Protective effects of metformin against volatile organic compounds-induced developmental toxicity in zebrafish...

Volatile organic compounds (VOCs) are widespread environmental pollutants associated with various health risks, including developmental toxicity. Our previous studies revealed a correlation between indoor VOCs exposure and an increased risk of congenital heart diseases (CHDs), which was confirmed by establishing a zebrafish exposure model. Metformin (MET), a classic hypoglycemic drug, has been identified to possess multiple properties. Based on previous research on the protective effects of metformin on air pollution, we propose a hypothesis of using metformin as protective agent against VOCs-induced developmental toxicity in zebrafish embryos and explore the underlying molecular mechanisms. The zebrafish embryos were exposed to the VOCs mixture (128 mg/L) alone or in combination with different concentrations of MET (0.5, 1.0 and 2.0 mg/mL) for 120 h. Toxicological indicators such as survival rate, hatching rate and morphological abnormalities (spinal curvature, yolk sac edema and body length reduction) were significantly alleviated by MET, especially in concentrations of 0.5 mg/mL. MET treatment effectively mitigated both cardiovascular impairments (pericardial edema and bradycardia) and neurodevelopmental deficits (locomotor activity). Transcriptomic profiling revealed MET-mediated modulation of apoptosis-related genes and cell cycle regulators. Pathway analyses identified significant enrichment in neurodevelopmental and cardiovascular functions, corroborated by acridine orange staining showing reduced apoptosis. Our findings demonstrate MET's anti-apoptotic protection against VOCs-induced developmental toxicity, suggesting its potential as a novel therapeutic intervention for pollution-related developmental disorders.