Potency matters: Impacts of embryonic exposure to nAChR agonists thiamethoxam and nicotine on hatching success, growth, and neurobehavior in larval zebrafish

Thiamethoxam (TM) is a neonicotinoid insecticide that acts as a nicotinic acetylcholine receptor (nAChR) agonist. While designed to specifically target invertebrate nAChRs, recent studies have reported adverse effects of neonicotinoid exposure in early life-stage fish. This study examined the health and neurobehavioral impacts of chronic exposure to various concentrations of TM or nicotine (NIC) in early life zebrafish (Danio rerio) in conjunction with in-silico molecular docking to compare their ligand-receptor interactions with vertebrate nAChR. Chronic exposure to both reduced survival by approximately 20% (163 µg TM/l) and 25-100% (≥0.49 µg NIC/l). Hatching and growth were impaired following exposure to ≥0.21 µg TM/l or 4.9 µg NIC/l. Both TM and NIC produced morphological and behavioral indicators of neurotoxicity, with more potent effects following NIC exposure. NIC impaired embryonic motor activity by 40% (49 µg NIC/l), while both TM and NIC significantly altered predator escape response in larvae, specifically the latency and the initial burst movement of the response were impacted. Molecular docking predicted variations in the type and strength of interactions that occur between NIC or TM and vertebrate nAChR. These findings demonstrate that chronic exposure to TM might impact general health and neurobehavior of early-stage zebrafish. Our data support hypotheses that TM presents low affinity for vertebrate nAChR but may still pose an adverse risk to larval fish growth and neurobehavior.