Developmental exposures to waterborne abused drugs alter physiological function and larval locomotion in early life stages of medaka fish

Environmental pollution by neuroactive pharmaceuticals from wastewater discharge is a major threat to aquatic ecosystems. However, the ecotoxicologic effect of waterborne abused drugs remains unclear. Embryos of medaka fish (Oryzias latipes) were exposed to aqueous solutions of 2 hallucinogenic drugs, ketamine (KET) and methamphetamine (MET) (0.004-40μM) to assess developmental toxicity, oxidative stress and behavioral alteration in early life stages. The environmentally relevant concentration (0.004μM) of both KET and MET significantly delayed blood circulation and hatching time in embryos and altered larval swimming behavior (e.g., maximum velocity and relative turn angle). KET and MET induced similar oxidative stress responses in embryos, which were unrecoverable in hatchlings in drug-free solutions. Early life exposure to the 2 drugs conferred distinct patterns in larval locomotion: KET induced hyperactivity and a less tortuous swimming path, but MET-treated larvae showed hypoactivity and a clockwise swimming direction at high doses. The alteration in locomotor responses were generally similar in mammals and zebrafish. We report sensitive biomarkers (e.g., heartbeat, hatching and swimming behavior) by developmental stage of medaka that reflect environmentally relevant exposures of abused drugs. They could be useful for ecological risk assessment of waterborne neuroactive drugs. The toxicity results implicate a potential ecotoxicological impact of controlled or abused drugs on fish development and populations in aquatic environments.