Network toxicology reveals mechanisms of Endosulfan-induced lung injury.

OBJECTIVE

Endosulfan, an organochlorine pesticide, consists of two isomers (α-Endosulfan and β-Endosulfan) and a primary metabolite, Endosulfan sulfate (END-SO4). Due to its pervasive environmental contamination and harmful effects-such as neurotoxicity, endocrine disruption, and reproductive toxicity in humans-END was included in the Stockholm Convention on Persistent Organic Pollutants (Annex A) in 2011, leading to its prohibition in many regions. The toxic effects of END have been extensively studied, but the specific mechanism of its lung injury remains unknown. This study explores how α/β-Endosulfan and END-SO4 may induce lung injury using in silico approaches.

METHODS

Toxicity prediction was performed using STopTox, ADMETlab 3.0, and Deep-PK. Network toxicology analyses were conducted via the Comparative Toxicogenomic Database, DAVID, Metascape, GeneMANIA, STRING, and Cytoscape. AUTODOCK was used for molecular docking of α/β-END and END-SO4 with key targets.

RESULTS

The study identified 4658 targets for α/β-END and 21 for END-SO4, with 126 linked to lung injury. Of these, 53 targets were common to both the compounds and lung injury, primarily associated with inflammation and fibrosis. Centrality analysis highlighted IL1B, TNF, and IL6 as key targets. Docking results showed binding affinities ranging from -4.53 to -8.32 kcal/mol between α/β-END, END-SO4, and IL1B/TNF.

CONCLUSION

These findings suggest that exposure to α/β-END and END-SO4 may trigger inflammation and fibrosis, contributing to lung injury. These findings provide a basis for further experimental studies aimed at validating the role of IL1B and TNF in α/β-END-induced lung injury.