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1.
Ecotoxicol Environ Saf ; 208: 111700, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396031

RESUMO

Sertraline (SER) is one of the most frequently detected antidepressant drugs in aquatic environments. However, knowledge regarding SER-induced behavioral alterations in fish is insufficient, as well as the mechanisms underlying SER-induced toxicity. The present study aimed to determine behavioral and molecular responses in larval fish following SER exposure with a focus on its mode of action. Zebrafish embryos (~6 h-post-fertilization, hpf) were exposed to one of three concentrations of SER (1, 10, 100 µg/L) for 6 days, respectively. Evaluated parameters included development, behavior, transcripts related to serotonin signaling, serotonin levels, and acetylcholinesterase activity. Accelerated hatching of zebrafish embryos was observed for those fish exposed to 100 µg/L SER at 54 hpf. Locomotor activity (e.g. distance moved and mobile cumulative duration) was significantly reduced in larval zebrafish following exposure to 10 and 100 µg/L SER. Conversely, larval fish showed increased dark-avoidance after exposure to 1-100 µg/L SER. Of the measured transcripts related to serotonin signaling, only serotonin transporter (serta) and serotonin receptor 2c (5-ht2c) mRNA levels were increased in fish in response to 10 µg/L SER treatment. However, serotonin levels were unaltered in larvae exposed to SER. There were no differences among groups in acetylcholinesterase activity at any concentration tested. Taking together, the results evidenced that exposure to SER alters behavioral responses in early-staged zebrafish, which may be related to the abnormal expression of 5-ht2c. This study elucidates molecular responses to SER and characterizes targets that may be sensitive to antidepressant pharmaceuticals in larval fish.


Assuntos
Antidepressivos/toxicidade , Comportamento Animal/efeitos dos fármacos , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/fisiologia , Animais , Antidepressivos/análise , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Locomoção/efeitos dos fármacos , Serotonina/metabolismo , Sertralina/análise , Transdução de Sinais/efeitos dos fármacos , Poluentes Químicos da Água/análise , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo
2.
Aquat Toxicol ; 226: 105564, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32683169

RESUMO

Millions of pharmaceuticals are prescribed each year. Wastewater treatment plants fail to remove all pharmaceuticals from discharge leading to detectable concentrations entering aquatic ecosystems where the compounds can encounter nontarget organisms. Selective serotonin reuptake inhibitor (SSRI) class of antidepressants interact with transporters in the brain and peripheral nervous system to change serotonin levels in the synapse. Sublethal exposure to SSRIs can impact fish feeding behaviors, which can have impacts on ecological fitness. We exposed hybrid striped bass (Morone saxatilis x Morone chrysops) to low, medium, and high concentrations of sertraline (4.5 ± 0.84 µg/L, 35.4 ± 2.18 µg/L, and 96.8 ± 6.4 µg/L) over six days with six additional recovery days. Concentrations were chosen to compare results with a mixture study previously completed in our lab. Every three days we tracked how long each bass took to consume four fathead minnows (Pimephales promelas) and conducted destructive sampling to obtain brain and plasma samples. Brain and plasma samples were analyzed for sertraline levels and we calculated whole brain serotonin levels. During the exposure period, bass showed an increased time to capture prey, but time to capture prey returned to control levels during the six-day recovery period. Sertraline was detected in brain and plasma during the duration of the experiment, though not always in a dose-dependent fashion. While we demonstrated a relationship between time to capture prey and decrease whole brain serotonin levels, the decrease in time to capture prey during the recovery period suggests the serotonin levels in the brain are not solely responsible for the outward behavioral expression observed.


