Effects of environmentally relevant concentrations of sertraline on the antipredator behavior of Scinax fuscovarius tadpoles

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Effects of environmentally relevant concentrations of sertraline on the antipredator behavior of Scinax fuscovarius tadpoles

https://doi.org/10.21203/rs.3.rs-1623314/v1

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Sertraline is one of the most commonly detected antidepressants in surface waters, raising concerns on potential, non-intended effects on the behavior of non-target organisms. In this study we experimentally evaluate whether sertraline, at environmentally relevant concentrations, influence the behavior of prey in response to their predators. Our model system comprised tadpoles of the treefrog Scinax fuscovarius as consumers, and larvae of the dragonfly Erythrodiplax sp as predators. This prey-predator system was exposed to sertraline concentrations of 0, 0.1 and 1.0 ug/L. We quantified tadpole activity rates, food intake rates, spatial avoidance, and hiding behavior, all of which are known to regulate predation risk. No main effects of sertraline were observed for any response variable; a main effect of predator presence was observed for spatial avoidance only. Most importantly, a significant sertraline-by-predator presence interaction term suggests that activity rates face to predator presence is influenced by sertraline. We in addition quantified response variables related to swimming kinematics, which are also known to regulate predation risk. Tadpoles exposed to sertraline spent less time swimming, swam for a shorter distance, and demanded more stimuli to initiate swimming. Overall, our results suggest that environmental contamination by sertraline may influence larval amphibian behavior in ways that could influence their fitness.

sertraline

antidepressants

antipredator behavior

swimming

tadpole

Amphibia

Environmental pollution by pharmaceuticals has become an area of priority concern due to the high volumes of consumption and the ample diversity of molecules available in the market. Global sales in 2021 totaled 1.27 trillion US dollars, an impressive 3.2-fold increase for a mere 27% population size increase over a 20-yr period (Statista 2021, UN 2022). The United States responds to nearly half of these sales, with more than 20,000 prescription products approved for human and 1,600 for animal use (IQVIA 2019; FDA 2020).

Pharmaceutical products are usually present in small concentrations in the environment, usually in the range of nanograms per liter, and are rarely toxic (Fent and Weston 2006; Richmond et al. 2017; Cizmas et al. 2015). However, pharmaceuticals are molecules designed for having biological effects and are continuously released in the environment, thereby creating an exposure scenario that could resemble chronic administration (Daughton and Ternes 1999). As such, pharmaceuticals can have a variety of sublethal effects, modifying individual morphology, physiology, reproduction and behavior (Saaristo et al. 2018; Richmond et al. 2017). In particular, behavioral effects of contaminants have been gaining attention for their potential to modulate species interactions (Saaristo et al. 2018, Weiss et al. 2012, Weiss et al. 2001, Donk et al. 2016) and generate trait-mediated indirect effects (Werner & Peacor 2003) that propagate in food webs far beyond affected species (Kidd et al. 2014)

There are several pathways by which pharmaceuticals can reach surface waters. These include non-adequate disposal of unused or expired products, and the excretion of both metabolized and non-metabolized molecules after human and animal consumption (Kostich et al. 2014). Indeed, not only many regions in both the developed and developing world lack adequate sanitary infrastructure, but conventional wastewater treatment plants (WWTPs) are incapable of withdrawing many pharmaceuticals (Rivera-Utrilla et al. 2013).

As a consequence, several studies report pharmaceutical contamination in surface waters. In the US, for example, a total of 93 pharmaceuticals including antibiotics, antihypertensives, analgesics, anticonvulsants, antilipidemic, contraceptives, stimulants, antihistamines and antidepressants has been recorded (Deo 2014).

Antidepressants constitute a particularly interesting class of pharmaceuticals to investigate effects on species interactions that are strongly regulated by individual behavior, such as predator-prey-resource interactions. Antidepressants are by design pharmaceuticals that modulate behavior in humans treating depression, obsessive compulsive disorders and panic disease, and it is plausible that behavior of non-target organisms would be similarly affected.

