Exposure Effects of Environmentally Relevant Concentrations of the Tricyclic Antidepressant Amitriptyline in Early Life Stage Zebrafish.

Antidepressants are one of the most globally prescribed classes of pharmaceuticals, and drug target conservation across phyla means that nontarget organisms may be at risk from the effects of exposure. Here, we address the knowledge gap for the effects of chronic exposure (28 days) to the tricyclic antidepressant amitriptyline (AMI) on fish, including for concentrations with environmental relevance, using zebrafish (Danio rerio) as our experimental model. AMI was found to bioconcentrate in zebrafish, was readily transformed to its major active metabolite nortriptyline, and induced a pharmacological effect (downregulation of the gene encoding the serotonin transporter; slc6a4a) at environmentally relevant concentrations (0.03 µg/L and above). Exposures to AMI at higher concentrations accelerated the hatch rate and reduced locomotor activity, the latter of which was abolished after a 14 day period of depuration. The lack of any response on the features of physiology and behavior we measured at concentrations found in the environment would indicate that AMI poses a relatively low level of risk to fish populations. The pseudopersistence and likely presence of multiple drugs acting via the same mechanism of action, however, together with a global trend for increased prescription rates, mean that this risk may be underestimated using current ecotoxicological assessment paradigms.

Are synthetic glucocorticoids in the aquatic environment a risk to fish?

The glucocorticosteroid, or glucocorticoid (GC), system is largely conserved across vertebrates and plays a central role in numerous vital physiological processes including bone development, immunomodulation, and modification of glucose metabolism and the induction of stress-related behaviours. As a result of their wide-ranging actions, synthetic GCs are widely prescribed for numerous human and veterinary therapeutic purposes and consequently have been detected extensively within the aquatic environment. Synthetic GCs designed for humans are pharmacologically active in non-mammalian vertebrates, including fish, however they are generally detected in surface waters at low (ng/L) concentrations. In this review, we assess the potential environmental risk of synthetic GCs to fish by comparing available experimental data and effect levels in fish with those in mammals. We found the majority of compounds were predicted to have insignificant risk to fish, however some compounds were predicted to be of moderate and high risk to fish, although the dataset of compounds used for this analysis was small. Given the common mode of action and high level of inter-species target conservation exhibited amongst the GCs, we also give due consideration to the potential for mixture effects, which may be particularly significant when considering the potential for environmental impact from this class of pharmaceuticals. Finally, we also provide recommendations for further research to more fully understand the potential environmental impact of this relatively understudied group of commonly prescribed human and veterinary drugs.