The pesticide fungicide difenoconazole modulates the biophysical properties of sodium channel Nav1.5.

Difenoconazole (DIF) is a widely used fungicide in agriculture, but it is unknown if it can modulate the excitability of the heart tissue. Thus, we investigated the acute effect of DIF on the electrical properties of heart tissue, with a particular focus on the cardiac sodium channel (Nav1.5) using transient expression of human Nav1.5 in human kidney cell (HEK) and human cardiomyocytes derived from induced pluripotent stem cells (CM-hiPSCs). DIF reduced the peak amplitude of sodium current (INa) in a concentration dependent manner. While DIF did not alter the voltage dependence of activation, it shifted the INa inactivation curve to more negative potentials and delayed the recovery from inactivation. In silico simulation identified aminoacids Thr1710 and Val1765 as critical for the interaction between DIF with Nav1.5. DIF partially blocked the late sodium current induced by deltamethrin, a pyrethroid pesticide, suggesting a potential interaction between these compounds in the environment. In CM-hiPSCs, DIF completely abolished the action potential. These findings suggest that DIF may modulate the biophysical properties of Nav1.5 and modulate cellular excitability which may cause reduced heart excitability, an DIF can also counteracting the effects of pyrethroid pesticides, but further studies using DIF concentrations closer to human exposure levels are necessary.