药的临床安全应用提供参考。方法:收集FAERS数据库中2004年第1季度-2021年第1季度的不良事件报告,根据首要怀疑药物,以替诺福韦酯为对照,利用报告比值比(ROR)法对拉米夫定妊娠相关不良事件(流产、自然流产、早产、低出生体重、死产和胎儿死亡、胎儿并发症)进行风险信号挖掘。并分别在HBV人群、HIV人群进行亚组分析。结果:以拉米夫定和替诺福韦酯为首要怀疑药物的妊娠期不良反应报告分别有4364例和3750例。与替诺福韦酯相比,拉米夫定妊娠相关不良反应风险信号未见升高。但在HBV人群中,拉米夫定所致的死产和胎儿死亡(ROR=2.09,95%CI:1.14~3.82)、胎儿并发症(ROR=3.04,95%CI:2.19~4.23)风险信号较替诺福韦酯显著增加,上述差异在HIV人群中并未观察到。结论:鉴于我国庞大的乙肝患者人群以及目前尚缺乏对两药妊娠期安全性的头对头系统性比较研究,基于FAERS的真实世界数据可为妊娠期乙肝患者个体化用药提供一定参考。

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

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。

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

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.

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

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.

Advancing Environmental Toxicology In Vitro:From Immortalized Cancer Cell Lines to 3D Models Derived from Stem Cells

In recent years,rapid industrial development has resulted in the production and exposure of a substantial number of compounds to the human body.This has created an urgent need in environmental toxicology for models that are efficient,accurate,and cost-effective in evaluating the health impacts of these compounds on humans.Over the past seven decades,various cancer cell lines and immortalized cell lines have made significant contributions to the advancement of research on organ toxicity.Pluripotent stem cell technology,especially toxicological models derived from pluripotent stem cells,presents modern environmental toxicologists with high-throughput,species-relevant,and predictive options.In this comprehensive review,we assess the characteristics of representative human cancer cell lines and immortalized cell lines in environmental toxicology,as well as introduce two distinct human pluripotent stem cell types and their innovative toxicological models.We explore their applications and prospects in the field of environmental toxicology,while also addressing the readiness of in vitro models to confront the emerging challenges of the future.

Environmental Toxicology:The Importance of Disease-Specific In Vitro Models

Environmental toxicology focuses on the effects of environmental chemicals on human health.To ensure a comprehensive assessment of exposure risks,it is crucial to consider populations that are already affected by preexisting medical conditions,as they may exhibit increased sensitivity to environmental contaminants.Various disease-specific animal models have been developed to simulate a range of diseases such as cancer,diabetes,and neurodevelopmental disorders.However,a significant limitation of these models is the presence of species variations.

人胚胎干细胞在药物毒性风险评估中的研究进展

人胚胎干细胞(hESCs)是来源于胚胎发育早期内细胞团的一类未分化的多能干细胞,具有自我更新和多向分化的生物学特性,在发育生物学、再生医学以及细胞治疗领域等方面已开展了广泛的研究。与常规药物毒性评估所采用的癌细胞或原代细胞不同,干细胞不仅能满足基础毒性评估,由于其多向分化的特点,可经诱导产生各种正常人体器官或组织细胞,为药物临床前评估提供多方面数据。与动物实验模型相比,h ESCs不仅避免了种属差异,还具备高通量、低成本的优势,在预测药物毒性效应方面具有广阔的前景。对目前hESCs在药物毒性风险评估中的研究进展进行总结,为体外药物毒性筛选试验提供新思路。

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

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.

Tetrabromobisphenol A(TBBPA): A controversial environmental pollutant

Tetrabromobisphenol A(TBBPA)is one of the most widely used brominated flame retardants and is extensively used in electronic equipment,furniture,plastics,and textiles.It is frequently detected in water,soil,air,and organisms,including humans,and has raised concerns in the scientific community regarding its potential adverse health effects.Human exposure to TBBPA is mainly via diet,respiration,and skin contact.Various in vivo and in vitro studies based on animal and cell models have demonstrated that TBBPA can induce multifaceted effects in cells and animals,and potentially exert hepatic,renal,neural,cardiac,and reproductive toxicities.Nevertheless,other reports have claimed that TBBPA might be a safe chemical.In this review,we re-evaluated most of the published TBBPA toxicological assessments with the goal of reaching a conclusion about its potential toxicity.We concluded that,although low TBBPA exposure levels and rapid metabolism in humans may signify that TBBPA is a safe chemical for the general population,particular attention should be paid to the potential effects of TBBPA on early developmental stages.

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

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.

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

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.

干细胞毒理学在大气污染健康风险评估中的应用

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.