Neurotoxicity of myclobutanil in zebrafish larvae via thyroid disruption and neuronal apoptosis.

Myclobutanil (MYC) is a systemic synthetic triazole-class fungicide extensively deployed in global agriculture. Residues of MYC are often detected in various ecosystems and biological systems. However, studies investigating its potential neurodevelopmental toxicity are still scarce. In this research, zebrafish embryos were treated with MYC (at 0, 0.5, and 1 mg/L) during 4 to 96 h post fertilization (hpf) to assess its neurotoxic effects and underlying molecular pathways. Our results revealed that MYC adversely affected embryonic development, manifesting as reduced hatching rate, decreased survival rate, lower heart rate, concurrently with elevated malformation and spontaneous movement. Locomotor dysfunction was observed following MYC exposure. MYC also attenuated central nervous system neurogenesis in Tg(HuC:EGFP) zebrafish, as evidenced by diminished cholinesterase activities and decreased transcription of neurodevelopmental genes. In addition, MYC disturbed thyroid hormone balance and modulated the transcriptional profile of hypothalamus-pituitary-thyroid (HPT) axis-related genes. Molecular docking suggests a strong binding interaction between catalytic residues of thyroid hormone receptor β and MYC. Subsequently, MYC triggered apoptosis in brain neurons by upregulating apoptotic genes. These neurotoxic effects were effectively counteracted after T3 administration, suggesting thyroid dysfunction as a vital mechanism of MYC-induced neurotoxicity. Overall, this study reveals that MYC induces neurotoxicity in zebrafish larvae through thyroid hormone disruption and neuronal apoptosis, providing new insights into the developmental neurotoxic risks of triazole fungicides.