{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T12:49:08Z","timestamp":1792500548091,"version":"4.5.0"},"reference-count":32,"publisher":"American Chemical Society (ACS)","issue":"41","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["101037090"],"award-info":[{"award-number":["101037090"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031951","name":"Sciensano","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100031951","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018774","name":"Bundesministerium f?r Klimaschutz, Umwelt, Energie, Mobilit?t, Innovation und Technologie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018774","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018699","name":"HORIZON EUROPE Digital, Industry and Space","doi-asserted-by":"publisher","award":["101091842"],"award-info":[{"award-number":["101091842"]}],"id":[{"id":"10.13039\/100018699","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We developed a bottom-up, data-driven approach for constructing a time-informed adverse outcome pathway (AOP) network for environmental chemical-induced cardiotoxicity. Mechanistic end points were systematically extracted from 339 in vitro and in vivo studies, yielding 1759 Key Event (KE) entries and 4938 Key Event Relationship (KER) entries, together with study metadata and essentiality evidence from intervention experiments. After quality filtering and minimum support thresholding, 62 unique KEs and 256 unique KERs were retained for network construction. Network analysis highlighted oxidative stress and mitochondrial dysfunction as prominent, highly connected KEs linking diverse upstream perturbations to downstream cardiomyocyte injury, inflammation, cardiac remodeling (fibrosis and hypertrophy), decreased myocardial contractility, and reduced left ventricular function. A central methodological finding was that temporal information was more informative at the level of KERs than at the level of KEs. The same KE could occur across multiple durations depending on the relationship in which it was embedded, whereas KER-level time-scale annotation resolved distinct acute, subacute, and chronic pathway patterns not apparent from KE timing alone. This framework provides an evidence-weighted synthesis of the most consistently supported cardiotoxicity mechanisms and introduces a temporal layer for the mechanistic interpretation of heterogeneous evidence.<\/jats:p>","DOI":"10.1021\/acs.est.6c00396","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T22:01:36Z","timestamp":1790978496000},"page":"29273-29284","source":"Crossref","is-referenced-by-count":0,"title":["A Data-Driven Approach\nfor the Development of a Time-Informed\nAdverse Outcome Pathway Network for the Cardiotoxicity of Environmental\nChemicals"],"prefix":"10.1021","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8159-1292","authenticated-orcid":true,"given":"Alexandra","family":"Schaffert","sequence":"first","affiliation":[{"name":"Tampere University , , ,","place":["Tampere, Finland, 33100"]},{"name":"Medical University Innsbruck , , ,","place":["Innsbruck, Austria, 6020"]},{"name":"Tampere University , , ,","place":["Tampere, Finland, 33100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8414-0569","authenticated-orcid":true,"given":"Sivakumar","family":"Murugadoss","sequence":"additional","affiliation":[{"name":"NILU The Climate and Environmental Research Institute , , ,","place":["Kjeller, Norway, 2007"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5834-1209","authenticated-orcid":true,"given":"Tom","family":"Roos","sequence":"additional","affiliation":[{"name":"Utrecht University , , ,","place":["Utrecht, The Netherlands, 3584"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7289-3122","authenticated-orcid":true,"given":"Nunzia","family":"Linzalone","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council , ,","place":["Pisa, Italy, 56124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Donzelli","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology, National Research Council , ,","place":["Pisa, Italy, 56124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronette","family":"Gehring","sequence":"additional","affiliation":[{"name":"Utrecht University , , ,","place":["Utrecht, The Netherlands, 3584"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Mertens","sequence":"additional","affiliation":[{"name":"Sciensano , , ,","place":["Ixelles, Belgium, 1050"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8700-4834","authenticated-orcid":true,"given":"Martin","family":"Paparella","sequence":"additional","affiliation":[{"name":"Medical University Innsbruck , , ,","place":["Innsbruck, Austria, 6020"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"issue":"25","key":"2026102007514128800_cit1","doi-asserted-by":"publisher","first-page":"2372","DOI":"10.1016\/j.jacc.2022.11.001","article-title":"Global Burden of Cardiovascular Diseases and\nRisks Collaboration, 1990\u20132021","volume":"80","author":"Lindstrom","year":"2022","journal-title":"J. Am.\nColl. Cardiol."},{"issue":"1","key":"2026102007514128800_cit2","doi-asserted-by":"publisher","first-page":"102120","DOI":"10.1016\/j.cpcardiol.2023.102120","article-title":"The Impact\nof Environmental Toxins on Cardiovascular Diseases","volume":"49","author":"Shrivastav","year":"2024","journal-title":"Curr. Probl. Cardiol."},{"issue":"9","key":"2026102007514128800_cit3","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1161\/CIRCRESAHA.123.323613","article-title":"Environmental Impacts\non Cardiovascular Health and Biology: An Overview","volume":"134","author":"Blaustein","year":"2024","journal-title":"Circ. Res."},{"key":"2026102007514128800_cit4","unstructured":"U.S. Environmental Protection Agency.\n          . Particle Pollution\nand Cardiovascular Effects. 2025. https:\/\/www.epa.gov\/pmcourse\/particle-pollution-and-cardiovascular-effects (accessed Aug 17, 2025)."},{"issue":"2","key":"2026102007514128800_cit5","doi-asserted-by":"publisher","first-page":"337","DOI":"10.14573\/altex.2301121","article-title":"Cardiotoxicity\nof chemicals: Current regulatory guidelines, knowledge gaps, and needs","volume":"40","author":"Schaffert","year":"2023","journal-title":"ALTEX"},{"key":"2026102007514128800_cit6","unstructured":"Parcopedia.\n          .  Cardiotoxicity as a New Hazard Class: An\nOECD Working Party\non Hazard Assessment (WPHA) Initiative. 2024. https:\/\/www.parcopedia.eu\/cardiotoxicity-as-a-new-hazard-class-an-oecd-working-party-on-hazard-assessment-wpha-initiative\/(accessed Aug 17, 2025)."},{"issue":"7","key":"2026102007514128800_cit7","doi-asserted-by":"publisher","first-page":"226","DOI":"10.3390\/jcdd9070226","article-title":"Cardiotoxicity\nof Chemical Substances: An Emerging Hazard Class","volume":"9","author":"Georgiadis","year":"2022","journal-title":"J. Cardiovasc. Dev. Dis."},{"issue":"3","key":"2026102007514128800_cit8","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1002\/etc.34","article-title":"Adverse outcome pathways: a conceptual framework\nto support ecotoxicology research and risk assessment","volume":"29","author":"Ankley","year":"2009","journal-title":"Environ. Toxicol. 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Saf."},{"key":"2026102007514128800_cit31","article-title":"Users\u2019 Handbook supplement\nto the Guidance\nDocument for developing and assessing Adverse Outcome Pathways","volume-title":"OECD Series on Adverse Outcome Pathways, No. 1","author":"OECD.","year":"2018"},{"key":"2026102007514128800_cit32","article-title":"SKIG Report 2023\u20132024\n\u2013 Society for the Advancement of AOPs Knowledgebase Interest\nGroup; JRC140403","author":"Wittwehr","year":"2025"}],"container-title":["Environmental Science &amp;\nTechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.est.6c00396","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/esthag\/article-pdf\/60\/41\/29273\/68738496\/acs.est.6c00396.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/esthag\/article-pdf\/60\/41\/29273\/68738496\/acs.est.6c00396.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T12:09:26Z","timestamp":1792498166000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/esthag\/article\/60\/41\/29273\/5444134\/A-Data-Driven-Approach-for-the-Development-of-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,2]]},"references-count":32,"journal-issue":{"issue":"41","published-online":{"date-parts":[[2026,10,2]]},"published-print":{"date-parts":[[2026,10,20]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.est.6c00396","relation":{},"ISSN":["0013-936X","1520-5851"],"issn-type":[{"value":"0013-936X","type":"print"},{"value":"1520-5851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,2]]}}}