{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T14:30:43Z","timestamp":1786631443249,"version":"build-2736575974"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2017,12,29]],"date-time":"2017-12-29T00:00:00Z","timestamp":1514505600000},"content-version":"vor","delay-in-days":2060,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Background: Information on the potential developmental toxicity (DT) of the majority of chemicals is scarce, and test capacities for further animal-based testing are limited. Therefore, new approaches with higher throughput are required. A screening strategy based on the use of relevant human cell types has been proposed by the U.S. Environmental Protection Agency and others. Because impaired neural crest (NC) function is one of the known causes for teratologic effects, testing of toxicant effects on NC cells is desirable for a DT test battery.<\/jats:p>\n                  <jats:p>Objective: We developed a robust and widely applicable human-relevant NC function assay that would allow for sensitive screening of environmental toxicants and defining toxicity pathways.<\/jats:p>\n                  <jats:p>Methods: We generated NC cells from human embryonic stem cells, and after establishing a migration assay of NC cells (MINC assay), we tested environmental toxicants as well as inhibitors of physiological signal transduction pathways.<\/jats:p>\n                  <jats:p>Results: Methylmercury (50 nM), valproic acid (&amp;gt; 10 \u00b5M), and lead-acetate [Pb(CH3CO2)4] (1 \u00b5M) affected the migration of NC cells more potently than migration of other cell types. The MINC assay correctly identified the NC toxicants triadimefon and triadimenol. Additionally, it showed different sensitivities to various organic and inorganic mercury compounds. Using the MINC assay and applying classic pharmacologic inhibitors and large-scale microarray gene expression profiling, we found several signaling pathways that are relevant for the migration of NC cells.<\/jats:p>\n                  <jats:p>Conclusions: The MINC assay faithfully models human NC cell migration, and it reveals impairment of this function by developmental toxicants with good sensitivity and specificity.<\/jats:p>","DOI":"10.1289\/ehp.1104489","type":"journal-article","created":{"date-parts":[[2012,5,9]],"date-time":"2012-05-09T14:55:07Z","timestamp":1336575307000},"page":"1116-1122","source":"Crossref","is-referenced-by-count":82,"title":["Evaluation of Developmental Toxicants and Signaling Pathways in a Functional Test Based on the Migration of Human Neural Crest Cells"],"prefix":"10.1021","volume":"120","author":[{"given":"Bastian","family":"Zimmer","sequence":"first","affiliation":[{"name":"Doerenkamp\u2013Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabsang","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute for Cell Engineering, Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina V","family":"Balmer","sequence":"additional","affiliation":[{"name":"Doerenkamp\u2013Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kesavan","family":"Meganathan","sequence":"additional","affiliation":[{"name":"Center of Physiology, Institute of Neurophysiology, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agapios","family":"Sachinidis","sequence":"additional","affiliation":[{"name":"Center of Physiology, Institute of Neurophysiology, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenz","family":"Studer","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan\u2013Kettering Institute, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Leist","sequence":"additional","affiliation":[{"name":"Doerenkamp\u2013Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2012,5,9]]},"reference":[{"issue":"3","key":"2026080509073454400_micit1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.14573\/altex.2011.3.175","article-title":"Can case study approaches speed implementation of the NRC report: \u201cToxicity Testing in the 21st Century: A Vision and a Strategy?","volume":"28","author":"Andersen","year":"2011","journal-title":"Altex"},{"issue":"3","key":"2026080509073454400_micit2","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nbt.1529","article-title":"Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling.","volume":"27","author":"Chambers","year":"2009","journal-title":"Nat Biotechnol"},{"issue":"2","key":"2026080509073454400_micit3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.reprotox.2011.11.111","article-title":"Developmental exposure to valproate and ethanol alters locomotor activity and retino-tectal projection area in zebrafish embryos.","volume":"33","author":"Cowden","year":"2012","journal-title":"Reprod Toxicol"},{"issue":"1","key":"2026080509073454400_micit4","first-page":"9","article-title":"Developmental neurotoxicity testing: recommendations for developing alternative methods for the screening and prioritization of chemicals.","volume":"28","author":"Crofton","year":"2011","journal-title":"Altex"},{"issue":"1","key":"2026080509073454400_micit5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/bdrb.20097","article-title":"Antifungal triazole derivative triadimefon induces ectopic maxillary cartilage by altering the morphogenesis of the first branchial arch.","volume":"80","author":"Di Renzo","year":"2007","journal-title":"Birth Defects Res B Dev Reprod Toxicol"},{"key":"2026080509073454400_micit6","article-title":"Embryos, Genes and Birth Defects","author":"Ferretti