The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells. (15th April 2022)

• Record Type: Journal Article
• Authors: Santos-Miranda, Artur; Joviano-Santos, Julliane V.; Cruz-Nascimento, Taynara; Neri, Elida Adalgisa; Souza, Diego Santos; Marques, Leisiane Pereira; Krieger, Jose E.; Roman-Campos, Danilo
• Is Part Of: Toxicology letters. Volume 359(2022)
• Page Start: 96
• Page End: 105
• Publication Date: 2022-04-15
• Subjects: Tebuconazole -- Heart -- Electrocardiogram -- Patch-clamp -- Action potential -- Arrhythmia; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2022.02.005
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is widely used in agriculture and its use has experienced a tremendous increase in the last decade. The long-term exposure of humans to this pesticide is a real threat because it is stable in water and soil. The association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity is evident, however, acute toxicological studies to reveal the toxicity of TEB are limited. This research paper addressed the acute exposure of TEB in murine hearts, cardiomyocytes, and human cardiomyocytes derived from an induced pluripotent stem cell (hiPSC-CMs), spelling out TEB's impact on electromechanical properties of the cardiac tissue. In ex vivo experiments, TEB dose dependently, caused significant electrocardiogram (ECG) remodeling with prolonged PR and QTc interval duration. The TEB was also able to change the action potential waveform in murine cardiomyocytes and hiPSC-CMs. These effects were associated with the ability of the compound to block the L-type calcium current (IC50 = 33.2 ± 7.4 μmol.l −1 ) and total outward potassium current (IC50 = 5.7 ± 1.5 μmol.l −1 ). TEB also increased the sodium/calcium exchanger current in its forward and reverse modes. Additionally, sarcomere shortening and calcium transient in isolated cardiomyocytes were enhanced when cells were exposed to TEB at 30 μmol.l −1 . Combined, our results demonstrated that acute TEB exposure affects the cardiomyocyte's electro-contractile properties and triggers the appearance of ECG abnormalities.