Selective Serotonin Recapture Inhibitors (SSRIs), including molecules such as fluoxetine, sertraline, paroxetine, citalopram, and its enantiomer escitalopram, constitute the most frequently prescribed class of antidepressants worldwide. This class of substances reduces the re-uptake of serotonin (5-hydroxytryptamine, 5-HT) in the synaptic cleft by binding at the 5-HT re-uptake transporter, thereby increasing the levels of serotonin available and reducing the symptoms of depression. Importantly, however, serotonin modulates neurotransmission in most animal phyla including cnidarians, flatworms, nematodes, annelids, mollusks, arthropods and chordates. In such a wide diversity of lineages serotonin was demonstrated to influence motor activity, locomotion, feeding, arousal, aggressiveness and social interactions (Bacqué-Cazenave et al. 2020). Therefore, SSRIs working as serotonin agonists could potentially alter the nature, strength and/or outcome of species interactions, such as predator-prey-resource interactions, by changes in the behavior of individual species.

Sertraline is among the top-selling SSRIs globally, and it is also among the SSRIs recorded more frequently and at highest concentrations in surface waters (Mole and Brooks 2019). Moreover, sertraline concentrations in wastewater are close to plasma concentrations known to cause measureable responses in humans and laboratory animals (Kostich et al. 2014). As a consequence, sertraline and its metabolite desmethyl-sertraline were among four pharmaceutical active ingredients of 56 detected in WWTP effluents, considered of potential risk to aquatic life and deserving additional studies (Kostich et al. 2014).

In this study we experimentally evaluate whether sertraline, at environmentally relevant concentrations, influences the interaction between predators and their prey. Our model system comprises tadpoles of the treefrog Scinax fuscovarius as consumers, and larvae of the dragonfly Erythrodiplax as predators. Tadpoles are among the most traditional model systems in community ecology (Srivastava et al. 2004) and a large body of literature has unveiled fundamental knowledge regarding the nature of predator-prey interactions manipulating tadpoles and dragonflies (e.g. Werner & McPeek 1994). We hypothesize that sertraline, as a serotonin agonist, could potentially interfere in prey behaviors that are known to be important in regulating both predation risk and foraging gain such as activity level, spatial avoidance and hiding, as well as swimming kinematics (Werner & Anholt 1993). Increasing activity rates, foraging speed and the time spent foraging increase resource acquisition but also visibility to, and encounter rates with predators (Werner & Anholt 1993). Thus, SSRIs in general, and sertraline in particular could influence behavioral decisions or locomotor performance by the prey in such a way that optimal behavioral solutions to this fundamental tradeoff would be disrupted, decreasing individual fitness. As far as we know there is only one study evaluating the behavioral responses of a tadpole exposed simultaneously to predators and sertraline (Barry 2018), but the only behavioral endpoint clearly related to predation risk in that study was swimming speed. Our study is thus the first to evaluate the consequences of sertraline on a full set of behaviors regulating predation-prey interactions.

Species. The treefrog Scinax fuscovarius (Amphibia; Anura; Hylidae) was chosen as a biological model for being common and widely distributed in southern, southeastern, and central Brazil, as well as in eastern Bolivia, Paraguay, northern Argentina and Uruguay. The species occurs in savannas, shrubland and wetlands, and is tolerant to habitat degradation as indicated by its occurrence in agricultural fields and cities. (IUCN 2020). The dragonfly Erythrodiplax is widely distributed in the American continent, occurring from Southern Canada to Southern Argentina and Chile (Garrison et al. 2006). Both species present a complex life cycle with terrestrial adults and aquatic larvae developing in lentic waterbodies including temporary ponds and marshes. As such, Scinax and Erythrodyplax are expected to interact with each other over large expanses of their ranges, including areas that could be subject to pharmaceutical contamination.

Generalities. Two egg masses of Scinax fuscovarius and 55 dragonfly larvae were collected in temporary ponds in rural landscapes of Brotas, State of São Paulo, Brazil (22°17′2″ S, 48°7′37″ W) and transported to the laboratory in the Escola de Artes, Ciências e Humanidades of the Universidade de São Paulo. Egg masses were kept in 50L plastic tanks filled with filtered tap water until hatching, after which larvae were fed JBL Novo Pleco Fish food (JBL GmbH, Neuhofen, Germany). Dragonfly larvae were individually kept in 300 mL plastic cups filled with filtered tap water where they were fed one Scinax fuscovarius tadpole every other day. Two days before the experiment feeding was interrupted to standardize hunger levels.

