Cao_2026_Environ.Pollut__128127

As an antifouling agent, tributyltin (TBT) is widely used in marine anti-fouling coatings. Recent studies have demonstrated that TBT exerts toxic effects on aquatic life and can be transferred to humans via the food chain. In this study, we investigated the impact of varying TBT concentrations on the brain and heart of zebrafish, as well as the underlying mechanisms involved. These findings suggest that TBT exposure caused varying degrees of oxidative stress in the brain and heart of zebrafish, increased lipid peroxidation levels, and induced inflammatory responses, apoptosis, and histopathological damage. Additionally, TBT exposure altered zebrafish behavior, significantly reduced the expression of tight junction protein genes (zo-1, occludin, and claudin-2) in the gut and brain, and suppressed acetylcholinesterase (AChE) activity in the brain. Untargeted metabolomics and gut microbiome analysis revealed that TBT exposure significantly altered the abundance and diversity of microbial communities, leading to metabolic disturbances, with the primary differential metabolites associated with nucleotide, glycerophospholipid, and purine metabolism. Gut microbiota dysbiosis was also strongly correlated with neuro-cardiovascular toxicological responses in zebrafish. Dysbiosis increased lipopolysaccharide (LPS) secretion. In the context of blood-brain barrier disruption, circulating LPS may reach the brain, potentially contributing to neuroinflammation and subsequent neural damage. Concurrently, elevated inflammatory cytokines were associated with activation of the hypothalamic-pituitary-interrenal (HPI) axis, increasing cortisol (Cor) levels, and correlating with cardiovascular system damage. Network toxicology and molecular docking analysis revealed that strong binding affinities between TBT and core targets, including BCL2, GAPDH, IL1B, IL6, TNF, and MMP9.