Effects of Dichlorvos on cardiac cells: Toxicity and molecular mechanism of action.

Intidhar Ben Salem, Manel Boussabbeh, Julie Pires Da Silva, Nour Elhouda Saidi, Salwa Abid-Essefi, Christophe Lemaire

Chemosphere 2023 Jul

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In this study we aimed to understand the underlying mechanism of Dichlorvos-induced toxicity in cardiac cells. For this end, cells were treated by 170 μM of Dichlorvos (DDVP) (corresponding to the IC50) and molecular events were monitored by flow cytometry and western blotting. We have first demonstrated that cell exposure to DDVP for 24 h induced cell death by necroptosis. In fact, cell treatment with DDVP upregulated RIP1 expression and we have shown that chemical inhibition of RIP1 kinase activity by necrostatin-1 (Nec-1) greatly prevented from the induced cell death. Besides, we have demonstrated that, while there was no observed cell death following short exposure to DDVP (6 h), autophagy was enhanced, as proven by the increase in the level of both Beclin-1 and LC3-II and the accumulation of the CytoID® autophagy detection probe. Besides, when autophagy was inhibited by chloroquine (CQ) the percentage of necroptosis was significantly increased, suggesting that autophagy acts to protect cardiac cells against the toxicity induced by this pesticide. Concurrently, we have shown that the inhibition of the deacetylase sirtuin 1 (SIRT1) by EX527 or its knockdown by siRNA significantly increased DDVP-induced necroptosis, whereas when SIRT1 was activated by resveratrol (RSV) a significant decrease in DDVP-induced cell death was observed. In addition, we revealed that when the autophagy was inhibited by CQ, we can't reveal the protective effect of RSV anymore. Altogether, these results suggest that activation of SIRT1 protects cardiac cells from the toxicity of DDVP through an autophagy-dependent pathway. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Intidhar Ben Salem, Manel Boussabbeh, Julie Pires Da Silva, Nour Elhouda Saidi, Salwa Abid-Essefi, Christophe Lemaire. Effects of Dichlorvos on cardiac cells: Toxicity and molecular mechanism of action. Chemosphere. 2023 Jul;330:138714