Potential Common Mechanisms of Cytotoxicity Induced by Organophosphorus Pesticides via NLRP3 Inflammasome Activation

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1β, IL-18), in which the order of cytotoxicity was dichlorvos > dipterex > dibrom > paraoxon > fenthion > dimethoate, based on the IC 50 values of 274, 410, 551, 585, 2,158, and 1,527,566 μM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1β, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate > paraoxon > dichlorvos > dibrom > (fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690 μM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning. Key Points The NLRP3 inflammasome potentially contributes to cytotoxicity induced by six types of OPPs Inhibition of the NLRP3 pathway effectively prevented cytotoxicity caused by six OPPs The study proposed targets for broad-spectrum antitoxic drugs to prevent OPPs-poisoning Plain Language Summary This study aimed to explore the role of Nod-like receptor 3 (NLRP3) inflammasome activation in organophosphorus pesticide (OPPs)-induced cytotoxicity. Six different OPPs, including dimethoate, paraoxon, dichlorvos, dibrom, fenthion, and dipterex, were introduced to BV2 cells and caused significant cytotoxicity along with increased expression of NLRP3 inflammasome complexes and downstream cytokines. Inversely, inhibition of NLRP3 protected against these OPPs. We believe that our study makes a significant contribution to the literature because it suggests that the NLRP3 inflammasome pathway may be a common mechanism of multi-OPPs-induced cytotoxicity. By introducing a therapeutic target for OPPs poisoning prevention, broad-spectrum antitoxic drugs may be designed to effectively protect against OPPs-induced cytotoxicity.