Assuntos
Bass/fisiologia , Química Encefálica/efeitos dos fármacos , Comportamento Predatório/efeitos dos fármacos , Inibidores de Captação de Serotonina/toxicidade , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Bass/sangue , Bass/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ecossistema , Comportamento Alimentar/efeitos dos fármacos , Serotonina/metabolismo
3.
Aquat Toxicol ; 218: 105337, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31739108

RESUMO

To understand effects of two widely used antidepressant on the antioxidant defense mechanism in the marine rotifer Brachionus koreanus, we assessed acute toxicity and measured population growth, reactive oxygen species (ROS) levels, glutathione (GSH) levels, and antioxidant enzymatic activities (GST, GR, and SOD) in response to fluoxetine hydrochloride (FLX) and sertraline hydrochloride (SER). The no observed effect concentration-24 h of fluoxetine and sertraline were 1000 µg/L and 450 µg/L, respectively, whereas the median lethal concentration (LC50)-24 h of fluoxetine and sertraline were 1560 µg/L and 507 µg/L, respectively. Both fluoxetine and sertraline caused significant reduction (P < 0.05) in the population growth rate indicating that both antidepressants have a potential adverse effect on life cycle parameters of B. koreanus. The intracellular ROS level and GSH level were significantly modulated (P < 0.05) in response to fluoxetine and sertraline. In addition, antioxidant enzymatic activities have shown significant modulation (P < 0.05) in response to FLX and SER in B. koreanus. Furthermore, transcriptional profiles of antioxidant genes (GSTs, SODs, and GR) have shown modulation in response to FLX compared to SER-exposed B. koreanus. Our results indicate that fluoxetine and sertraline induce oxidative stress, leading to reduction in the population density and modulation of antioxidant defense mechanism in the marine rotifer B. koreanus.


Assuntos
Antidepressivos/toxicidade , Fluoxetina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Rotíferos/efeitos dos fármacos , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Antioxidantes/metabolismo , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Estágios do Ciclo de Vida/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Rotíferos/crescimento & desenvolvimento , Rotíferos/metabolismo
4.
Ecotoxicol Environ Saf ; 183: 109486, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31377518

RESUMO

The increasing use of Sertraline (SER) as antidepressant and its consequent presence in the aquatic environment is raising concern about the chronic effects of this pharmaceutical to aquatic organisms. As the current concentrations of SER in surface waters are typically in the low ng/L range, acute toxicity is unlikely to occur. However, prolonged exposure to low concentrations of SER may lead to sub-lethal effects in aquatic organisms, including alterations in important physiological functions like growth, reproduction, behaviour, and also in key biochemical processes, such as those associated with neurotransmission and redox balance. To test this hypothesis, we selected the amphipod Gammarus locusta, a keystone species used in ecotoxicological hazard assessment. In the present study, juveniles' G. locusta from a permanent laboratory culture were chronically exposed to low concentrations of SER (8-1000 ng/L) in a bioassay that lasted for 48 days, allowing for a life-cycle study including effects on reproduction. At the lowest SER concentrations with environmental relevance (8, 40 and 200 ng/L) we detected no significant changes in key ecological endpoints such as survival, growth, reproduction and movement behaviour, or in any of the biochemical markers analysed. However, at 1000 ng/L SER (a concentration one order of magnitude higher than the levels reported in aquatic environments) females showed a significant increase in movement versus control, whereas no activity changes were observed in males. Overall, these findings indicate that G. locusta females are potentially more susceptible to the chronic effects of SER. Moreover, the current environmental SER concentrations are unlikely to affect amphipod's ecological endpoints because only SER concentrations higher than the levels reported in aquatic environments produced effects on the behaviour of G. locusta females. However, the increasing consumption of SER, highlights the importance of monitoring its chronic risk to the aquatic wildlife.