Tadpoles selected for the experiment were within a narrow range of body sizes (5.46 ± 0.40 mg, mean ± 1 SE, N = 20) and developmental stages (Stage 25 of Gosner 1960) and healthy as judged by external morphology and behavior. Dragonfly larvae selected for the experiment were within a body size range capable of eating manipulated tadpoles (total length 8.65 ± 0.33 mm, N = 14).

Active Pharmaceutical Ingredient. Sertraline was manipulated as sertraline hydrochloride (CAS Number 79617-96-2). The reagent employed was provided by Eurofarma and had a purity of 99,6% with 99,8% w/w and less than 20 ppm trace metals. Sertraline hydrochloride (molecular weight 342.69 g/mol) is a water soluble (solubility 3.52 mg/L), basic (pka = 9.47) and lipophilic (Kow = 1.37) salt with a strong tendency to adsorb to sediments (Koc = 4.17) (Pubchem 2019). Stock solutions were prepared weekly using ultrapure water.

Experimental Design. We performed a 12-day laboratory experiment to test the hypothesis that sertraline, at environmentally relevant concentrations, impacts Scinax fuscovarius behavior when exposed to dragonfly larvae.

The experiment followed a fully factorial design crossing sertraline concentrations and predator presence. Sertraline was manipulated at 0 (i.e., the control); 0.1 and 1.0 ug/L (or, equivalently 0, 0.1119 and 1,1199 ug/L sertraline hydrochloride), therefore bracketing concentrations recorded in surface water bodies (Mole and Brooks, 2019). To maintain an approximately constant concentration of sertraline over the course of the experiment, half of the test solution was renewed after 6 days of experiment (considering a half-life of sertraline in effluents and river water of 6.9 days; Jakinska et al. 2014).

Each experimental unit consisted of a 41 X 29 X 12.5 cm plastic box containing 7 L of test solution and 10 Scinax fuscovarius tadpoles. Half of the experimental units contained, in addition, one Erythrodiplax sp larva in a mesh cage in one of the sides of the box. Caged predators could not actually prey on the tadpoles, but its chemical cues freely diffused in the experimental container. No predator treatments contained one empty mesh cage as a sham control. Tadpoles were fed daily with JBL Novo Pleco Fish food (JBL GmbH, Neuhofen, Germany) (see below). Dragonflies were fed daily with a tadpole from our holding tanks. Each treatment was replicated 4 times, resulting in a total of 24 plastic boxes.

Assessed behavioral responses included activity rates, spatial avoidance, and food intake rates. Activity rates were measured as the number of tadpoles active at any given moment. Spatial avoidance was measured as the number of tadpoles located in the opposite side of the predator; to facilitate measuring tadpole spatial avoidance, an adhesive tape in the outside of the box divided the box in two halves. Hiding behavior was measured as the number of tadpoles hiding under a 11 X 11 cm ceramic tile placed 0.5 cm above the bottom in the opposite side of the predator cage. The ceramic tile, which served as a refuge for tadpoles, was placed in the box in the 7th day of experiment. Thus, activity rates and spatial avoidance were recorded in the first half of the experiment and hiding behavior in the second half of the experiment. Food intake rate was measured as follows. Tadpoles were fed daily with one pre-dried, pre-weighted food pellet placed in the bottom of the box for approximately 20 minutes. After this period, the remaining food was withdrawn, dried in a drying oven, and weighted using a semi-analytical balance (Ohaus Corporation, Pine Brook, NJ). Intake rate was measured as the difference between the initial dry mass and final dry mass. In each experimental unit a total of 20 records were made for activity rates, spatial avoidance and hiding behavior and 8 records for food intake. In the analyses the mean of these records per experimental unit was employed as the response variable.

At the 12th day the experiment was finished, and all tadpoles and dragonflies were preserved in a 1:1 solution of 70% ethanol and 5% formaldehyde.

