An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish

McDonald, M. Danielle

doi:10.1016/j.cbpc.2017.03.007

Cited by 47 publications

(55 citation statements)

References 169 publications

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“…Indeed, the widespread tissue distribution of toadfish SERT found in the current study further strengthened the hypothesis that there would be initial increases in plasma 5-HT after FLX treatment. Our results generally support this hypothesis, as no increase was observed at the lowest dose (1 µg g −1 ) of FLX (comparable to the upper limit of typical therapeutic doses in humans; see McDonald, 2017), a moderate increase was evident at 10 µg g −1 FLX, and a dramatic and rapid increase over several time points was measured at 50 µg g −1 FLX. Such results indicate a progressive blockade of systemic SERT and suggest that SERT in tissues does play a substantial role in modulating peripheral 5-HT dynamics.…”

Section: Discussionsupporting

confidence: 87%

“…As calculated from the Hill model, the toadfish SERT K m (2.08±0.45 µmol l −1 ) is similar to reported K m estimates for zebrafish SERTA (4.20 µmol l −1 and 2.13 µmol l −1 ; Wang et al, 2006;Severinsen et al, 2008), while mammalian K m estimates range from 0.28 to 0.70 µmol l −1 (Ramamoorthy et al, 1993;Chang et al, 1996;Owens et al, 1997;Chen et al, 1998b;Mortensen et al, 1999). Such differences in affinity may reflect differences in local internal 5-HT concentrations between these organismal groups (reviewed by McDonald, 2017), and the difference of three orders of magnitude between the toadfish SERT K m value (μmol l −1 ) and actual circulating concentrations (nmol l −1 ) are probably indicative of the levels of 5-HT in the immediate vicinity of the transporters (e.g. the synapse or proximal to 5-HT-producing tissues) rather than in the general circulation (see McDonald, 2017).…”

Section: Discussionsupporting

confidence: 83%

“…Such differences in affinity may reflect differences in local internal 5-HT concentrations between these organismal groups (reviewed by McDonald, 2017), and the difference of three orders of magnitude between the toadfish SERT K m value (μmol l −1 ) and actual circulating concentrations (nmol l −1 ) are probably indicative of the levels of 5-HT in the immediate vicinity of the transporters (e.g. the synapse or proximal to 5-HT-producing tissues) rather than in the general circulation (see McDonald, 2017). The Hill model fitted our transport data better than the Michaelis-Menten model that has been used for other mammal and fish SERTs (Chang et al, 1996;Mortensen et al, 1999;Wang et al, 2006;Severinsen et al, 2008;Fontana et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Fully understanding SERT and other aspects of 5-HT signaling in teleosts is critical as SSRIs are increasingly found as pollutants in aquatic environments, where they can potentially interfere with 5-HT signaling in exposed organisms (Kolpin et al, 2002;Brooks et al, 2005;Barnes et al, 2008;Ramirez et al, 2009;reviewed in Brooks et al, 2003;Silva et al, 2015;McDonald, 2017). Furthermore, understanding the characteristics and functions of SERT earlier in evolution will enhance understanding of its role in mammals.…”

Section: Introductionmentioning

confidence: 99%

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Molecular and functional characterization of the Gulf toadfish serotonin transporter (SERT; SLC6A4)

Amador

McDonald

2018

Journal of Experimental Biology

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The serotonin transporter (SERT) functions in the uptake of the neurotransmitter serotonin (5-HT) from the extracellular milieu and is the molecular target of the selective serotonin re-uptake inhibitors (SSRIs), a common group of anti-depressants. The current study comprehensively assesses the sequence, tissue distribution, transport kinetics and physiological function of a teleost SERT. The 2022 bp toadfish SERT sequence encodes a protein of 673 amino acids, which shows 83% similarity to zebrafish SERT and groups with SERT of other teleosts in phylogenetic analysis. SERT mRNA is ubiquitous in tissues and is expressed at high levels in the heart and, within the brain, in the cerebellum. SERT cRNA expressed in oocytes demonstrates a value of 2.08±0.45 μmol l, similar to previously reported values for zebrafish and human SERT. Acute systemic blockade of SERT by intraperitoneal administration of the SSRI fluoxetine (FLX) produces a dose-dependent increase in plasma 5-HT, indicating effective inhibition of 5-HT uptake from the circulation. As teleosts lack platelets, which are important 5-HT sequestration sites in mammals, the FLX-induced increase in plasma 5-HT suggests that toadfish tissues may normally be responsible for maintaining low 5-HT concentrations in the bloodstream.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular and functional characterization of the Gulf toadfish serotonin transporter (SERT; SLC6A4)

