Environmentally Relevant Concentrations of Avermectin Disrupt Neural and Vascular Development in Zebrafish via Toll-Like Receptor (TLR) Signaling

Avermectin (AVM) is a widely used antiparasitic agent in aquaculture. However, its extensive application has raised environmental concerns due to residual toxicity affecting nontarget aquatic organisms. This study investigates the developmental toxicity of AVM in zebrafish embryos and larvae with a focus on underlying mechanisms. Exposure to AVM at ≥125 μg/L significantly increased mortality, while 50 and 125 μg/L reduced hatching success, heart rates, and body length and increased deformities. Neural and vascular toxicity included a decreased fluorescence of central and dopaminergic neurons, shortened motor neuron synapses, abnormal vascular development, and reduced intersegmental vessel anastomosis rates. AVM exposure elevated reactive oxygen species levels, neutrophil counts, and apoptotic cell counts, thereby triggering oxidative stress, inflammation, and apoptosis. Transcriptome sequencing and molecular docking suggested that AVM activates the Toll-like receptor (TLR) and focal adhesion pathways, primarily through TLR4. Rescue experiments using the TLR4 inhibitor TLR4-IN-C34 partially mitigated neural and vascular toxicity. This study provides molecular insights into AVM-induced ecological toxicity and emphasizes its risks to aquatic organisms.