We also tested the effects of sertraline on tadpole swimming kinematics. However, because the assessment of swimming kinematics would involve handling of the experimental animals, with likely influence on other behavioral responses, tadpoles employed in this test were reared separately, but simultaneously, to the abovementioned experiment. Three 30-L aquaria received the same test solutions (0; 0.1 and 1.0 ug/L sertraline) and 20 tadpoles each, following the same maintenance procedure described above. After twelve days of exposure each tadpole was placed in a 15 cm Petri dish, filled with water from the same aquaria tested, and filmed for 45 seconds using a Mobile Samsung A5 Full HD video with 30 frames per second (FPS). The recording was made in a dark room to reduce animal stress. A small brush was used to gently stimulate swimming. We employed the software Ctrax v1.4 (Branson et al. 2009) to evaluate time spent swimming (s), average swimming speed (cm/s), total cumulative displacement (cm) after the first 3 stimuli, and the number of stimuli required to stimulate swimming.

Chemical analysis. As quality control, after 6 and 12 days of experiment we measured basic water quality parameters including temperature, dissolved oxygen, pH, and conductivity for each experimental unit using a YSI ProDSS multiparameter probe (YSI, Yellow Springs, OH, USA). At the end of the experiment, water samples from the 30 L aquaria were collected and frozen for determination of actual concentrations of sertraline. For the liquid-liquid extraction (LLE), 10 mL of sample were transferred to a 15 mL polypropylene tube, followed by the addition of 2 g of NaCl, 100 uL of imipramine-d3 50 ng/mL and 2 mL of ethyl acetate. This mixture was vortexed using BenchMixer™ XL multi-tube vortexer (Benchmark Scientific, Sayreville, NJ, USA) for 60 min at 2,500 rpm. Samples were centrifuged at 3,500 rpm for 5 min and the organic layer was transferred to a glass tube and dried under nitrogen stream (40°C) using a TurboVap evaporation system (Biotage, Uppsala, Sweden). Samples were resuspended with 100 µL of a solution of water and methanol (80:20, v/v) containing 0.1% formic acid and 2 mmol/L ammonium formate. Ten µL were injected into LC–MS/MS system.

The analysis was performed on a Nexera X2 high-performance liquid chromatography system coupled to an LCMS8060 triple quadrupole mass spectrometer (Shimadzu, Kyoto, Japan). Chromatographic separation was performed in a C18 stationary phase column (Waters, 50 mm x 2.1 mm x 1.7 µm; Milford, Massachusetts, USA), maintained at 40°C. Elution was in isocratic mode, with a mobile phase composed of ultrapure water (A) containing 0.1% formic acid and 2 mmol/L of ammonium formate and methanol (B). Elution was started at 50% B, maintained in this condition for 5.5 minutes of run, at a mobile phase flow rate of 0.4 mL/min.

The mass spectrometer was equipped with an electrospray ionization source operating in positive mode. The mass spectrometer conditions were: interface temperature at 300°C, desolvation line temperature at 250°C, heat block temperature at 400°C, drying gas flow (N₂) at 10 L/min, heating gas (N₂) at 10 L/min, nebulizing gas flow (N₂) at 3 L/min and collision gas pressure (Ar) at 270 kPa. Data acquisition was performed in multiple reaction monitoring (MRM) mode. For each compound, two MRM transitions were selected, one for quantification and one for qualification. Data were acquired and processed using LabSolutions 5.97 software (Shimadzu, Kyoto, Japan).

Data analysis. Response of experimental populations (activity rates, spatial avoidance, hiding behavior, intake rates) and individuals (swimming speed) to sertraline, predator presence and their interactions were analyzed using Two-Way Analysis of Variance (ANOVA) after checking for the assumptions of normality and homoscedasticity. All analyses was conducted with the software PAST 4.3 (Hammer 2020).

Physical and chemical water quality parameters. Basic water quality parameters across all experimental containers and sampling dates were 24.13 ± 0.15°C (temperature; average + 1SE), 7.32 ± 0.09 (pH), 120.44 ± 2.66 uS/cm (conductivity) and 6.26 ± 0.11 mg/L (dissolved oxygen). Predator, sertraline or their interaction had no significant effects on any water quality parameter either after 6 or 12 days of experiment; there was a significant trend for a reduction in dissolved oxygen levels throughout the experiment (ANOVA F_1,47=180.5, p < 0.001). By the end of the experiment measured sertraline concentrations in the 0.1 and 1.0 ug/L treatments were respectively 0.0335 ug/L and 0.6425 ug/L.

