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<p>Aldrin, an organochlorine pesticide (insecticide), is almost completely banned around the world, but its chemical stability favors the detection in countries in which it was already banned. The toxicity of Aldrin to mammals is already document, mostly related to the central nervous system involvement, including mechanisms such as apoptosis and GABAergic inhibition. However the cardiotoxicity of Aldrin is poorly explored. Here, we evaluated the acute toxicity of Aldrin to the heart excitability, focusing on the involvement of the cardiac sodium channel, Na<sub>v</sub>1.5. Using isolated ex vivo mice preparation in a concentration-dependent manner Aldrin changed the&#xa0;electrocardiogram&#xa0;(ECG) of mice, increasing the PR, QRS and QT interval. Also, Aldrin increased the action potential (AP) duration and reduced the maximal velocity of AP depolarization from mice ventricular cardiomyocyte and also from human cardiomyocyte derived from induced pluripotent stem cell. Using heterologous expression system to express the human isoform of Na<sub>v</sub>1.5, in a concentration dependent manner, Aldrin reduced the peak amplitude of sodium current (I<sub>Na</sub>). Notably, Aldrin shifted the inactivation curve to more hyperpolarized potential, indicating increased channel inactivation at more negative voltages, and also displayed a use and a voltage-dependency to I<sub>Na</sub> block. Interesting, Aldrin did not change the activation parameters of Nav1.5, neither the recovery from inactivation and also did not display enhanced interaction with the closed-state inactivation mode of Na<sub>v</sub>1.5. Using docking simulation, Aldrin interacted with critical residues involved in the gating properties of I<sub>Na</sub>. Thus, Aldrin causes acute electrical cardiotoxicity to mammals, in nanomolar range, suggesting that monitoring the presence of Aldrin in communities that use this compound may be necessary.</p>

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Acute electro cardiotoxicity of pesticide Aldrin: unexpected role of Nav1.5

  • 期刊论文

  • 发表日期：

    2025年7月1日

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  • Diego Santos Souza,
  • Samuel Santos Beserra,
  • Leisiane Pereira Marques,
  • Michael Ramon de Lima Conceição,
  • Artur Santos-Miranda,
  • Karina Oliveira Mota,
  • Aimée Obolari Durço,
  • Vinicius Fogaça-Santos,
  • Jorge Lucas Teixeira-Fonseca,
  • Elida Adalgisa Neri,
  • Jose E. Krieger,
  • Danilo Roman-Campos

摘要

Aldrin, an organochlorine pesticide (insecticide), is almost completely banned around the world, but its chemical stability favors the detection in countries in which it was already banned. The toxicity of Aldrin to mammals is already document, mostly related to the central nervous system involvement, including mechanisms such as apoptosis and GABAergic inhibition. However the cardiotoxicity of Aldrin is poorly explored. Here, we evaluated the acute toxicity of Aldrin to the heart excitability, focusing on the involvement of the cardiac sodium channel, Nav1.5. Using isolated ex vivo mice preparation in a concentration-dependent manner Aldrin changed the electrocardiogram (ECG) of mice, increasing the PR, QRS and QT interval. Also, Aldrin increased the action potential (AP) duration and reduced the maximal velocity of AP depolarization from mice ventricular cardiomyocyte and also from human cardiomyocyte derived from induced pluripotent stem cell. Using heterologous expression system to express the human isoform of Nav1.5, in a concentration dependent manner, Aldrin reduced the peak amplitude of sodium current (INa). Notably, Aldrin shifted the inactivation curve to more hyperpolarized potential, indicating increased channel inactivation at more negative voltages, and also displayed a use and a voltage-dependency to INa block. Interesting, Aldrin did not change the activation parameters of Nav1.5, neither the recovery from inactivation and also did not display enhanced interaction with the closed-state inactivation mode of Nav1.5. Using docking simulation, Aldrin interacted with critical residues involved in the gating properties of INa. Thus, Aldrin causes acute electrical cardiotoxicity to mammals, in nanomolar range, suggesting that monitoring the presence of Aldrin in communities that use this compound may be necessary.