5 research outputs found
Human Therapeutic Plasma Levels of the Selective Serotonin Reuptake Inhibitor (SSRI) Sertraline Decrease Serotonin Reuptake Transporter Binding and Shelter-Seeking Behavior in Adult Male Fathead Minnows
Selective serotonin reuptake inhibitors (SSRIs) represent
a class
of pharmaceuticals previously reported in aquatic ecosystems. SSRIs
are designed to treat depression and other disorders in humans, but
are recognized to elicit a variety of effects on aquatic organisms,
ranging from neuroendocrine disruption to behavioral perturbations.
However, an understanding of the relationships among mechanistic responses
associated with SSRI targets and ecologically important behavioral
responses of fish remains elusive. Herein, linking Adverse Outcomes
Pathways (AOP) models with internal dosimetry represent potential
approaches for developing an understanding of pharmaceutical risks
to aquatic life. We selected sertraline as a model SSRI for a 28-d
study with adult male fathead minnows. Binding activity of the serotonin
reuptake transporter (SERT), previously demonstrated in mammals and
fish models to respond to sertraline exposure, was selected as an
endpoint associated with therapeutic activity. Shelter-seeking behavior
was monitored using digital tracking software to diagnose behavioral
abnormalities. Fish plasma levels of sertraline exceeding human therapeutic
doses were accurately modeled from external exposure concentrations
when pH influences on ionization and log D were considered. We observed
statistically significant decreases in binding at the therapeutic
target (SERT) and shelter-seeking behavior when fish plasma levels
exceeded human therapeutic thresholds. Such observations highlights
the strengths of coupling physiologically based pharmacokinetic modeling
and AOP approaches and suggest that internal dosimetry should be monitored
to advance an understanding of the ecological consequences of SSRI
exposure to aquatic vertebrates