Assuntos
Anfípodes/efeitos dos fármacos , Antidepressivos/toxicidade , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Feminino , Masculino , Reprodução/efeitos dos fármacos , Testes de Toxicidade Crônica
5.
Artigo em Inglês | MEDLINE | ID: mdl-31466416

RESUMO

The ecotoxicity of psychiatric pharmaceuticals to aquatic organisms is being increasingly recognized. However, current ecological studies focus on the effects of individual psychiatric pharmaceuticals, with little attention being given to their combined effects. In this study, the interactive effects of two psychiatric pharmaceuticals, sertraline (SER) and diphenhydramine (DPH), on bioconcentration and biochemical and behavioral responses were investigated in crucian carp (Carassius auratus) after seven days of exposure. DPH was found to increase the accumulation of SER in fish tissues relative to SER-alone exposure. In addition, the mixture of SER and DPH significantly changed the activities of antioxidant enzymes and led to significant increases in malondialdehyde content, relative to SER alone. Concerning the neurotoxicity, relative to SER-alone exposure, brain AChE activity was significantly enhanced in fish following the combined exposure. Regarding behavioral responses, swimming activity and shoaling behavior were significantly altered in co-exposure treatments compared with the SER alone. Moreover, the inhibition effects on the feeding rates were increased in co-exposure treatments compared to SER alone. Collectively, our results suggest that the mixtures of psychiatric pharmaceuticals may pose more severe ecological risks to aquatic organisms compared to these compounds individually.


Assuntos
Carpas/fisiologia , Difenidramina/toxicidade , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Acetilcolinesterase/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Sinergismo Farmacológico , Malondialdeído/metabolismo , Natação
6.
Environ Pollut ; 254(Pt B): 113029, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454584

RESUMO

Neurotransmission plays an essential role during the central nervous system (CNS) development. During the last years, several studies based on the changes produced in neurotransmitters of aquatic organisms caused by pharmaceuticals have been reported. Daphnia magna, the aquatic ecotoxicological model organism, shares several of the neurotransmitters targeted by antidepressant and other neuro-active drugs with vertebrates. Therefore, a method based on liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) has been applied for the first time to study the levels of 41 neurotransmitters in Daphnia magna under the effect of four different neuro-active pharmaceuticals (sertraline, venlafaxine, duloxetine and fluoxetine). In addition, the performance of LC-HRMS was studied in terms of linearity, sensitivity, intra- and inter-day precision, and overall robustness. The developed analytical method using LC-HRMS is a new tool for neurotoxicology research using the Daphnia magna model. As a result, general differences on the concentrations of those neurotransmitters exposed to the mentioned pharmaceuticals were observed.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Daphnia/química , Cloridrato de Duloxetina/toxicidade , Fluoxetina/toxicidade , Espectrometria de Massas/métodos , Neurotransmissores/química , Sertralina/toxicidade , Cloridrato de Venlafaxina/toxicidade , Animais , Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/crescimento & desenvolvimento , Organismos Aquáticos/metabolismo , Daphnia/efeitos dos fármacos , Daphnia/metabolismo , Cloridrato de Duloxetina/análise , Fluoxetina/análise , Modelos Animais , Neurotransmissores/metabolismo , Sertralina/análise , Cloridrato de Venlafaxina/análise , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
7.
Aquat Toxicol ; 213: 105222, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31212248

RESUMO

Pharmaceutically active compounds are major contaminants of aquatic environments that show direct and indirect effects on aquatic organisms even at low concentrations. The aim of this study was to assess the effects of the illicit drug methamphetamine and the antidepressant sertraline on clonal marbled crayfish Procambarus virginalis. Crayfish exposed to the environmentally relevant concentrations of methamphetamine of ∼1 µg L-1 did not exhibit significant differences from unexposed controls in distance moved, velocity, and activity level with or without available shelter. Sertraline-exposed (∼1 µg L-1) crayfish were significantly more active, regardless of available shelter, and moved greater distances when shelter was available, compared to control crayfish. Crayfish exposed to methamphetamine and sertraline spent significantly more time outside the shelters compared to controls. Sertraline-exposed crayfish spawned more frequently and showed higher mortality than controls. The results suggest that the low environmental concentrations of the tested compounds could alter the behavior and life history traits of crayfish, resulting in higher reproductive effort and mortality.


