Exemestane induces liver toxicity in zebrafish larvae by upregulating the p53 signaling pathway

Exemestane is an aromatase inhibitor that is used for the treatment of breast cancer. The aim of this study was to evaluate the effects of exemestane on liver development of zebrafish embryos. In this study, zebrafish embryos at 72 h post-fertilization (hpf) were exposed to varying concentrations (1, 2, and 3 mg/L) of exemestane for 72 h (until 144 hpf). The results demonstrated that exemestane exposure significantly reduced liver area and expanded the yolk sac in a dose-dependent manner, accompanied by progressive lipid accumulation. At the highest concentration (3 mg/L), exemestane markedly downregulated the expression of key liver development markers, including fatty acid-binding protein (fabp10a) and ceruloplasmin (cp). The study further revealed that exemestane exposure at 2 mg/L and 3 mg/L significantly increased reactive oxygen species (ROS) levels while decreasing the activities of antioxidant enzymes, specifically catalase (CAT) and superoxide dismutase (SOD). Interestingly, higher concentrations of exemestane resulted in reduced levels of the lipid peroxidation product malondialdehyde (MDA) and decreased mitochondrial numbers. Additionally, exemestane treatment altered the expression of genes related to sugar and lipid metabolism and upregulated pro-apoptotic genes, including bax, p53, and caspase 3, in zebrafish embryos. A crucial finding was that p53 knockdown in zebrafish embryos effectively mitigated the hepatotoxic effects induced by exemestane. These collective results indicate that exemestane induces hepatotoxicity in zebrafish primarily through activation of the p53 signaling pathway. This study provides valuable insights into the potential hepatotoxic effects of exemestane, offering important references for its clinical safety evaluation.