P, ed","year":"2006"},{"issue":"1","key":"2026080509073454400_micit7","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1083\/jcb.200909003","article-title":"Plasticity of cell migration: a multiscale tuning model.","volume":"188","author":"Friedl","year":"2010","journal-title":"J Cell Biol"},{"issue":"6","key":"2026080509073454400_micit8","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/S0890-6238(02)00059-X","article-title":"Neural crest cell motility in valproic acid.","volume":"16","author":"Fuller","year":"2002","journal-title":"Reprod Toxicol"},{"issue":"2","key":"2026080509073454400_micit9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1177\/1087057110393340","article-title":"A quantitative, facile, and high-throughput image-based cell migration method is a robust alternative to the scratch assay.","volume":"16","author":"Gough","year":"2011","journal-title":"J Biomol Screen"},{"issue":"1","key":"2026080509073454400_micit10","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0736-4679(97)00241-2","article-title":"Heavy metal toxicity, Part I: arsenic and mercury.","volume":"16","author":"Graeme","year":"1998","journal-title":"J Emerg Med"},{"issue":"9553","key":"2026080509073454400_micit11","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1016\/S0140-6736(06)69665-7","article-title":"Developmental neurotoxicity of industrial chemicals.","volume":"368","author":"Grandjean","year":"2006","journal-title":"Lancet"},{"issue":"1","key":"2026080509073454400_micit12","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/toxsci\/kfn154","article-title":"PCB126 exposure disrupts zebrafish ventricular and branchial but not early neural crest development.","volume":"106","author":"Grimes","year":"2008","journal-title":"Toxicol Sci"},{"issue":"29","key":"2026080509073454400_micit13","doi-asserted-by":"crossref","first-page":"6590","DOI":"10.1523\/JNEUROSCI.5747-03.2004","article-title":"Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis.","volume":"24","author":"Hao","year":"2004","journal-title":"J Neurosci"},{"issue":"7259","key":"2026080509073454400_micit14","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1038\/4601080a","article-title":"Chemical regulators have overreached.","volume":"460","author":"Hartung","year":"2009","journal-title":"Nature"},{"issue":"2","key":"2026080509073454400_micit15","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.reprotox.2006.04.009","article-title":"The need for developmental neurotoxicity studies in risk assessment for developmental toxicity.","volume":"22","author":"Hass","year":"2006","journal-title":"Reprod Toxicol"},{"key":"2026080509073454400_micit16","article-title":"Drugs and Pregnancy: Human Teratogenesis and Related Problems","author":"Hawkins DF, ed","year":"1983"},{"issue":"1A","key":"2026080509073454400_micit17","first-page":"347","article-title":"Different effects of valproic acid on proliferation and migration of malignant glioma cells in vitro.","volume":"21","author":"Knupfer","year":"2001","journal-title":"Anticancer Res"},{"issue":"8","key":"2026080509073454400_micit18","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.4161\/cc.7.8.5641","article-title":"The stem cells of the neural crest.","volume":"7","author":"Le Douarin","year":"2008","journal-title":"Cell Cycle"},{"issue":"4","key":"2026080509073454400_micit19","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/nprot.2010.35","article-title":"Derivation of neural crest cells from human pluripotent stem cells.","volume":"5","author":"Lee","year":"2010","journal-title":"Nat Protoc"},{"issue":"7262","key":"2026080509073454400_micit20","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/nature08320","article-title":"Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs.","volume":"461","author":"Lee","year":"2009","journal-title":"Nature"},{"key":"2026080509073454400_micit21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1289\/ehp.11447","article-title":"A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426.","volume":"117","author":"Makris","year":"2009","journal-title":"Environ Health Perspect"},{"issue":"2","key":"2026080509073454400_micit22","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1290\/1071-2690(2000)036<0088:IVTPOT>2.0.CO;2","article-title":"In vitro teratogenic potential of two antifungal triazoles: triadimefon and triadimenol.","volume":"36","author":"Menegola","year":"2000","journal-title":"In Vitro Cell Dev Biol Anim"},{"key":"2026080509073454400_micit23","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1289\/ehp.0800207","article-title":"Human neurospheres as three-dimensional cellular systems for developmental neurotoxicity testing.","volume":"117","author":"Moors","year":"2009","journal-title":"Environ Health Perspect"},{"key":"2026080509073454400_micit24","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1289\/ehp.8670113","article-title":"Species differences in pharmacokinetics and drug teratogenesis.","volume":"70","author":"Nau","year":"1986","journal-title":"Environ Health Perspect"},{"key":"2026080509073454400_micit25","article-title":"Toxicity Testing in the 21st Century: A Vision and a Strategy","author":"NRC (National Research Council)","year":"2007"},{"key":"2026080509073454400_micit26","unstructured":"OECD (Organisation for Economic Co-operation and Development)\n          . 2007. OECD Guideline for Testing of Chemicals. Developmental Neurotoxicity Study. Test No. 426.Available: http:\/\/www.oecd-ilibrary.org\/content\/book\/9789264067394-en [accessed 14 June 2012]."