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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

Prenatal amoxicillin exposure induces Developmental toxicity in fetal mice and its characteristics

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Journal of Environmental Sciences 2024年第3期137卷 287-301页

作者： Yongguo Dai Yu Peng Wen Hu Yi Liu Hui Wang Department of Pharmacology Wuhan University School of Basic Medical SciencesWuhan 430071China Department of Pharmacy Zhongnan Hospital of Wuhan UniversityWuhan 430071China Hubei Provincial Key Laboratory of developmentally Originated Disease Wuhan 430071China

Amoxicillin,a widely used antibiotic in human and veterinary pharmaceuticals,is now considered as an“emerging contaminant”because it exists widespreadly in the environment and brings a series of adverse outcomes.Currently,systematic studies about the Developmental toxicity of amoxicillin are still lacking.We explored the potential effects of amoxicillin exposure on pregnancy outcomes,maternal/fetal serum phenotypes,and fetal multiple organ development in mice,at different doses(75,150,300 mg/(kg·day))during late-pregnancy,or at a dose of 300 mg/(kg·day)during different stages(mid-/latepregnancy)and courses(single-/multi-course).Results showed that prenatal amoxicillin exposure(PAmE)had no significant infuence on the body weights of dams,but it could inhibit the physical development and reduce the survival rate of fetuses,especially during the midpregnancy.Meanwhile,PAmE altered multiple maternal/fetal serum phenotypes,especially in fetuses.Fetal multi-organ function results showed that PAmE inhibited testicular/adrenal steroid synthesis,long bone/cartilage and hippocampal development,and enhanced ovarian steroid synthesis and hepatic glycogenesis/lipogenesis,and the order of severity might be gonad(testis,ovary)>liver>others.Further analysis found that PAmE-induced multiorgan developmental and functional alterations had differences in stages,courses and fetal gender,and the most obvious changes might be in high-dose,late-pregnancy and multicourse,but there was no typical rule of a dose-response relationship.In conclusion,this study confirmed that PAmE could cause abnormal development and multi-organ function alterations,which deepens our understanding of the risk of PAmE and provides an experimental basis for further exploration of the long-term harm.

关键词： Amoxicillin Prenatal exposure Fetal development Organ function Developmental toxicity

Acute Developmental toxicity of Panax notoginseng in Zebrafish Larvae

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Chinese Journal of Integrative Medicine 2023年第4期29卷 333-340页

作者： WANG Rong-rong LI Ting ZHANG Lei HU Zheng-yan ZHOU Li SHAN Le-tian HUANG Jia-wei LI Lan College of Pharmacy Zhejiang Chinese Medical UniversityHangzhou 310053China Department of Plastic and Aesthetic Center the First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003China School of Biological and Chemical Engineering Zhejiang University of Science and TechnologyHangzhou 310058China Center for Disease Control and Prevention of Zhejiang Province Hangzhou 310051China Zhejiang Institute of Orthopedics and Traumatology the First Affiliated HospitalZhejiang Chinese Medical UniversityHangzhou 310006China Department of Pediatrics the First Affiliated HospitalZhejiang Chinese Medical UniversityHangzhou 310006China

Objective:To evaluate toxicity of raw extract of Panax notoginseng(rPN)and decocted extract of PN(dPN)by a toxicological assay using zebrafish larvae,and explore the mechanism by RNA sequencing assay.Methods:Zebrafish larvae was used to evaluate acute toxicity of PN in two forms:rPN and dPN.Three doses(0.5,1.5,and 5.0μg/mL)of dPN were used to treat zebrafishes for evaluating the Developmental toxicity.Behavior abnormalities,body weight,body length and number of vertebral roots were used as specific phenotypic endpoints.RNA sequencing(RNA-seq)assay was applied to clarify the mechanism of acute toxicity,followed by real time PCR(qPCR)for verification.High performance liquid chromatography analysis was performed to determine the chemoprofile of this herb.Results:The acute toxicity result showed that rPN exerted higher acute toxicity than d PN in inducing death of larval zebrafishes(PDevelopmental toxicity of dPN.No other adverse outcome was observed during the experimental period.RNA-seq data revealed 38 genes differentially expressed in dPN-treated zebrafishes,of which carboxypeptidase A1(cpa1)and opioid growth factor receptor-like 2(ogfrl2)were identified as functional genes in regulating body development of zebrafishes.qPCR data showed that dPN significantly down-regulated the mRNA expressions of cpa1 and ogfrl2(both PDevelopmental toxicity of dPN,suggesting potential risk of its clinical application in children.