Assuntos
Organismos Aquáticos/efeitos dos fármacos , Organismos Aquáticos/crescimento & desenvolvimento , Astacoidea/efeitos dos fármacos , Astacoidea/crescimento & desenvolvimento , Comportamento Animal/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Metanfetamina/toxicidade , Sertralina/toxicidade , Animais , Invertebrados , Poluentes Químicos da Água/toxicidade
8.
Sci Total Environ ; 654: 129-134, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30439689

RESUMO

Sertraline hydrochloride (Ser-HCl), a widely used antidepressant, becomes an aquatic contaminant via metabolic excretion and improper disposal; however, it is unknown how Ser-HCl affects aquatic microbial communities. The present study investigated the effects of Ser on the structures of aquatic microbial communities via high-throughput sequencing analyses. Ser-HCl treatment inhibited the growth of two model algae (the green alga, Chlorella vulgaris, and the cyanobacterium, Microcystis aeruginosa) and decreased the chlorophyll a (Chl-a) concentration in the microcosm to reduce the photosynthetic efficiency. High-throughput sequencing analyses showed that exposure to Ser-HCl disturbed the balance of cyanobacteria species by stimulating the growth of specific cyanobacteria. Among eukaryotes, the richness as well as the diversity indices were significantly enhanced after 5 days of Ser-HCl treatment but sharply decreased with exposure time. Nucleariida occupied an absolute majority (97.83%) within the eukaryotes, implicating that Ser-HCl disturbed the ecological equilibrium in microcosms. Ser-HCl will continue to be an environmental contaminant due to its wide usage and production. Our current study clarified the potential ecological risk of Ser-HCl to aquatic microorganisms. These findings suggest that more attention should be given to the negative effects of these bioactive pollutants on aquatic environments.


Assuntos
Antidepressivos/toxicidade , Chlorella vulgaris/efeitos dos fármacos , Microbiota/efeitos dos fármacos , Microcystis/efeitos dos fármacos , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Chlorella vulgaris/genética , Chlorella vulgaris/metabolismo , Clorofila/metabolismo , Ecotoxicologia , Sequenciamento de Nucleotídeos em Larga Escala , Microbiota/genética , Microbiota/fisiologia , Microcystis/genética , Microcystis/metabolismo , Fotossíntese/efeitos dos fármacos , RNA Ribossômico 16S/genética
9.
Toxicol Sci ; 163(2): 609-619, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29850907

RESUMO

Selective serotonin reuptake inhibitors are used as first line treatment in major depressive disorder. However, selective serotonin reuptake inhibitors have also been associated with sexual disorders, abnormalities, and sexual dysfunction, although mechanisms are unclear. The aim of this project was to investigate the possible endocrine disrupting effect of sertraline (SER) on sex steroid production in male rats exposed to 3 therapeutically realistic doses of SER 1.25, 5, and 20 mg/kg/day. To achieve this, we analyzed all the major steroids in testis, adrenals, brain, and plasma using Liquid chromatography tandem mass spectrometry. Furthermore, we investigated the potential effects on gene expression on the major genes involved in testicular, adrenal and brain steroidogenesis using quantitative PCR. Moreover, plasma luteinizing hormone (LH) levels were analyzed. We observed significant reduction in steroid production, in particular on the testicular Δ-4 axis and on the adrenal CYP17-hydroxylase axis. Effects in brain and plasma were less pronounced. Testicular gene transcription was also significantly down-regulated except for the CYP19 (aromatase) gene. In contrast, no effects on the adrenal gene expression were observed, except for an up-regulation of the CYP17. Plasma LH and LH/TS were increased, in particular in the lowest exposure group, indicating some degree of compensatory hypogonadism. In conclusion, this study demonstrates extensive endocrine disruption during SER exposure in male rats, both directly on steroid production in major endocrine tissues, but also indirectly by affecting gene expression. Furthermore, increased LH levels may augment decreased sex steroid production, in particular testosterone production, inducing a state of compensatory hypogonadism.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Expressão Gênica/efeitos dos fármacos , Hipogonadismo/induzido quimicamente , Hormônio Luteinizante/sangue , Sertralina/toxicidade , Testículo/efeitos dos fármacos , Testosterona/biossíntese , Glândulas Suprarrenais/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Hipogonadismo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Testículo/metabolismo , Testosterona/genética
10.
Environ Toxicol Pharmacol ; 61: 107-115, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29883902

