The Pesticide Pyrethroid Metabolite 3-Phenoxybenzoic Acid (3-PBA) Impairs Human Cardiac Nav1.5 and Action Potential Depolarization
4 affiliations
- 1Laboratory of Cardiobiology, Department of Biophysics, São Paulo Federal University, São Paulo, Brazil
- 2Center for Research and Molecular Diagnostic of Genetic Diseases, Department of Biophysics, São Paulo Federal University, São Paulo, Brazil
- 3Laboratory of Heart Biophysics, Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe Brazil
- 4Laboratory of CardioBiology, Department of Biophysics, Federal University of São Paulo, Botucatu Street, 862, Biological Science Building, 7nd floor, São Paulo, Brazil
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.
Graphical Abstract:
Pyrethroid 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.
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BibTeX
@article{conceicao2026pesticide,
title = {{The Pesticide Pyrethroid Metabolite 3-Phenoxybenzoic Acid (3-PBA) Impairs Human Cardiac Nav1.5 and Action Potential Depolarization}},
author = {Michael Ramon de Lima Conceição and Leisiane Pereira Marques and Fabiana da Silva Alcantara and Rafael Leite Tavares de Morais and Vinicius Fogaça-Santos and Diego Jose Belato Orts and João Bosco Pesquero and Diego Santos de Souza and Danilo Roman-Campos},
journal = {Cardiovascular Toxicology},
year = {2026},
month = oct,
doi = {10.1007/s12012-026-10212-w},
url = {https://doi.org/10.1007/s12012-026-10212-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The Pesticide Pyrethroid Metabolite 3-Phenoxybenzoic Acid (3-PBA) Impairs Human Cardiac Nav1.5 and Action Potential Depolarization
AU - Michael Ramon de Lima Conceição
AU - Leisiane Pereira Marques
AU - Fabiana da Silva Alcantara
AU - Rafael Leite Tavares de Morais
AU - Vinicius Fogaça-Santos
AU - Diego Jose Belato Orts
AU - João Bosco Pesquero
AU - Diego Santos de Souza
AU - Danilo Roman-Campos
PY - 2026
DA - 2026/10/25
JO - Cardiovascular Toxicology
DO - 10.1007/s12012-026-10212-w
UR - https://doi.org/10.1007/s12012-026-10212-w
AB - 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. Graphical Abstract: Pyrethroid 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.
SN - 1530-7905
SN - 1559-0259
ER -