关键词： Panaxnotoginseng zebrafishlarvae Developmental toxicity RNAsequencing

Developmental toxicity of TCBPA on the nervous and cardiovascular systems of zebrafish (Danio rerio): A combination of transcriptomic and metabolomics

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Journal of Environmental Sciences 2023年第5期127卷 197-209页

作者： Wentao Liu Yifan Pan Lu Yang Yun Xie Xuanyue Chen Jing Chang Weiyu Hao Lifei Zhu Bin Wan Research Center for Eco-Environmental Sciences Chinese Academy of SciencesBeijing 100085China University of Chinese Academy of Sciences Beijing 100049China Agricultural Information Institute Chinese Academy of Agricultural SciencesBeijing 100081China Institute of Food Safety Chinese Academy of Inspection and QuarantineBeijing 100176China Beijing Academy of Agriculture and Forestry Sciences Beijing 100097China

Tetrachlorobisphenol A(TCBPA),a widely used halogenated flame retardant,is frequently detected in environmental compartments and human samples.However,unknown Developmental toxicity and mechanisms limit the entire understanding of its effects.In this study,zebrafish(Danio rerio)embryos were exposed to various concentrations of TCBPA while a combination of transcriptomics,behavioral and biochemical analyzes as well as metabolomics were applied to decipher its toxic effects and the potential mechanisms.We found that TCBPA could interfere with nervous and cardiovascular development through focal adhesion and extracellular matrix-receptor(ECM-receptor)interaction pathways through transcriptomic analysis.Behavioral and biochemical analysis results indicated abnormal swimming behavior of zebrafish larvae.Morphological observations revealed that TCBPA could cause the loss of head blood vessels.Metabolomic analysis showed that arginine-related metabolic pathways were one of the main pathways leading to TCBPA Developmental toxicity.Our study demonstrated that by using omics,TCBPA was shown to have neurological and cardiovascular Developmental toxicity and the underlying mechanisms were uncovered and major pathways identified.

关键词： Tetrachlorobisphenol A(TCBPA) Zebrafish Developmental toxicity Transcriptomics Metabolomics

Developmental toxicity and programming alterations of multiple organs in offspring induced by medication during pregnancy

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Acta Pharmaceutica Sinica B 2023年第2期13卷 460-477页

作者： Zhengjie Lu Yu Guo Dan Xu Hao Xiao Yongguo Dai Kexin Liu Liaobin Chen Hui Wang Department of Pharmacology Wuhan University School of Basic Medical ScienceWuhan 430071China Department of Orthopedic Surgery Zhongnan Hospital of Wuhan UniversityWuhan 430071China Hubei Provincial Key Laboratory of developmentally Originated Disorder Wuhan 430071China

Medication during pregnancy is widespread,but there are few reports on its fetal safety.Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways,multiple organs,and multiple targets.Its mechanisms involve direct ways such as oxidative stress,epigenetic modification,and metabolic activation,and it may also be indirectly caused by placental dysfunction.Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming,functional homeostasis changes,and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids.The organ Developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification.Combined with the latest research results of our laboratory,this paper reviews the latest research progress on the Developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy,which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases.

关键词： Medication Pregnancy Multiple organs Developmental toxicity developmental programming Maternal-derived glucocorticoids Gender differences Multi-generational genetic effects

Comparison of Developmental toxicity of different surface modified CdSe/ZnS QDs in zebrafish embryos

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Journal of Environmental Sciences 2021年第2期33卷 240-249页

作者： Naying Zheng Jinhui Yan Wang Qian Chao Song Zhenghong Zuo Chengyong He State Key Laboratory of Cellular Stress Biology School of Life SciencesXiamen UniversityXiamen 361005China Freshwater Fisheries Research Center Chinese Academy of Fishery SciencesWixi 214081China

Quantum dots(QDs)are new types of nanomaterials.Few studies have focused on the effect of different surface modified QDs on embryonic development.Herein,we compared the in vivo toxicity of Cd Se/Zn S QDs with carboxyl(-COOH)and amino(-NH 2)modification using zebrafish embryos.After exposure,the two Cd Se/Zn S QDs decreased the survival rate,hatching rate,and embryo movement of zebrafish.Moreover,we found QDs attached to the embryo membrane before hatching and the eyes,yolk and heart after hatching.The attached amount of carboxyl QDs was more.Consistently,the Cd content in embryos and larvae was higher in carboxyl QD-treatment.We further observed that the two QDs caused zebrafish pericardial edema and cardiac dysfunction.In line with it,both carboxyl and amino QDs upregulated the transcription levels of cardiac development-related genes,and the levels were higher in carboxyl QD-treated groups.Furthermore,the chelator of Cd^2+diethylene triamine pentacetate acid could partially rescued the Developmental toxicity caused by the two types of QDs suggesting that both the nature of QDs and the release of Cd^2+contribute to the Developmental toxicity.In conclusion,the two Cd Se/ZnS QDs have Developmental toxicity and affect the cardiac development,and the carboxyl QDs is more toxic possibly due to the higher affinity and more release to embryos and larvae.Our study provides new knowledge that the surface functional modification of QDs is critical on the development on aquatic species,which is beneficial to develop and applicate QDs more safely and environmentfriendly.