RESUMO

Although sertraline is widely prescribed as relatively safe antidepressant drug, hepatic toxicity was reported in some patients with sertraline treatment. The present study was conducted to investigate the morphometric, hepatotoxicity, and change in gene expression of drug metabolizing enzymes. Male healthy adult rabbits (Oryctolagus cuniculus) ranging from 1050 to 1100 g were exposed to oral daily doses of sertraline (0, 1, 2, 4, 8 mg/kg) for 9 weeks. The animals were subjected to morphometric, hepatohistological, histochemical and quantitative real-time polymerase chain reaction analyses. Sertraline chronic exposure induced morphometric changes and provoked histological and histochemical alterations including: hepatocytes hydropic degeneration, necrosis, nuclear alteration, sinusoidal dilation, bile duct hyperplasia, inflammatory cells infiltration, portal vessel congestion, Kupffer cells hyperplasia, portal fibrosis and glycogen depletion. In addition, the gene expression of drug and arachidonic acid metabolizing enzymes were reduced significantly (p value <0.05). The most affected genes were cyp4a12, ephx2, cyp2d9 and cyp1a2, demonstrating 5 folds or more down-regulation. These findings suggest that chronic sertraline treatment induced toxic histological alterations in the hepatic tissues and reduced the gene expression of drug metabolizing enzymes. Patients on chronic sertraline treatment may be on risk of hepatotoxicity with reduced capacity to metabolize drugs and fatty acids.


Assuntos
Antidepressivos/toxicidade , Fígado/efeitos dos fármacos , Inibidores de Captação de Serotonina/toxicidade , Sertralina/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Crônica , Sistema Enzimático do Citocromo P-450/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Glucuronosiltransferase/genética , Glicogênio/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Coelhos , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia
11.
Ecotoxicology ; 27(2): 144-153, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29349647

RESUMO

Due to their potential for affecting the modulation of behaviour, effects of selective serotonin reuptake inhibitors (SSRIs) in the environment are particularly interesting regarding interspecies interactions and non-consumptive effects (NCEs) induced by predator cues in prey organisms. We evaluated the effects of sertraline (0.4, 40 ng/L, 40 µg/L) over 8 days on activity and habitat choice in the freshwater snail Radix balthica, on snails' boldness in response to mechanical stimulation (simulating predator attack), and their activity/habitat choice in response to chemical cues from predatory fish. We hypothesised that sertraline exposure would detrimentally impact NCEs elicited by predator cues, increasing predation risk. Although there were no effects of sertraline on NCEs, there were observed effects of chemical cue from predatory fish on snail behaviour independent of sertraline exposure. Snails reduced their activity in which the percentage of active snails decreased by almost 50% after exposure to fish cue. Additionally, snails changed their habitat use by moving away from open (exposed) areas. The general lack of effects of sertraline on snails' activity and other behaviours in this study is interesting considering that other SSRIs have been shown to induce changes in gastropod behaviour. This raises questions on the modes of action of various SSRIs in gastropods, as well as the potential for a trophic "mismatch" of effects between fish predators and snail prey in aquatic systems.


