The study of intestinal toxicity induced by gossypol acetic acid and the mechanism using zebrafish model and network toxicology.

Gossypol acetic acid (GAA), a natural product obtained from the cottonseed, has various bioactivities, including antiviral, anti-tumor and anti-inflammatory properties, among others. However, the potential intestinal toxicity of GAA is poorly studied. Here, the intestinal toxicity and the underlying mechanism were investigated in vivo using zebrafish and network toxicology. After exposure from 3 days post fertilization (dpf) to 6 dpf, GAA could notably affect the zebrafish gut barrier by reducing the microvilli and goblet cells, and subsequently affected the intestinal function, including decreasing the intestinal peristalsis and peristalsis number, endocytic capacity. In addition, GAA promoted the intestinal infiltration of neutrophil cells and cell death in the intestine. Furthermore, the mechanism study by network toxicology, molecular docking and RT-qPCR, showed that GAA could affect lipid metabolism, redox balance, apoptosis, inflammation and pyroptosis by regulating PPAR/NLRP3/GSDMD pathways. Taken together, these results will help to deeply understand GAA's harmful effects and underlying mechanisms.