关键词： Quantum dots Surface modification Fish Cardiac development Developmental toxicity

Developmental toxicity and Potential Teratogenicity of Compound Danshen Tablet, Angong Niuhuang Pill, and Lidan Paishi Tablet in Zebrafish Embryos

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Chinese Herbal Medicines 2017年第1期9卷 74-79页

作者： Jie-feng Chen Tong Liu Dan-ping Huang Qi-di He Zuan-guang Chen Mei-cun Yao School of Pharmaceutical Sciences Sun Yat-sen University Guangzhou 510006 China Third Affiliated Hospital of Sun Yat-sen University Guangzhou 510000 China

Objective Herbal medicines containing toxic herbs or minerals such as Compound Danshen Tablet （CDT）, Angong Niuhuang Pill （ANP）, and Lidan Paishi Tablet （LPT） are avoided or used with caution for pregnant women because of potential teratogenicity. To understand their mechanism, they were chosen as model subjects for the research. Methods Zebrafish embryos were used to evaluate their potential teratogenic risk in vitro. Results All of them showed teratogenic and lethal effects in zebrafish embryos, with the ECs0 values at 351,793, and 220 μg/mL, and LC50 values at 41 7, 596, and 380 μg/mL, respectively. CDT and LPT, displaying week potential teratogenicity as their teratogenicity indexes were greater than 1, induced tail malformation and cardiac edema mainly in zebrafish embryos, respectively. Conclusion The results provide the significant guidance of clinical safety of medication.

关键词： Chinese patent medicines Developmental toxicity drug safety potential teratogenicity zebrafish embryos

Zebrafish:a predictive model for assessing Developmental toxicity and teratotoxicity of drugs

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Zebrafish:a predictive model for assessing developmental tox...

Developmental toxicity evaluation of Rhizoma Atractylodis Macrocephalae:in-vivo and in-vitro studies

中国药理学会第十一次全国学术会议

作者： CHEN Ru-jia,ZHU Jun-jing,ZHU Xiao-yu,ZHANG Yong,LI Chun-qi (1.Hunter Biotechnology,Inc.,Transfarland,Xiaoshan Economic & Technology Development Zone,Hangzhou 311231,China)

OBJECTIVE Conventional assessment of Developmental toxicity and teratotoxicity in mammalian models is laborious and time consuming.Since the early 1980s,alternative methods for assessing Developmental toxicity have been developed,including in vitro cell differentiation assays using either primary cell cultures or immortalized cell lines,the in vitro rodent whole embryo culture test and the in vivo frog embryo teratogenesis assay(FETAX).In vitro tests have been of limited value in predicting the effect of drugs on human embryonic and fetal development.Disadvantages of the in vivo FETAX assay include that xenopus do not have a characterized chemical metabolic pathway and they are insensitive to halogenated aromatic hydrocarbons.New screening technologies is required to generate data directly for risk assessment or for prioritization of compounds for further testing in mammals.Zebrafish is emerging as an alternative vertebrate animal model for assessing toxicity and safty of compounds,in part due to its transpatency,rapid development, and simplicity of compound delivery.METHODS Zebrafish of the AB wild-type strain were reared under standard conditions.Larvae were collected from natural spawnings,staged according to established criteria.Seven known mammalian-teratogenic compounds were as follows:bisphenol A,ethanol,lead nitrate,lithium chloride,tobacco leachate,caffeine and sudanⅠ.Three mammalian non-tera-totoxicity compounds were sucrose,saccharin and biotin.Zebrafish were exposed to three concentrations(LC,MNLCand 1/2 MN-LC) in each compound from 6 hpf to 120 hpf,30 zebrafish wree treated with each concentration.After treatment,10 zebrafish from each group were randomly selected and images were acquired using a dissecting stereomicroscope.We assessed the endpoints of evelop-mental toxicity and teratotoxicity at 120 hpf.RESULTS All 7 known mammalian-teratogenic compounds induced evelopmental toxicity in zebrafish.The major teratotoxicity were pericardial edema,head malformation,liver morphology malformation,circulat

关键词： zebrafish Developmental toxicity teratotoxicity animal model

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Developmental toxicity evaluation of Rhizoma Atractylodis Ma...

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

中国毒理学会第五次全国学术大会

作者： Kelvin Sze-Yin Leung Kingfai Cheng Chan Wing Leung Hong Kong Baptist UniversityL The Chinese University of Hong Kong

＜正＞Backgroud Rhizoma Atractylodis Macrocephalae （RAM）is the dried rhizome of Atractylodes macrocephala Koidz in the Compositae family.It is a commonly used tonic herb in China in the treatment of diarrhea,lack of appetite, anorexia,mental fatigue and other symptoms.This herb has also been used for thousands of years to treat pregnant disorders for preventing abortion during early pregnancy.However, there is no sufficient evidence so far to identify its embryotoxicity and teratogenicity.

关键词： Rhizoma Atractylodis Macrocephalae Developmental toxicity mouse embryonic stem cell

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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