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

Abstract

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.

Bioaccumulation and trophic dilution of human pharmaceuticals across trophic positions of an effluent-dependent wadeable stream

“…It has been demonstrated to suppress microbial respiration [47], modify bacterial community structure [48] and alter fish behaviour [27] at low microgram per litre concentrations. Similar to diphenhydramine, previous studies with sertraline, which also blocks serotonin reuptake transport, have also highlighted the effects on fish anxiety behaviour when plasma concentrations exceeded human C max values [17]. In the present study, sertraline was not observed in fish tissue but accumulated to relatively high levels in bivalves.…”

“…For example, uptake and elimination of ionizable pharmaceuticals (over 70% of drugs are ionizable) by fish [12,13] and invertebrates [14] are modified by surface water pH [13,[15][16][17]. Unfortunately, environmental modelling approaches for predicting fate, transport, exposure and bioaccumulation, which were designed to address historical contaminants (e.g.…”

Ecological effects of pharmaceuticals in aquatic systems—impacts through behavioural alterations

“…According to the literature reviewed here, it is clear that antidepressants, psychiatric drugs (benzodiazepines) and antihistamines can induce behavioural changes in fish at concentrations ranging from low ng l 21 to low mg l 21 [33,36,42,49], which are close to the concentrations found in natural systems [21,29]. Although this suggests that ecological effects of pharmaceuticals may occur in aquatic systems dominated by wastewater effluent, effects of some pharmaceuticals were found only at higher, not environmentally relevant, concentrations.…”

Comparative Pharmacology and Toxicology of Pharmaceuticals in the Environment: Diphenhydramine Protection of Diazinon Toxicity in Danio rerio but Not Daphnia magna

“…If the mammalian DPH C max value (0.05 μg/ mL) is used as a surrogate for an internal therapeutic dose in fish (10,16,26), then zebrafish DPH plasma levels would be expected to range from 30 to 7,500× of the human therapeutic dose. Bird et al (23) identified a protective DPH effect for OP poisoning in rats treated with 30 mg/kg, which corresponds to ∼43× higher dosage than required to reach a therapeutic effect (0.7 mg/kg).…”

“…To begin to address the existing data gaps for pharmaceutical impacts in the environment, comparative pharmacology and toxicology approaches may be developed through "read-across" processes (8). Because conservation of critical molecular receptors for pharmaceuticals exist across aquatic vertebrates (9)(10)(11), it appears possible to utilize such information from target organisms (e.g., human, mammal) to prioritize chemicals for further study (12,13) and support more robust ERA and environmental decisions (14)(15)(16). To organize mammalian data for read-across to aquatic species, an adverse outcome pathway (AOP) (17) provides a critical structural framework for understanding therapeutic mechanism of action (MOA)-specific responses; employing AOPs was recently recommended for future studies examining environmental impacts of pharmaceuticals (18).…”