Mechanistic insights into pyraclostrobin-induced hepatotoxicity in zebrafish via the gut-liver axis

Pyraclostrobin dysregulates bile acid homeostasis via the gut-liver axis. • Pyraclostrobin disrupts hepatic arachidonic acid steroid and metabolism. • Gut microbiota dysbiosis exacerbates pyraclostrobin hepatotoxicity. • Docking results confirm the inhibition of CYP7A1 and BSEP by pyraclostrobin. Pyraclostrobin is one of the most widely used fungicides globally; however, the mechanisms underlying its hepatotoxicity at environmentally relevant concentrations remain poorly understood. This study demonstrates that exposure to pyraclostrobin at environmentally relevant concentrations (15 and 30 μg/L) induces liver injury in zebrafish by disrupting the homeostasis of the gut-liver axis and bile acid metabolism. The results showed that aquatic exposure to pyraclostrobin at these concentrations leads to the substantial accumulation in the liver and gut tissues of zebrafish. This accumulation caused hepatic vacuolation and dysfunction, intestinal villi defects, impaired gut barrier function, and a significant upregulation of proinflammatory cytokines, including TNF-alpha and IL-1 beta. Integrated multi-omics analysis revealed that pyraclostrobin exposure disrupted arachidonic acid metabolism and steroid hormone biosynthesis in the liver, induced gut microbiota dysbiosis, and exacerbated hepatic immune and metabolic dysfunction by modulating bile acid cycling through the gut-liver axis. Molecular docking studies suggested possible interactions between pyraclostrobin and both the rate-limiting enzyme in bile acid synthesis (cholesterol 7α-hydroxylase; CYP7A1) and the bile salt export pump (BSEP), potentially contributing to bile acid metabolic disorders. This study identifies a novel mechanism through which environmentally relevant concentrations of pyraclostrobin induce liver injury via bile acid accumulation and inflammatory responses through the gut-liver axis. It highlights the necessity of assessing the long-term exposure risks of pyraclostrobin to nontarget organisms at realistic environmental concentrations. Download: Download high-res image (281KB) Download: Download full-size image