Survival. No tadpoles or dragonflies died throughout the experiment.

Larval behavior. Although neither sertraline nor predator presence had significant effects on Scinax fuscovarius activity rates, a significant sertraline-by-predator presence interaction term was observed as a consequence of the much higher activity rates of tadpoles exposed to sertraline at 1 ug/L in the no-predator treatment (Fig. 1a, Table 1). Spatial avoidance was significantly influenced by predator presence, as more tadpoles tended to remain in the distal half of the experimental container when predators were present. No significant effects of sertraline and of a sertraline-by-predator interaction term on spatial avoidance were detected (Fig. 1c, Table 1). Finally, no significant effects of predator presence, sertraline, or their interactions were detected on food intake rates or hiding behavior (Fig. 1b, 1d; Table 1).

Table 1

Results of a two-way ANOVA for effects of predator presence, sertraline, and their interactions on *Scinax fuscovarius* activity rates, food intake rates, spatial avoidance, and hiding behavior.
		degrees of freedom	F	p
Activity rates	Sertraline	2	1.619	0.226
	Predator	1	2.468	0.134
	Sertraline X Predator	2	3.846	0.041
Food intake	Sertraline	2	0.996	0.389
	Predator	1	0.011	0.917
	Sertraline X Predator	2	1.135	0.343
Spatial avoidance	Sertraline	2	0.220	0.804
	Predator	1	4.406	0.050
	Sertraline X Predator	2	1.245	0.312
Hiding	Sertraline	2	1.878	0.182
	Predator	1	0.726	0.405
	Sertraline X Predator	2	0.548	0.588

Larval swimming kinematics. Significant effects of sertraline were observed on time spent swimming (F = 3.822 p < 0.0277), total displacement (F = 0.036 p < 0.0356) and number of stimuli needed to induce tadpole movement (F = 6.198 p < 0.0037). By contrast, no significant effects of sertraline were observed on swimming speed (Fig. 2).

Pharmaceuticals are widespread contaminants in urban and periurban surface waters. In this study we found that exposure to environmentally relevant doses of sertraline, one of the most widely consumed SSRI antidepressants globally, can influence larval amphibian behavior and swimming kinematics in ways that could influence their fitness. However, sertraline effects were subtle and manifested mainly, although consistently, on locomotor performance. In fact, concentrations as low as 0.1 ug/L were sufficient to reduce time spent swimming and total displacement of larval Scinax fuscovarius; no effect on swimming speed was observed. Furthermore, these same concentrations were sufficient to reduce individual responsiveness to stimuli, as more stimuli were necessary to induce swimming in treated tadpoles.

Few are the studies that have quantified the swimming kinematics of amphibian larvae exposed to SSRIs and SSNRIs (i.e., selective serotonin and norepinephrine reuptake inhibitors). Barry (2014) and Barry (2018) exposed Sclerophrys arabicus tadpoles to fluoxetine (0.03, 0.3 and 3 ug/L) and to sertraline, fluoxetine, venlafaxine and a mixture of them (0.5 and 2 ug/L) respectively. Consistent with our findings, the author found that sertraline had no effect on swimming speed, otherwise affected by fluoxetine and venlafaxine (Barry 2014, 2018).

No main effects of sertraline on activity rates, food intake rates, spatial avoidance or hiding behavior were observed in our study. However, a significant sertraline-by-predator presence interaction term on activity rate was detected due to the notable increase in activity rate of tadpoles in the absence of predators at 1 ug/L. This is one further indication that locomotion can be disrupted by an SSRI. In the only other comparable study, Barry (2018) found that low doses of fluoxetine and venlafaxine increased activity rates, as inferred from the measured reduction in the percent time spent motionless. Contrary to our findings, however, the same was not observed for tadpoles exposed to sertraline. Overall, it appears that disruption of the locomotor performance of anuran larvae is a potentially common consequence of exposure to SSRIs, but the results are highly variable.

