The Pesticide Pyrethroid Metabolite 3-Phenoxybenzoic Acid (3-PBA) Impairs Human Cardiac Nav1.5 and Action Potential Depolarization

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.