},{"issue":"4","key":"2026080509073454400_micit27","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1065\/espr2006.01.014","article-title":"Triadimefon causes branchial arch malformations in Xenopus laevis embryos.","volume":"13","author":"Papis","year":"2006","journal-title":"Environ Sci Pollut Res Int"},{"issue":"2","key":"2026080509073454400_micit28","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/1520-6866(2001)21:2<121::AID-TCM2>3.0.CO;2-N","article-title":"Action of valproic acid on Xenopus laevis development: teratogenic effects on eyes.","volume":"21","author":"Pennati","year":"2001","journal-title":"Teratog Carcinog Mutagen"},{"issue":"5","key":"2026080509073454400_micit29","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/j.ntt.2010.04.053","article-title":"The use of developmental neurotoxicity data in pesticide risk assessments.","volume":"32","author":"Raffaele","year":"2010","journal-title":"Neurotoxicol Teratol"},{"key":"2026080509073454400_micit30","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1146\/annurev.cellbio.042308.113231","article-title":"Collective cell migration.","volume":"25","author":"Rorth","year":"2009","journal-title":"Annu Rev Cell Dev Biol"},{"issue":"1","key":"2026080509073454400_micit31","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1093\/toxsci\/63.1.74","article-title":"Methylmercury-induced decrement in neuronal migration may involve cytokine-dependent mechanisms: a novel method to assess neuronal movement in vitro.","volume":"63","author":"Sass","year":"2001","journal-title":"Toxicol Sci"},{"issue":"1","key":"2026080509073454400_micit32","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1093\/toxsci\/kfr034","article-title":"Assessment of chemical-induced impairment of human neurite outgrowth by multiparametric live cell imaging in high-density cultures.","volume":"121","author":"Stiegler","year":"2011","journal-title":"Toxicol Sci"},{"issue":"12","key":"2026080509073454400_micit33","doi-asserted-by":"crossref","first-page":"2984","DOI":"10.1002\/ajmg.a.33454","article-title":"Craniofacial birth defects: the role of neural crest cells in the etiology and pathogenesis of Treacher Collins syndrome and the potential for prevention.","volume":"152A","author":"Trainor","year":"2010","journal-title":"Am J Med Genet A"},{"issue":"11","key":"2026080509073454400_micit34","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1038\/npp.2010.97","article-title":"The mood stabilizers valproic acid and lithium enhance mesenchymal stem cell migration via distinct mechanisms.","volume":"35","author":"Tsai","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"2026080509073454400_micit35","unstructured":"U.S. EPA (U.S. Environmental Protection Agency)\n          . 2009. The U.S. Environmental Protection Agency\u2019s Strategic Plan for Evaluating the Toxicity of Chemicals. EPA\/100\/K-09\/001.Available: www.epa.gov\/spc\/toxicitytesting\/docs\/toxtest_strategy_032309.pdf [accessed 14 June 2012]."},{"issue":"453","key":"2026080509073454400_micit36","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1080\/08035320600885846","article-title":"Today\u2019s epidemics in children: possible relations to environmental pollution and suggested preventive measures.","volume":"95","author":"van den Hazel","year":"2006","journal-title":"Acta Paediatr Suppl"},{"issue":"3","key":"2026080509073454400_micit37","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1007\/s12015-011-9230-1","article-title":"Effects of cryopreservation on the transcriptome of human embryonic stem cells after thawing and culturing.","volume":"7","author":"Wagh","year":"2011","journal-title":"Stem Cell Rev"},{"issue":"1","key":"2026080509073454400_micit38","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1093\/toxsci\/kfr254","article-title":"Integration of dosimetry, exposure, and high-throughput screening data in chemical toxicity assessment.","volume":"125","author":"Wetmore","year":"2011","journal-title":"Toxicol Sci"},{"issue":"3","key":"2026080509073454400_micit39","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/cdd.2010.109","article-title":"Coordinated waves of gene expression during neuronal differentiation of embryonic stem cells as basis for novel approaches to developmental neurotoxicity testing.","volume":"18","author":"Zimmer","year":"2011","journal-title":"Cell Death Differ"},{"issue":"2","key":"2026080509073454400_micit40","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1093\/toxsci\/kfr054","article-title":"Sensitivity of dopaminergic neuron differentiation from stem cells to chronic low-dose methylmercury exposure.","volume":"121","author":"Zimmer","year":"2011","journal-title":"Toxicol Sci"}],"container-title":["Environmental Health Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-pdf\/120\/8\/1116\/66406482\/ehp.1104489.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-pdf\/120\/8\/1116\/66406482\/ehp.1104489.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:43:43Z","timestamp":1786628623000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-lookup\/doi\/10.1289\/ehp.1104489"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,5,9]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2012,5,9]]},"published-print":{"date-parts":[[2012,8,1]]}},"URL":"https:\/\/doi.org\/10.1289\/ehp.1104489","relation":{},"ISSN":["0091-6765","1552-9924"],"issn-type":[{"value":"0091-6765","type":"print"},{"value":"1552-9924","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,5,9]]}}}