The pesticide fungicide difenoconazole modulates the biophysical properties of sodium channel Nav1.5

IF 2.7 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro Pub Date : 2026-01-01 Epub Date: 2025-09-24 DOI:10.1016/j.tiv.2025.106152

V. Fogaça-Santos , F.S. Alcântara , M.R.L. Conceição , L.P. Marques , J.L. Teixeira-Fonseca , D.J.B. Orts , J. Branquinho , R.L. Morais , K.O. Mota , D.S. Souza , J.B. Pesquero , D. Roman-Campos

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引用次数: 0

Abstract

Difenoconazole (DIF) is a widely used fungicide in agriculture, but it is unknown if it can modulate the excitability of the heart tissue. Thus, we investigated the acute effect of DIF on the electrical properties of heart tissue, with a particular focus on the cardiac sodium channel (Na_v1.5) using transient expression of human Na_v1.5 in human kidney cell (HEK) and human cardiomyocytes derived from induced pluripotent stem cells (CM-hiPSCs). DIF reduced the peak amplitude of sodium current (I_Na) in a concentration dependent manner. While DIF did not alter the voltage dependence of activation, it shifted the I_Na inactivation curve to more negative potentials and delayed the recovery from inactivation. In silico simulation identified aminoacids Thr1710 and Val1765 as critical for the interaction between DIF with Na_v1.5. DIF partially blocked the late sodium current induced by deltamethrin, a pyrethroid pesticide, suggesting a potential interaction between these compounds in the environment. In CM-hiPSCs, DIF completely abolished the action potential. These findings suggest that DIF may modulate the biophysical properties of Na_v1.5 and modulate cellular excitability which may cause reduced heart excitability, an DIF can also counteracting the effects of pyrethroid pesticides, but further studies using DIF concentrations closer to human exposure levels are necessary.

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农药杀菌剂异苯唑调节钠通道Nav1.5的生物物理性质。

二苯醚康唑（DIF）是一种广泛应用于农业的杀菌剂，但它是否能调节心脏组织的兴奋性尚不清楚。因此，我们研究了DIF对心脏组织电学特性的急性影响，特别关注了钠通道（Nav1.5），通过在人肾细胞（HEK）和诱导多能干细胞（CM-hiPSCs）衍生的人心肌细胞中瞬时表达人Nav1.5。DIF以浓度依赖性的方式降低了钠电流（INa）的峰值幅度。虽然DIF没有改变激活的电压依赖性，但它使INa失活曲线向更多的负电位移动，并延迟了从失活恢复的时间。硅模拟鉴定出氨基酸Thr1710和Val1765对DIF与Nav1.5之间的相互作用至关重要。DIF部分阻断了溴氰菊酯（一种拟除虫菊酯类杀虫剂）诱导的后期钠电流，表明这些化合物在环境中可能存在相互作用。在CM-hiPSCs中，DIF完全消除了动作电位。这些发现表明，DIF可能调节Nav1.5的生物物理特性，并调节细胞兴奋性，从而可能导致心脏兴奋性降低，并且DIF还可以抵消拟除虫菊酯杀虫剂的影响，但需要使用更接近人类暴露水平的DIF浓度进行进一步研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.