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

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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
Total Authors: 8
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