Unveiling the toxicity and mechanisms of 2,4-dichlorophenoxyacetic acid in hypertension: a molecular-level perspective

2,4-dichlorophenoxyacetic acid (2,4-D), a common herbicide, is widely used in agricultural activities. Prolonged and low-level exposure to 22,4-D increases the likelihood of adverse effects on human health. Nonetheless, the intricate toxicological mechanisms behind its influence on hypertension remain poorly understood. This study utilized ADMET, network toxicology, molecular docking, molecular dynamics, and gut microbiota analyses to explore the toxicological mechanisms underlying hypertension induced by 2,4-D. Common targets of 2,4-D and hypertension were retrieved from ChEMBL, SwissTargetPrediction, GeneCards, and OMIM databases. The ADMETlab (2.0) database was utilized to conduct ADMET analysis, which indicated potential health risks associated with 2,4-D. Eighteen potential targets associated with the toxicity of 2,4-D in relation to hypertension were identified and subsequently narrowed down to five key targets: ACE, REN, TNF, PPARG, and ADRB2 via STRING database and Cytoscape software. Enrichment analyses through GO and KEGG revealed that 2,4-D primarily affects renin secretion and the renin-angiotensin system in its hypertensive toxicity. Molecular docking analysis results showed that 2,4-D has significant binding affinities with both ACE and REN. Molecular dynamics simulations indicated that the structural stability of the ACE-2,4-D complex was notably higher than that of the REN-2,4-D complex. Finally, 2,4-D may also interact with gut microbiota and their metabolites, potentially influencing TNF and PPARG pathways and contributing to the development of hypertension. This research offers a thorough assessment using computational techniques on the toxic effects of 2,4-D on hypertension, presenting approaches for systematically evaluating the health risks posed by 2,4-D.