Assuntos
Inibidores de Captação de Serotonina/toxicidade , Sertralina/toxicidade , Caramujos/fisiologia , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade , Animais
12.
Aquat Toxicol ; 196: 117-123, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29367071

RESUMO

Antidepressants are among the most prescribed pharmaceuticals throughout the world. Their presence has already been detected in several aquatic ecosystems worldwide and their effects on non-target organisms justify the growing concern of both the public and regulatory authorities. These emerging pollutants do not occur as isolated compounds but rather as multi-component mixtures, which may lead to increased adverse effects compared to individual compounds. Freshwater and marine algae seem particularly sensitive to pharmaceuticals, including antidepressants. Studies assessing the toxicity of antidepressant mixture to algae focused mainly on binary mixtures of selective serotonin reuptake inhibitors. In the present experiment, the freshwater algae Raphidocelis subcapitata (formerly known as Pseudokirchneriella subcapitata) and the marine diatom Skeletonema marinoi were exposed to equitoxic mixtures of 9 antidepressants (fluvoxamine, fluoxetine, sertraline, duloxetine, venlafaxine, clomipramine, amitriptyline, and citalopram) at different concentrations. The growth inhibition was measured. Results showed that the toxicity of this mixture was higher than the effects of each individual component, highlighting simple additivity or synergistic effects, whereas tested concentrations were below the 10% inhibition concentration (IC10) of each compound. Moreover, the QSAR analysis highlighted that antidepressants would act through narcosis (non-specific mode of action) towards the two species of algae. However, more specific effects can be observed by differentiating compounds with a primary/secondary amine from those with a tertiary amine. These mixture effects on algal species have to be assessed, especially since any impacts on phytoplankton could ultimately impact higher trophic levels (less food, secondary poisoning).


Assuntos
Aminas/química , Antidepressivos/toxicidade , Clorófitas/efeitos dos fármacos , Diatomáceas/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Antidepressivos/química , Clorófitas/crescimento & desenvolvimento , Diatomáceas/crescimento & desenvolvimento , Fluoxetina/toxicidade , Sertralina/toxicidade , Cloridrato de Venlafaxina/toxicidade , Poluentes Químicos da Água/química
13.
Toxicol Lett ; 281: 20-25, 2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28844482

RESUMO

The use of antidepressants in pregnant women is rising, with rates up to 7.5% in the United States. Selective serotonin reuptake inhibitors (SSRIs) are currently the most common antidepressant prescribed to pregnant women. The teratogenic effects of SSRI exposure are debated because of discrepancies in epidemiological studies. As an alternative to epidemiological and animal studies, human embryonic stem cell research (hESC) provides a human-based experimental model to examine the risks of prenatal SSRI exposure. Neural crest stem cells (NCSCs) play an important role in craniofacial and cardiac development as precursors to craniofacial bones and heart septa. This study examines the effects of paroxetine (Paxil) and sertraline (Zoloft) exposure on proliferation, migration, and AP-2α protein expression of NCSC in vitro. hESCs were exposed to paroxetine and sertraline at three concentrations while undergoing directed differentiation into NCSCs. Our results indicate exposure to paroxetine significantly increased proliferation, migration, and AP-2α protein expression in NCSCs. Exposure to sertraline significantly decreased proliferation and significantly increased AP-2α protein expression in NCSC. This evidence suggests paroxetine and sertraline alter normal NCSC behavior and may thereby disrupt cardiac and craniofacial development.


Assuntos
Antidepressivos/toxicidade , Células-Tronco Embrionárias/efeitos dos fármacos , Crista Neural/efeitos dos fármacos , Inibidores de Captação de Serotonina/toxicidade , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células-Tronco Embrionárias/citologia , Regulação da Expressão Gênica , Humanos , Crista Neural/citologia , Paroxetina/toxicidade , Sertralina/toxicidade , Fator de Transcrição AP-2/genética , Fator de Transcrição AP-2/metabolismo
14.
Toxicol In Vitro ; 44: 154-163, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28712878

