Toxic effects of streptozotocin (STZ)-induced zebrafish and the response mechanism of liver transcriptome

Abstract

Streptozotocin (STZ) is commonly used to induce diabetes, but its efficacy and systemic toxicity in zebrafish remain controversial. This study evaluated the dose-dependent effects of STZ in adult zebrafish and explored the molecular mechanisms underlying hepatotoxicity using transcriptome profiling. Adult zebrafish were intraperitoneally injected with varying doses of STZ (50 - 350 mg/kg). Following treatment, survival rates, fasting blood glucose levels, and histopathological changes were systematically assessed. Subsequently, RNA-sequencing of liver tissues from the 350 mg/kg STZ-treated group was performed to investigate transcriptomic alterations and genomic variations. STZ doses ≥ 150 mg/kg caused significant mortality and multi-organ damage, including pancreatic pyknosis and severe hepatic degeneration. Notably, STZ failed to induce hyperglycemia, instead causing a downward trend in blood glucose. Transcriptomic analysis identified 7,351 differentially expressed genes. Functional enrichment revealed that STZ induced a global suppression of metabolic pathways (lipids, carbohydrates, and amino acids) and activated apoptosis and signal transduction. Furthermore, increased SNP frequencies and transition bias provided evidence of STZ-induced genomic instability. High-dose STZ in zebrafish leads to acute systemic toxicity and metabolic collapse rather than establishing a stable diabetic model. These findings highlight the severe hepatotoxic risks of STZ and provide molecular insights into its non-specific damage, suggesting the need for extreme caution in zebrafish diabetes modeling.