Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay
The vast landscape of environmental chemicals has motivated the need for alternative methods to traditional whole-animal bioassays in toxicity testing. Embryonic stem (ES) cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, w...
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| creator | Chandler, Kelly J Barrier, Marianne Jeffay, Susan Nichols, Harriette P Kleinstreuer, Nicole C Singh, Amar V Reif, David M Sipes, Nisha S Judson, Richard S Dix, David J Kavlock, Robert Hunter, 3rd, Edward S Knudsen, Thomas B |
| description | The vast landscape of environmental chemicals has motivated the need for alternative methods to traditional whole-animal bioassays in toxicity testing. Embryonic stem (ES) cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, we evaluated 309 environmental chemicals, mostly food-use pesticides, from the ToxCast™ chemical library using a mouse ES cell platform. ES cells were cultured in the absence of pluripotency factors to promote spontaneous differentiation and in the presence of DMSO-solubilized chemicals at different concentrations to test the effects of exposure on differentiation and cytotoxicity. Cardiomyocyte differentiation (α,β myosin heavy chain; MYH6/MYH7) and cytotoxicity (DRAQ5™/Sapphire700™) were measured by In-Cell Western™ analysis. Half-maximal activity concentration (AC₅₀) values for differentiation and cytotoxicity endpoints were determined, with 18% of the chemical library showing significant activity on either endpoint. Mining these effects against the ToxCast Phase I assays (∼500) revealed significant associations for a subset of chemicals (26) that perturbed transcription-based activities and impaired ES cell differentiation. Increased transcriptional activity of several critical developmental genes including BMPR2, PAX6 and OCT1 were strongly associated with decreased ES cell differentiation. Multiple genes involved in reactive oxygen species signaling pathways (NRF2, ABCG2, GSTA2, HIF1A) were strongly associated with decreased ES cell differentiation as well. A multivariate model built from these data revealed alterations in ABCG2 transporter was a strong predictor of impaired ES cell differentiation. Taken together, these results provide an initial characterization of metabolic and regulatory pathways by which some environmental chemicals may act to disrupt ES cell growth and differentiation. |
| doi_str_mv | 10.1371/journal.pone.0018540 |
| format | Article |
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Embryonic stem (ES) cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, we evaluated 309 environmental chemicals, mostly food-use pesticides, from the ToxCast™ chemical library using a mouse ES cell platform. ES cells were cultured in the absence of pluripotency factors to promote spontaneous differentiation and in the presence of DMSO-solubilized chemicals at different concentrations to test the effects of exposure on differentiation and cytotoxicity. Cardiomyocyte differentiation (α,β myosin heavy chain; MYH6/MYH7) and cytotoxicity (DRAQ5™/Sapphire700™) were measured by In-Cell Western™ analysis. Half-maximal activity concentration (AC₅₀) values for differentiation and cytotoxicity endpoints were determined, with 18% of the chemical library showing significant activity on either endpoint. Mining these effects against the ToxCast Phase I assays (∼500) revealed significant associations for a subset of chemicals (26) that perturbed transcription-based activities and impaired ES cell differentiation. Increased transcriptional activity of several critical developmental genes including BMPR2, PAX6 and OCT1 were strongly associated with decreased ES cell differentiation. Multiple genes involved in reactive oxygen species signaling pathways (NRF2, ABCG2, GSTA2, HIF1A) were strongly associated with decreased ES cell differentiation as well. A multivariate model built from these data revealed alterations in ABCG2 transporter was a strong predictor of impaired ES cell differentiation. Taken together, these results provide an initial characterization of metabolic and regulatory pathways by which some environmental chemicals may act to disrupt ES cell growth and differentiation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0018540</identifier><identifier>PMID: 