Potential Mechanisms Underlying Carbimazole-Induced Cardiotoxicity and Hepatotoxicity in Zebrafish

Abstract

Carbimazole, a first-line antithyroid agent, alleviates hyperthyroidism by inhibiting thyroid hormone synthesis. However, its clinical use is complicated by adverse effects such as cardiotoxicity and hepatotoxicity, underscoring the need to elucidate its mechanisms in model organisms. In this study, zebrafish embryos at 6-h postfertilization (hpf) were continuously exposed to increasing carbimazole concentrations, with systematic assessment of developmental and physiological parameters. Results demonstrated that concentrations above 3.5 μg/mL caused significant mortality and delayed hatching. Dose-dependent developmental abnormalities included shortened body length, reduced swim bladder area, and pericardial edema. Further analyses indicated carbimazole-induced cardiotoxicity characterized by impaired cardiac development, decreased heart rate, and dysregulation of apoptosis-related genes. A diminished fluorescence area suggested compromised cardiac tissue integrity. Concurrently, hepatotoxicity manifested as yolk sac enlargement and altered expression of liver-specific genes, indicating disrupted hepatic function. RNA sequencing (RNA-seq) analyses indicated that at 120 hpf, the 5-μg/mL carbimazole-treated group exhibited 158 upregulated genes and 562 downregulated genes compared with the wild-type (WT) group. GO and KEGG enrichment analyses revealed disruptions in several signaling pathways associated with liver metabolism and cardiac development, including metabolism, FoxO signaling, and the p53 signaling pathway. These findings demonstrate that carbimazole induces early embryonic developmental abnormalities, cardiotoxicity, and hepatotoxicity in zebrafish. This research provides new insights into carbimazole toxicity and valuable perspectives for optimizing its clinical dosing regimen.

Keywords: carbimazole; cardiotoxicity; development toxicity; transcriptomic analysis; zebrafish.