2026-10-09T20:58:50Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34059593 2026-10-02T21:03:47Z category_7 category_12 category_272 category_734 category_132 portal_63 item_type_3 month_year_10_2026

A Data-Driven Approach for the Development of a Time-Informed Adverse Outcome Pathway Network for the Cardiotoxicity of Environmental Chemicals Alexandra Schaffert (18805524) Sivakumar Murugadoss (8223108) Tom Roos (25303637) Nunzia Linzalone (25303640) Gabriele Donzelli (25303643) Ronette Gehring (1598206) Birgit Mertens (18057790) Martin Paparella (15358214) Medicine Cell Biology Environmental Sciences not elsewhere classified Biological Sciences not elsewhere classified Infectious Diseases minimum support thresholding downstream cardiomyocyte injury chronic pathway patterns central methodological finding mechanistic end points ke timing alone 62 unique kes 256 unique kers mechanistic interpretation weighted synthesis vivo studies temporal layer temporal information systematically extracted study metadata quality filtering mitochondrial dysfunction intervention experiments framework provides environmental chemicals environmental chemical driven approach cardiac remodeling 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. 2026-10-02T00:00:00Z Dataset Dataset 10.1021/acs.est.6c00396.s003 https://figshare.com/articles/dataset/A_Data-Driven_Approach_for_the_Development_of_a_Time-Informed_Adverse_Outcome_Pathway_Network_for_the_Cardiotoxicity_of_Environmental_Chemicals/34059593 CC BY-NC 4.0