The paucity of responses of larval Scinax fuscovarius to the nonlethal predator presence was surprising. The only response variable for which a significant main effect of predator presence was observed was spatial avoidance: proportionally more tadpoles were found distant from the predator cage when predators were present than when predators were absent. Differently from other amphibian larvae (e.g. Relyea 2001), Scinax larvae were not less active, did not present lower intake rates and did not hide more frequently when predators were present. This, in spite of the fact that, clearly, experimental tadpoles were within the size range of Erythrodiplax prey (i.e., they did not reach a size refuge from predation over the course of the experiment) as caged dragonflies were fed similarly sized tadpoles from our holding tanks.

In the absence of strong predator-induced behavioral changes, a test for the hypothesis of a modulating role of sertraline on predator-prey interactions is hindered. The key to this surprising result may lie on the recognition that larval amphibians present widely different locomotion patterns, and that these locomotion patterns may be important in mediating predation risk by dragonflies. Azevedo-Ramos et al. (1992) recorded distance covered, rapidity and survival times of four tadpole species exposed to free-ranging dragonfly Gynacantha membranalis, including a species of Scinax (Scinax ruber; other species were Boana geographica, Osteocephalus taurinus and Phyllomedusa tarsius). The longest survival times were precisely those of Scinax; a comparative analysis of locomotion patterns led the authors to suggest that this was because the species moves infrequently and fast. Species that had the opposite locomotion strategy such as Boana geographica, i.e., frequent and slow movement, had low survival times. These results suggest that Scinax may be at the same time difficult to locate and to catch by these sit-and-wait predators, which may favor coexistence of Scinax and dragonflies in temporary and semipermanent ponds throughout much of their ranges. Although we did not quantify predation rate per se, under this adaptive scenario deciding when to swim, and for how long, may significantly contribute to an individual chance of surviving. Mere 0.1 ug/L of sertraline were sufficient to alter these decisions (number of stimuli required to induce swimming; total displacement), meaning that costly behavioral decisions could be happening in many urban and periurban waterbodies across the globe.

That these sertraline concentrations are potentially found in surface waterbodies is indicated both by a global review of the still fragmentary but growing evidence for surface water contamination (0.8-127.7 ng/L sertraline; Mole and Brooks 2019) and our own data (0-76.2 ng/L sertraline in 50 streams draining catchments distributed across a gradient in urbanization in the Metropolitan Region of São Paulo, where Scinax fuscovarius and Eryhtrodiplax naturally occur; Schiesari et al. unpublished data). Interestingly, in contaminated waterbodies predators and prey may have a disruption of the serotonergic system significantly exceeding that expected from the abovementioned concentrations. This is so because of a potentially additive effect of several co-occurring antidepressants – such as sertraline, fluoxetine, citalopram, bupropion, amitriptyline, and venlafaxine in urban streams (Schiesari et al. unpublished data) – that could further increase the availably of serotonin in the synaptic clef close to that resulting from human therapeutic levels of SSRIs. Much remains to be learned regarding the potentially unintended consequences of the environmental contamination by antidepressants.

The authors declare that no funds, grants or other support were received during the preparation of this manuscript

Competing interests

The authors have no relevant financial or non-financial interests to disclose

Author Contribiutions Statement

HAB formulated the research question, conducted the experiment, analyzed and interpreted data and wrote the first draft of the manuscript under the supervision of LS. AFM and JLC conducted the chemical analyses and interpreted data. All authors reviewed the final version of the manuscript.

Acknowledgements

We thank Eurofarma Laboratórios S.A for donating the pharmaceutical active ingredient sertraline hydrochloride, Jessica Maria de Jesus Ferreira, Bruna Borella Querido and João Pedro Calil Barcellos Leite for help in field work, João Pedro Calil Barcellos Leite for help in the experiment, and Rodolfo Pelinson for help in the kinematic analysis and graphic elements. LS was funded by the São Paulo Research Foundation (FAPESP Grant 2015-18790-3) over the course of this study. This study was conducted under collection permits by ICMBio (17559-11) and following protocols approved by the Ethics Commission on Animal Use in Experimentation of EACH-USP (CEUA/EACH-USP 1/2019).

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No competing interests reported.

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Effects of environmentally relevant concentrations of sertraline on the antipredator behavior of Scinax fuscovarius tadpoles

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