Silica Nanoparticles Disturb Ion Channels and Transmembrane Potentials of Cardiomyocytes and Induce Lethal Arrhythmias in Mice.

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 Ca ²⁺ 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.
Competing Interests: The authors report no conflicts of interest in this work.
(© 2020 Liu et al.)