Amador

McDonald

2018

Journal of Experimental Biology

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“…Further, these events are also in use for another AOP currently under development (https://aopwiki.org/aops/98). The utilization of 5-HTT inhibition as the molecular initiating event for AOP 98 is based on existing literature on mollusks, crustaceans, and fish (Bossus et al 2014;McDonald 2017). Such connections emphasize the utility of read-across approaches to develop information networks while maximizing application of existing literature and guiding future investigations to close data gaps.…”

Section: Aop Development Using Bivalvesmentioning

confidence: 99%

Application of Biomarker Tools Using Bivalve Models Toward the Development of Adverse Outcome Pathways for Contaminants of Emerging Concern

Khan

Burgess

2020

Enviro Toxic and Chemistry

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As contaminant exposures in aquatic ecosystems continue to increase, the need for streamlining research efforts in environmental toxicology using predictive frameworks also grows. One such framework is the adverse outcome pathway (AOP). An AOP framework organizes and utilizes toxicological information to connect measurable molecular endpoints to an adverse outcome of regulatory relevance via a series of events at different levels of biological organization. Molecular endpoints or biomarkers are essential to develop AOPs and are valuable early warning signs of the toxicity of pollutants, including contaminants of emerging concern. Ecological risk-assessment approaches using tools such as biomarkers and AOPs benefit from identification of molecular targets conserved across species. Bivalve models are useful in such approaches and integral to our understanding of ecological and human health risks associated with contaminant exposures. We discuss the value of using biomarker approaches in bivalve models to meet the demands of twenty-first-century toxicology.

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Predicting Environmental Risks of Pharmaceuticals from Wholesale Data: An Example from Norway

Welch

Moe

Sharikabad

et al. 2023

Enviro Toxic and Chemistry

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Environmental risk assessment (ERA) of pharmaceuticals relies on available measured environmental concentrations, but often such data are sparse. Predicted environmental concentrations (PECs), calculated from sales weights, are an attractive alternative but often cover only prescription sales. We aimed to rank, by environmental risk in Norway, approximately 200 active pharmaceutical ingredients (APIs) over 2016–2019, based on sales PECs. To assess the added value of wholesale and veterinary data, we compared exposure and risk predictions with and without these additional sources. Finally, we aimed to characterize the persistence, mobility, and bioaccumulation of these APIs. We compared our PECs to available Norwegian measurements, then, using public predicted‐no‐effect concentrations, we calculated risk quotients (RQs) and appended experimental and predicted persistence and bioaccumulation. Our approach overestimated environmental concentrations compared with measurements for 18 of 20 APIs with comparable predictions and measurements. Seventeen APIs had mean RQs >1, indicating potential risk, while the mean RQ was 2.05 and the median 0.001, driven by sex hormones, antibiotics, the antineoplastic abiraterone, and common painkillers. Some high‐risk APIs were also potentially persistent or bioaccumulative (e.g., levonorgestrel [RQ = 220] and ciprofloxacin [RQ = 56]), raising the possibility of impacts beyond their RQs. Exposure and risk were also calculated with and without over‐the‐counter sales, showing that prescriptions explained 70% of PEC magnitude. Likewise, human sales, compared with veterinary, explained 85%. Sales PECs provide an efficient option for ERA, designed to overestimate compared with analytical techniques and potentially held back by limited data availability and an inability to quantify uncertainty but, nevertheless, an ideal initial approach for identification and ranking of risks. Environ Toxicol Chem 2023;00:1–18. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

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An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish

Cited by 47 publications

References 169 publications

Molecular and functional characterization of the Gulf toadfish serotonin transporter (SERT; SLC6A4)

Molecular and functional characterization of the Gulf toadfish serotonin transporter (SERT; SLC6A4)

Application of Biomarker Tools Using Bivalve Models Toward the Development of Adverse Outcome Pathways for Contaminants of Emerging Concern

Predicting Environmental Risks of Pharmaceuticals from Wholesale Data: An Example from Norway

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