Chronic exposure to environmentally relevant Bisphenol F induces hepatic injury and inflammation in Zebrafish.

Bisphenol F (BPF), a major substitute for bisphenol A (BPA), has raised safety concerns. To evaluate its hepatotoxicity at environmentally relevant concentrations, zebrafish larvae (5-day exposure) and adults (120-day exposure) were exposed to 2, 20, and 200 μg/L BPF. BPF exposure inhibited liver development in larvae, as evidenced by reduced liver area, and to trigger inflammatory responses, as shown by increased neutrophil counts. BPF also altered the expression of inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) and liver function-associated genes. In adult zebrafish, chronic exposure resulted in liver injury, characterized by histopathological changes, altered gene expression, and elevated ALT/AKP levels. Using network toxicology, 103 common targets between BPF exposure and liver injury were identified. Subsequent PPI network and functional enrichment analyses implicated the Toll-like receptor signaling pathway. TLR4 was validated as a direct BPF target through molecular docking, and its inhibition successfully reduced the inflammatory response. These findings indicate that chronic exposure to environmentally relevant BPF induces hepatic injury and inflammation in zebrafish across life stages, providing critical evidence for BPF ecological risk assessment.