Antitussive drug dextromethorphan induces developmental impairment in zebrafish.

Dextromethorphan (DXM) is a common ingredient in cough and cold remedies. Despite its widespread presence in aquatic environments, the impact of DXM on fish remains largely unknown. This study evaluated the developmental impairment of zebrafish embryos exposed to DXM from 2 hours post-fertilization (hpf) to 14 days post-fertilization (dpf) at five different exposure concentrations: 0.06, 0.61, 8.12, 76.3, and 827 μg/L. Results indicated a concentration-dependent increase in bioconcentration of DXM at 7 dpf and 14 dpf. The LC50 at 14 dpf was 93.3 μg/L, demonstrating DXM has a high toxicity to zebrafish larvae. Additionally, DXM reduced body length and heart rate, and elevated malformation in a dose-dependent manner in larvae at 72 hpf, 7 dpf and 14 dpf. Biochemical analysis (DNA conformations and 8-hydroxy-2deoxyguanosine level) and transcriptomic analysis (DNA damage and cell cycle) indicated that DXM triggered DNA damage in larvae. Concurrently, DXM triggered DNA damage response (e.g., cell cycle arrest, DNA repair failure, and cell apoptosis) in larvae at 7 dpf and 14 dpf. These results help explain DXM caused severe developmental impairment via DNA damage-related pathways in zebrafish larvae, highlighting the importance of focusing on ecological and public health risks of DXM in natural environment.