{
  "abstract": "Pyrethroid insecticides (PYRs) are widely used worldwide, and their primary metabolite, 3-phenoxybenzoic acid (3-PBA), serves as a near-ubiquitous biomarker of human exposure to PYRs. While epidemiological data consistently link urinary 3-PBA to increased cardiometabolic risk and coronary heart disease, the underlying electrophysiological mechanisms of its direct potential cardiotoxicity remain unexplored. Parent PYRs are known to exert cardiotoxic effects by enhancing the late sodium current (INa-L) and inducing arrhythmia, but the direct effect of 3-PBA on heart excitability has not been previously investigated. This study demonstrates that 3-PBA interacts with human cardiac Nav1.5 expressed in Human Embryonic Kidney (HEK293) cells, and significantly increases INa-L in a concentration-dependent manner with an EC50 of 51.3 ± 5.1 µM. The metabolite does not alter the voltage dependence of activation and inactivation, but it significantly delays the recovery from inactivation of the peak sodium current. In human induced pluripotent stem cell–derived cardiomyocytes (CM-hiPSCs) and adult rat ventricular myocytes, 3-PBA reduced maximal depolarization rate (dV/dt), indicating impaired depolarization dynamics and reduced peak sodium current. At the organ level, acute exposure in isolated rat hearts did not significantly alter standard ECG parameters. Collectively, these findings suggest that 3-PBA is not electrophysiologically inert but directly modulates cardiac sodium channel function, although at supraphysiological concentration. This provides new evidence of the biological activity of 3-PBA and suggests that its cardiotoxic potential may become clinically relevant under conditions of high dose and chronic exposure or in susceptible populations.\n\nGraphical Abstract:\n\nPyrethroid metabolite 3-phenoxybenzoic acid (3-PBA) increased the late sodium current in Nav1.5 expressed in Human embryonic kidney 293 and delayed the recovery from inactivation. Also, 3-PBA in relevant concentration to human toxicology reduced the maximal rate of action potential depolarization (dV/dt) in rat ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocyte. In the ECG of ex vivo heart preparation 3-PBA 1 μM caused non-effect. This provides evidence of the biological activity of 3-PBA and suggests that its cardiotoxic potential may become clinically relevant under conditions of high dose and chronic exposure or in susceptible populations. Created by Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 ativecommons.org/licenses/by/4.0/). Gemini 3.1 Pro was used to refine the layout and visual presentation of the graphical abstract. The authors reviewed, verified, and approved all generated content.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Cardiobiology, Department of Biophysics, São Paulo Federal University, São Paulo, Brazil",
    "Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, São Paulo Federal University, São Paulo, Brazil",
    "Laboratory of Heart Biophysics, Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe Brazil",
    "Laboratory of CardioBiology, Department of Biophysics, Federal University of São Paulo, Botucatu Street, 862, Biological Science Building, 7nd floor, São Paulo, Brazil"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Michael Ramon de Lima Conceição"
    },
    {
      "affs": [
        0
      ],
      "name": "Leisiane Pereira Marques"
    },
    {
      "affs": [
        0
      ],
      "name": "Fabiana da Silva Alcantara"
    },
    {
      "affs": [
        1
      ],
      "name": "Rafael Leite Tavares de Morais"
    },
    {
      "affs": [
        0
      ],
      "name": "Vinicius Fogaça-Santos"
    },
    {
      "affs": [
        0
      ],
      "name": "Diego Jose Belato Orts"
    },
    {
      "affs": [
        1
      ],
      "name": "João Bosco Pesquero"
    },
    {
      "affs": [
        2
      ],
      "name": "Diego Santos de Souza"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Danilo Roman-Campos"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/15nj1jef06ng6.bib",
  "cited_by": 0,
  "doi": "10.1007/s12012-026-10212-w",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13696605/",
  "id": "15nj1jef06ng6",
  "issns": [
    "1530-7905",
    "1559-0259"
  ],
  "landing_url": "https://doi.org/10.1007/s12012-026-10212-w",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2705|Cardiac electrophysiology and arrhythmias"
    ]
  ],
  "openalex": "W7223560641",
  "pdf_url": "https://europepmc.org/articles/PMC13696605?pdf=render",
  "pmcid": "PMC13696605",
  "pmid": "42928408",
  "published": "2026-10-25",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/15nj1jef06ng6.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:56Z",
      "native_id": "PMC13696605",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s12012-026-10212-w"
    },
    {
      "first_seen": "2026-10-30T12:21:18Z",
      "native_id": "MED:42928408",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42928408"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2705|Cardiac electrophysiology and arrhythmias",
      "subfield": "cardiovascular"
    }
  ],
  "title": "The Pesticide Pyrethroid Metabolite 3-Phenoxybenzoic Acid (3-PBA) Impairs Human Cardiac Nav1.5 and Action Potential Depolarization",
  "title_text": "The Pesticide Pyrethroid Metabolite 3-Phenoxybenzoic Acid (3-PBA) Impairs Human Cardiac Nav1.5 and Action Potential Depolarization",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:33:55Z",
  "url": "https://research.draconitic.com/paper/15nj1jef06ng6",
  "venue": "Cardiovascular Toxicology",
  "versions": []
}