21666745</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>ABC transporters ; Animals ; Antioxidants ; Binding sites ; Bioassays ; Biological Assay ; Biology ; Bone morphogenetic protein receptor type II ; Cancer therapies ; Cardiomyocytes ; Cell Adhesion - drug effects ; Cell Death - drug effects ; Cell differentiation ; Cell Differentiation - drug effects ; Cell Line ; Chemicals ; Cytotoxicity ; Differentiation (biology) ; Embryogenesis ; Embryonic growth stage ; Embryonic stem cells ; Embryonic Stem Cells - cytology ; Embryonic Stem Cells - drug effects ; Embryos ; Endpoint Determination ; Environmental Pollutants - toxicity ; Environmental protection ; Enzymes ; Gene expression ; Genes ; Genomics ; Homeostasis ; Hypoxia ; Laboratories ; Male ; Mice ; Models, Biological ; Multivariate Analysis ; Myosin ; Oxygen ; Pax6 protein ; Pesticides ; Pluripotency ; R&D ; Reactive oxygen species ; Research & development ; Signaling ; Stem cells ; Toxicity testing ; Toxicity Tests - methods ; Toxicology ; Transcription ; Transcription factors</subject><ispartof>PloS one, 2011-06, Vol.6 (6), p.e18540</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. 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Embryonic stem (ES) cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, we evaluated 309 environmental chemicals, mostly food-use pesticides, from the ToxCast™ chemical library using a mouse ES cell platform. ES cells were cultured in the absence of pluripotency factors to promote spontaneous differentiation and in the presence of DMSO-solubilized chemicals at different concentrations to test the effects of exposure on differentiation and cytotoxicity. Cardiomyocyte differentiation (α,β myosin heavy chain; MYH6/MYH7) and cytotoxicity (DRAQ5™/Sapphire700™) were measured by In-Cell Western™ analysis. Half-maximal activity concentration (AC₅₀) values for differentiation and cytotoxicity endpoints were determined, with 18% of the chemical library showing significant activity on either endpoint. Mining these effects against the ToxCast Phase I assays (∼500) revealed significant associations for a subset of chemicals (26) that perturbed transcription-based activities and impaired ES cell differentiation. Increased transcriptional activity of several critical developmental genes including BMPR2, PAX6 and OCT1 were strongly associated with decreased ES cell differentiation. Multiple genes involved in reactive oxygen species signaling pathways (NRF2, ABCG2, GSTA2, HIF1A) were strongly associated with decreased ES cell differentiation as well. A multivariate model built from these data revealed alterations in ABCG2 transporter was a strong predictor of impaired ES cell differentiation. Taken together, these results provide an initial characterization of metabolic and regulatory pathways by which some environmental chemicals may act to disrupt ES cell growth and differentiation.</description><subject>ABC transporters</subject><subject>Animals</subject><subject>Antioxidants</subject><subject>Binding sites</subject><subject>Bioassays</subject><subject>Biological Assay</subject><subject>Biology</subject><subject>Bone morphogenetic protein receptor type II</subject><subject>Cancer therapies</subject><subject>Cardiomyocytes</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Death - drug effects</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Line</subject><subject>Chemicals</subject><subject>Cytotoxicity</subject><subject>Differentiation (biology)</subject><subject>Embryogenesis</subject><subject>Embryonic growth stage</subject><subject>Embryonic stem cells</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Embryonic Stem Cells - drug effects</subject><subject>Embryos</subject><subject>Endpoint Determination</subject><subject>Environmental Pollutants - toxicity</subject><subject>Environmental protection</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genomics</subject><subject>Homeostasis</subject><subject>Hypoxia</subject><subject>Laboratories</subject><subject>Male</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Multivariate Analysis</subject><subject>Myosin</subject><subject>Oxygen</subject><subject>Pax6 protein</subject><subject>Pesticides</subject><subject>Pluripotency</subject><subject>R&D</subject><subject>Reactive oxygen species</subject><subject>Research & development</subject><subject>Signaling</subject><subject>Stem cells</subject><subject>Toxicity testing</subject><subject>Toxicity Tests - methods</subject><subject>Toxicology</subject><subject>Transcription</subject><subject>Transcription 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V</au><au>Reif, David M</au><au>Sipes, Nisha S</au><au>Judson, Richard S</au><au>Dix, David J</au><au>Kavlock, Robert</au><au>Hunter, 3rd, Edward S</au><au>Knudsen, Thomas B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-06-07</date><risdate>2011</risdate><volume>6</volume><issue>6</issue><spage>e18540</spage><pages>e18540-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The vast landscape of environmental chemicals has motivated the need for alternative methods to traditional whole-animal bioassays in toxicity testing. Embryonic stem (ES) cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, we evaluated 309 environmental chemicals, mostly food-use pesticides, from the ToxCast™ chemical library using a mouse ES cell platform. ES cells were cultured in the absence of pluripotency factors to promote spontaneous differentiation and in the presence of DMSO-solubilized chemicals at different concentrations to test the effects of exposure on differentiation and cytotoxicity. Cardiomyocyte differentiation (α,β myosin heavy chain; MYH6/MYH7) and cytotoxicity (DRAQ5™/Sapphire700™) were measured by In-Cell Western™ analysis. Half-maximal activity concentration (AC₅₀) values for differentiation and cytotoxicity endpoints were determined, with 18% of the chemical library showing significant activity on either endpoint. Mining these effects against the ToxCast Phase I assays (∼500) revealed significant associations for a subset of chemicals (26) that perturbed transcription-based activities and impaired ES cell differentiation. Increased transcriptional activity of several critical developmental genes including BMPR2, PAX6 and OCT1 were strongly associated with decreased ES cell differentiation. Multiple genes involved in reactive oxygen species signaling pathways (NRF2, ABCG2, GSTA2, HIF1A) were strongly associated with decreased ES cell differentiation as well. A multivariate model built from these data revealed alterations in ABCG2 transporter was a strong predictor of impaired ES cell differentiation. Taken together, these results provide an initial characterization of metabolic and regulatory pathways by which some environmental chemicals may act to disrupt ES cell growth and differentiation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21666745</pmid><doi>10.1371/journal.pone.0018540</doi><tpages>e18540</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1304892202 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | ABC transporters Animals Antioxidants Binding sites Bioassays Biological Assay Biology Bone morphogenetic protein receptor type II Cancer therapies Cardiomyocytes Cell Adhesion - drug effects Cell Death - drug effects Cell differentiation Cell Differentiation - drug effects Cell Line Chemicals Cytotoxicity Differentiation (biology) Embryogenesis Embryonic growth stage Embryonic stem cells Embryonic Stem Cells - cytology Embryonic Stem Cells - drug effects Embryos Endpoint Determination Environmental Pollutants - toxicity Environmental protection Enzymes Gene expression Genes Genomics Homeostasis Hypoxia Laboratories Male Mice Models, Biological Multivariate Analysis Myosin Oxygen Pax6 protein Pesticides Pluripotency R&D Reactive oxygen species Research & development Signaling Stem cells Toxicity testing Toxicity Tests - methods Toxicology Transcription Transcription factors |
| title | Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T08%3A57%3A44IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Evaluation%20of%20309%20environmental%20chemicals%20using%20a%20mouse%20embryonic%20stem%20cell%20adherent%20cell%20differentiation%20and%20cytotoxicity%20assay&rft.jtitle=PloS%20one&rft.au=Chandler,%20Kelly%20J&rft.date=2011-06-07&rft.volume=6&rft.issue=6&rft.spage=e18540&rft.pages=e18540-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0018540&rft_dat=%3Cgale_plos_%3EA476888644%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1304892202&rft_id=info:pmid/21666745&rft_galeid=A476888644&rft_doaj_id=oai_doaj_org_article_5d5d41f27bda48b6a63e677cabf91696&rfr_iscdi=true |