Background: The toxicity of silica nanoparticles (SiNPs) on cardiac electrophysiology has seldom been evaluated.
Methods: Patch-clamp was used to investigate the acute effects of SiNP-100 (100 nm) and SiNP-20 (20 nm) on the transmembrane potentials (TMPs) and ion channels in cultured neonatal mouse ventricular myocytes. Calcium mobilization in vitro, cardiomyocyte ROS generation, and LDH leakage after exposure to SiNPs in vitro and in vivo were measured using a microplate reader. Surface electrocardiograms were recorded in adult mice to evaluate the arrhythmogenic effects of SiNPs in vivo. SiNP endocytosis was observed using transmission electron microscopy.
Results: Within 30 min, both SiNPs (10^{− 8}– 10^{− 6} g/mL) did not affect the resting potential and I_K1 channels. SiNP-100 increased the action potential amplitude (APA) and the I_Na current density, but SiNP-20 decreased APA and I_Na density. SiNP-100 prolonged the action potential duration (APD) and decreased the I_to current density, while SiNP-20 prolonged or shortened the APD, depending on exposure concentrations and increased I_to density. Both SiNPs (10^{− 6} g/mL) induced calcium mobilization but did not increase ROS and LDH levels and were not endocytosed within 10 min in cardiomyocytes in vitro. In vivo, SiNP-100 (4– 10 mg/kg) and SiNP-20 (4– 30 mg/kg) did not elevate myocardial ROS but increased LDH levels depending on dose and exposure time. The same higher dose of SiNPs (intravenously injected) induced tachyarrhythmias and lethal bradyarrhythmias within 90 min in adult mice.
Conclusion: SiNPs (i) exert rapid toxic effects on the TMPs of cardiomyocytes in vitro largely owing to their direct interfering effects on the I_Na and I_to channels and Ca²⁺ homeostasis but not I_K1 channels and ROS levels, and (ii) induce tachyarrhythmias and lethal bradyarrhythmias in vivo. SiNP-100 is more toxic than SiNP-20 on cardiac electrophysiology, and the toxicity mechanism is likely more complicated in vivo.
Keywords: silica nanoparticle, cardiac electrophysiology, transmembrane potential, ion channel, nanotoxicology