{
  "abstract": "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.",
  "abstract_shown": true,
  "affiliations": [
    "Mechanistic and Applied Toxicology (MAT), Faculty of Medicine and Health Technology, Tampere University, 33100Tampere, Finland.",
    "Institute of Medical Biochemistry, Medical University Innsbruck, 6020Innsbruck, Austria.",
    "Tampere Institute for Advanced Study, Tampere University, 33100Tampere, Finland.",
    "Health Effects Laboratory, Department of Environmental Chemistry and Health Effects, NILU The Climate and Environmental Research Institute, 2007Kjeller, Norway.",
    "Department of Population Health Sciences, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, 3584Utrecht, The Netherlands.",
    "Institute of Clinical Physiology, National Research Council, 56124Pisa, Italy.",
    "Scientific Department of Chemical and Physical Health Risks, Sciensano, 1050Ixelles, Belgium."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Alexandra Schaffert",
      "orcid": "0000-0001-8159-1292"
    },
    {
      "affs": [
        3
      ],
      "name": "Sivakumar Murugadoss",
      "orcid": "0000-0001-8414-0569"
    },
    {
      "affs": [
        4
      ],
      "name": "Tom Roos",
      "orcid": "0000-0002-5834-1209"
    },
    {
      "affs": [
        5
      ],
      "name": "Nunzia Linzalone",
      "orcid": "0000-0002-7289-3122"
    },
    {
      "affs": [
        5
      ],
      "name": "Gabriele Donzelli"
    },
    {
      "affs": [
        4
      ],
      "name": "Ronette Gehring"
    },
    {
      "affs": [
        6
      ],
      "name": "Birgit Mertens"
    },
    {
      "affs": [
        1
      ],
      "name": "Martin Paparella",
      "orcid": "0000-0002-8700-4834"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6d4ehaswne2bg.bib",
  "cited_by": 0,
  "doi": "10.1021/acs.est.6c00396",
  "fulltext_url": "https://europepmc.org/articles/PMC13689818",
  "id": "6d4ehaswne2bg",
  "issns": [
    "0013-936X",
    "1520-5851"
  ],
  "landing_url": "https://europepmc.org/article/MED/42899643",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2307|Environmental Toxicology and Ecotoxicology"
    ]
  ],
  "openalex": "W7216003411",
  "pdf_url": "https://europepmc.org/articles/PMC13689818?pdf=render",
  "pmcid": "PMC13689818",
  "pmid": "42899643",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/6d4ehaswne2bg.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:37Z",
      "native_id": "MED:42899643",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42899643"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2307|Environmental Toxicology and Ecotoxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "A Data-Driven Approach for the Development of a Time-Informed Adverse Outcome Pathway Network for the Cardiotoxicity of Environmental Chemicals.",
  "title_text": "A Data-Driven Approach for the Development of a Time-Informed Adverse Outcome Pathway Network for the Cardiotoxicity of Environmental Chemicals.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:37Z",
  "url": "https://research.draconitic.com/paper/6d4ehaswne2bg",
  "venue": "Environmental science & technology",
  "versions": []
}