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.

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.

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.

The ex vivo and in vivo biological performances of graphene oxide and the impact of surfactant on graphene oxide's biocompatibility

Graphene oxide（GO）displays promising properties for biomedical applications including drug delivery and cancer therapeutics.However,GO exposure also raises safety concerns such as potential side effects on health.Here,the biological effects of GO suspended in phosphate buffered saline（PBS）with or without 1% nonionic surfactant Tween 80 were investigated.Based on the ex vivo experiments,Tween 80 significantly affected the interaction between GO and peripheral blood from mice.GO suspension in PBS tended to provoke the aggregation of diluted blood cells,which could be prevented by the addition of Tween 80.After intravenous administration,GO suspension with or without 1% Tween 80 was quickly eliminated by the mononuclear phagocyte system.Nevertheless,GO suspension without Tween 80 showed greater accumulation in lungs than that containing 1% Tween 80.In contrast,less GO was found in livers for GO suspension compared to Tween 80 assisted GO suspension.Organs including hearts,livers,lungs,spleens,kidneys,brains,and testes did not reveal histological alterations.The indexes of peripheral blood showed no change upon GO exposure.Our results together demonstrated that Tween 80 could greatly alter GO＇s biological performance and determine the pattern of its biodistribution in mice.

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.