Toxicological Study on Chiral Fluoxetine Exposure to Adult Zebrafish (Danio rerio): Enantioselective and Sexual Mechanism on Disruption of the Brain Serotonergic System.

The increasing number of people with depression worldwide has led to concerns regarding antidepressant contamination in aquatic environments, which could have the risk of negative effects on aquatic organisms. Chirality increases its toxicity potentials. Accordingly, we investigated the negative effects of racemic (rac-), R-, and S-FX at environmental levels (100 ng/L) on the brain serotonergic system in zebrafish (Danio rerio) for 42 days. Additionally, we measured the whole-body concentrations of FX and norfluoxetine (NFX). We found that S-FX exposure disrupted the brain serotonergic system more severely than rac- and R-FX exposure. The mechanism underlying this disruption induced by S-FX was sex-specific, with female zebrafish showing disruption of the serotonin (5-HT) release process but male zebrafish showing disruption of the 5-HT synthesis process. In addition, enantioselective enrichment and biotransformation (R-FX to R-NFX and S-FX to S-NFX) occurred in zebrafish. Sex-specific accumulation was also observed, with higher concentrations in females. Our study provides evidence for enantiomer- and sex-specific effects of FX exposure at biologically relevant concentrations. More broadly, our study demonstrated that SSRI antidepressants, such as FX, can affect aquatic life by causing important shifts in not only their active sites of the serotonin transporter.