# Integrated Network Toxicology and Metabolomics Reveal the Ovarian Toxicity Mechanisms of Chronic Carbofuran Exposure in Female Mice

## TL;DR

This study explores how chronic exposure to the pesticide carbofuran causes ovarian damage in female mice, revealing mechanisms involving endocrine disruption and metabolic changes.

## Contribution

The study introduces a novel integration of network toxicology and metabolomics to uncover carbofuran's ovarian toxicity mechanisms.

## Key findings

- Carbofuran exposure caused dose-dependent ovarian damage, including reduced follicular reserve and disrupted hormone levels.
- Network toxicology identified 38 targets, with EGFR, GSK3B, APP, and JAK2 as core proteins showing high affinity.
- Metabolomics revealed altered pathways in amino acid biosynthesis and arginine/proline metabolism.

## Abstract

Carbofuran, a widely used carbamate pesticide, is an endocrine disruptor with documented reproductive toxicity, yet the mechanisms underlying its ovarian toxicity remain incompletely understood. This study employed integrated network toxicology and untargeted metabolomics to investigate these mechanisms in female C57BL/6J mice that had been chronically exposed to carbofuran (0.5 or 2.0 mg/kg for 45 days, once daily). Methods included histopathological evaluation, serum hormone ELISA, network prediction of toxicity targets, molecular docking, and metabolomics profiling. Results demonstrated that carbofuran exposure induced dose-dependent ovarian damage, including reduced follicular reserve, increased atresia, abnormal corpus luteum, and disrupted hormone levels. Network toxicology identified 38 common targets, with EGFR, GSK3B, APP, and JAK2 as core proteins, indicating potential high affinity. Metabolomics suggests significant alterations in pathways such as phenylalanine, tyrosine, tryptophan biosynthesis and arginine/proline metabolism. Our collective evidence indicates that carbofuran may induce ovarian toxicity through multifaceted mechanisms involving endocrine disruption, oxidative stress, inflammatory activation, and metabolic disturbance. This study provides novel experimental insights into the reproductive toxicity mechanisms of carbofuran, offering a theoretical basis for health risk assessment and intervention strategies.