Integrated Network Toxicology and Metabolomics Elucidate Mechanisms of Carbosulfan-Induced Respiratory Toxicity in Rats

TL;DR

This study explores how the insecticide carbosulfan causes lung damage in rats by combining network toxicology, metabolomics, and molecular docking to identify key pathways and targets involved in respiratory toxicity.

Contribution

The study introduces a novel system-level approach integrating network toxicology and metabolomics to elucidate mechanisms of carbosulfan-induced respiratory toxicity.

Findings

Carbosulfan exposure caused lung damage and elevated pro-inflammatory cytokines in rats.

Network toxicology identified 51 potential targets, including SRC, EGFR, and CYP3A4, linked to respiratory toxicity.

Metabolomics revealed disruptions in antioxidant defense and energy metabolism pathways.

Abstract

Carbosulfan is a widely used carbamate insecticide, yet its mechanisms of respiratory toxicity remain poorly understood. This study integrated network toxicology, untargeted metabolomics, and molecular docking to systematically investigate the potential mechanisms of carbosulfan-induced respiratory toxicity in male Sprague Dawley rats. Rats were administered a single oral dose of carbosulfan (125 or 250 mg/kg) and assessed after 12 h. Exposure resulted in significant pathological lung damage, characterized by disrupted alveolar architecture, inflammatory cell infiltration, and increased serum levels of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α. Network toxicology analysis identified 51 potential targets associated with respiratory toxicity, with core targets including SRC, EGFR, PTGS2, CXCL8, CYP3A4, and NR3C1. Enriched pathways were primarily related to neuroactive ligand–receptor interaction, VEGF signaling, and arachidonic acid metabolism. Untargeted metabolomics revealed significant metabolic perturbations in pathways central to antioxidant defense and energy homeostasis, including glutathione metabolism, the tricarboxylic acid cycle, and arginine biosynthesis. Molecular docking confirmed stable in silico binding affinities between carbosulfan and the predicted core targets. Integrative analysis suggests that carbosulfan exposure is associated with respiratory damage, potentially through interconnected mechanisms involving oxidative stress, inflammation, and disruption of cell signaling and metabolic enzyme systems. However, given the acute high-dose nature of the model and the interpretative integration of multi-omics data, these findings should be considered hypothesis-generating. This study provides a novel system-level perspective on carbosulfan-induced respiratory toxicity and highlights key pathways and targets for future validation in chronic exposure models.

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