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

3-PBA significantly increases the late sodium current (INa-L) of human cardiac Nav1.5 expressed in HEK293 cells in a concentration-dependent manner.

• The EC50 for the INa-L increase was 51.3 ± 5.1 µM.
• Nav1.5 was expressed in HEK293 cells and studied electrophysiologically.
• Parent pyrethroids are known to enhance INa-L, and this result shows the metabolite also interacts with the channel.

3-PBA did not alter the voltage dependence of Nav1.5 activation or inactivation.

• The abstract states the metabolite 'does not alter the voltage dependence of activation and inactivation'.
• The effects were therefore on other gating properties, such as late current and recovery from inactivation.

3-PBA significantly delays the recovery from inactivation of the peak sodium current.

• This effect occurred even though steady-state activation and inactivation curves were unchanged.
• Slower recovery would be expected to reduce channel availability at higher rates of stimulation.

3-PBA reduced the maximal depolarization rate (dV/dt) of the action potential in human iPSC-derived cardiomyocytes and adult rat ventricular myocytes.

• The reduction in dV/dt indicates impaired depolarization dynamics and reduced peak sodium current.
• Effects were observed in both CM-hiPSCs and adult rat ventricular myocytes, i.e., in a human-derived and a native adult cardiac cell model.

Acute 3-PBA exposure in isolated rat hearts did not significantly alter standard ECG parameters.

• The experiments were performed at the organ level in isolated (ex vivo) rat hearts.
• No significant changes were reported in standard ECG parameters after acute exposure.

The authors conclude that 3-PBA is not electrophysiologically inert and directly modulates cardiac sodium channel function, but at supraphysiological concentrations.

• The EC50 of ~51 µM is higher than concentrations typical of human exposure, hence 'supraphysiological'.
• The authors suggest that cardiotoxic potential may become clinically relevant under high-dose and chronic exposure or in susceptible populations.
• The work addresses a gap: epidemiological studies link urinary 3-PBA to cardiometabolic risk and coronary heart disease, but direct electrophysiological mechanisms were unexplored.