The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells

Author(s)

Santos-Miranda, Artur ; Joviano-Santos, V. Julliane ; Cruz-Nascimento, Taynara ; Neri, Elida Adalgisa ; Souza, Diego Santos ; Marques, Leisiane Pereira ; Krieger, Jose E. ; Roman-Campos, Danilo

• Document type: Journal article
• Source: Toxicology Letters; v. 359, p. 10-pg., 2022-04-15.

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 mu mol.l(-1)) and total outward potassium current (IC50 = 5.7 +/- 1.5 mu mol.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 mu mol.l(-1). Combined, our results demonstrated that acute TEB exposure affects the cardiomyocyte's electrocontractile properties and triggers the appearance of ECG abnormalities. (AU)

• FAPESP's process: 18/22830-9 - Involvement of the Ca2+/ Calmodulin/CAMKII signaling axis in the electrical and contractile dysfunctions of the heart in the chronic phase of Chagas Disease
• Grantee: Artur Santos Miranda
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/18918-0 - Role of nitric oxide in cardiac arrhythmias during Hypothyroidism
• Grantee: Diego Santos de Souza
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/05584-7 - Assessment of acute and chronic toxicity of the heart and brain exposed to pesticides found in potable water in Brazil
• Grantee: Danilo Roman Campos
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 19/21304-4 - Arrhythmogenic mechanisms in right heart diseases
• Grantee: Danilo Roman Campos
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/14635-1 - Modeling of monogenic diseases for physiopathological studies and pharmacological tests using specialized cells derived from iPSCs
• Grantee: João Bosco Pesquero
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/20777-3 - Genetic variants of the Nav 1.5 sodium channel and its therapeutic implications.
• Grantee: Julliane Vasconcelos Joviano dos Santos
• Support Opportunities: Scholarships in Brazil - Post-Doctoral