RESUMO

Antidepressants are commonly employed for the treatment of major depressive disorders and other psychiatric conditions. We investigated the relatively acute cytotoxic effects of three commonly prescribed antidepressants: fluoxetine, sertraline, and clomipramine on rat primary blood brain barrier endothelial cells over a concentration range of 0.1-100µM. At therapeutic concentrations (0.1µM) no significant cytotoxicity was observed after 4, 24, or 48h. At high therapeutic to overdose concentrations (1-100µM), antidepressants reduced cell viability in proportion to their concentration and exposure duration. At 1µM, antidepressants significantly reduced mitochondrial membrane potential. At drug concentrations producing ~50% inhibition of cell viability, all drugs significantly reduced cellular oxygen consumption rates, activities of mitochondrial complexes I and III, and triggered a significant increase of lactate production. Fluoxetine (6.5µM) and clomipramine (5.5µM) also significantly lowered transcellular transport of albumin. The mechanism of cellular cytotoxicity was evaluated and at high concentrations all drugs significantly increased the production of reactive oxygen species, and significantly increased the activity of the pro-apoptotic caspases-3, 8, and 9. Comet assays revealed that all drugs were genotoxic. Pre-incubation of cells with glutathione significantly ameliorated antidepressant-induced cytotoxicity, indicating the potential benefit of treatment of overdosed patients with antioxidants.


Assuntos
Antidepressivos/toxicidade , Clomipramina/toxicidade , Células Endoteliais/efeitos dos fármacos , Fluoxetina/toxicidade , Sertralina/toxicidade , Animais , Barreira Hematoencefálica/citologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/metabolismo , Metabolismo Energético/efeitos dos fármacos , Glutationa/farmacologia , Ácido Láctico/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo
15.
Biomed Res Int ; 2017: 5792621, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28626759

RESUMO

Toxicity attributed to sertraline has been demonstrated recently in different cell types and also in some organisms. We investigated the effect of sertraline on planarians, which are considered suitable for investigations in neurotoxicology and currently are widely used as an animal model in neuropharmacological studies. Planarians treated with 10 µM sertraline showed a rapid reduction in their spontaneous movement until they became completely motionless and then showed a series of asynchronous paroxysms (seizures) followed by progressive tissue damage, beginning 48 h after the sertraline treatment, and died approximately 72 h later. Our data showed that sertraline does not cause planarian death within the range of therapeutic concentrations; however, behavioral alterations were observed with concentrations that can be considered compatible with therapeutic ones, such as a significant reduction in planarian locomotory activity at 0.4 µM. Treatment with 4 µM sertraline had a significant effect, reducing planarian locomotory activity and increasing the number of asynchronous paroxysms; both effects were significantly maintained even 24 h after the sertraline was withdrawn. These behavioral changes observed at low micromolar concentrations suggest that sertraline might have residual biological consequences for planarians, even after it is withdrawn.


Assuntos
Comportamento Animal/efeitos dos fármacos , Planárias , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Sertralina/toxicidade , Animais , Relação Dose-Resposta a Droga , Convulsões/patologia
16.
J Cardiovasc Pharmacol ; 70(2): 119-127, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28459713

RESUMO

Selective serotonin reuptake inhibitors are prescribed to 6%-10% of pregnant women in the United States. Using an intrauterine plus neonatal exposure model to represent exposure throughout human pregnancy, we hypothesized sertraline exposure would impact intracardiac serotonin signaling and lead to small left heart syndrome in the absence of maternal psychopathology. C57BL/6 adult female mice received sertraline (5 mg·kg·d IP) or saline throughout pregnancy to time of delivery. Pups maintained exposure on postnatal days 1-14 to encompass the developmental window analogous to human gestation. Sertraline-exposed mice had increased cardiac hydroxyproline content, decreased 5-HT2B receptor mRNA levels, and increased 5-HT2A receptor and serotonin transporter mRNA levels on postnatal day 21 (P < 0.05). These changes were associated with diminished exercise capacity at 6 weeks (P < 0.05) and decreased adult shortening fraction and stroke volume at 5 months. Isolated cardiomyocytes from neonatal sertraline-exposed mice had significantly decreased proliferation, cross-sectional area, and phosphorylation of Akt (P < 0.05 vs. neonatal control mice). Perinatal sertraline exposure alters neonatal cardiac development and produces long-standing changes in adult cardiac function and exercise capacity. Further studies are needed to assess whether similar findings are present in the growing population that has been exposed to selective serotonin reuptake inhibitors during development.


Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Inibidores de Captação de Serotonina/toxicidade , Sertralina/toxicidade , Volume Sistólico/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Volume Sistólico/fisiologia
17.
Bull Environ Contam Toxicol ; 98(6): 753-757, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28386654

RESUMO

The purpose of this study was to evaluate the steroidogenic effects of sertraline, a popular selective serotonin reuptake inhibitor, on larval fathead minnow (FHM; Pimephales promelas) and adult FHM. Larvae were exposed to 0.1, 1, and 10 µg/L sertraline for 28 days and analyzed for differential mRNA expression of 11ß-hydroxysteroid dehydrogenase (11ß-HSD), 20ß-hydroxysteroid dehydrogenase (20ß-HSD), aromatase (CYP19a), nuclear thyroid receptor alpha (TRα), and normalized to RP-L8. Adult FHM were exposed to 3 or 10 µg/L sertraline for 7 days and analyzed for differential expression of the same genes with the addition of thyroid receptor beta (TRß). Larval FHM exposed to 0.1 µg/L had a significant upregulation of both 20ß-HSD and TRα while adult FHM exposed to 10 µg/L had a significant upregulation of 11ß-HSD expression in brain tissue. The significance of these findings with respect to survival, growth and reproduction are currently unknown, but represent areas for future research.


Assuntos
Cyprinidae/fisiologia , Sertralina/toxicidade , Esteroides/metabolismo , Poluentes Químicos da Água/toxicidade , Animais , Aromatase , Cyprinidae/metabolismo , Feminino , Masculino , Reprodução/efeitos dos fármacos , Poluentes Químicos da Água/metabolismo
18.
Mar Environ Res ; 128: 88-97, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27255123

RESUMO

Widespread contamination of coastal environments by emerging compounds includes low concentrations of pharmaceuticals. These pollutants are not currently incorporated in monitoring programs despite their effects on non-target organisms are very little documented. Among the selective serotonin reuptake inhibitor (SSRI) antidepressants, sertraline (SRT) is one of the most prescribed globally. In this work, earlier life stages of Amphibalanus amphitrite, Brachionus plicatilis and Mytilus galloprovincialis were exposed to environmental concentrations of SRT in order to study both sub-lethal and lethal responses in 24/48 h-tests. Low concentrations of SRT altered significantly swimming behavior in A. amphitrite and B. plicatilis giving 48 h-EC50 (µg/L) of 113.88 and 282.23, respectively whereas higher values were observed for mortality and immobilization. EC50 embryotoxicity with M. galloprovincialis was 206.80 µg/L. This work add new data about SRT ecotoxicity on marine invertebrates and confirms the applicability of behavioral endpoints to evaluate the environmental impact of antidepressants in marine organisms.


Assuntos
Antidepressivos/toxicidade , Organismos Aquáticos/fisiologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Sertralina/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Invertebrados , Mytilus , Rotíferos , Testes de Toxicidade
19.
Environ Sci Pollut Res Int ; 24(1): 725-731, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27752949

RESUMO

Exposure to human antidepressants has been shown to disrupt locomotion and other foot-mediated mechanisms in aquatic snails. We tested the effect of three selective serotonin reuptake inhibitor (SSRI)- and one selective serotonin-norepinephrine reuptake inhibitor (SNRI)-type antidepressants on the righting response in the marine snail, Ilyanassa obsoleta. All four antidepressants (fluoxetine, sertraline, paroxetine, venlafaxine) significantly increased righting time compared with controls with an exposure time as short as 1 h. Dose responses were nonmonotonic with effects seen mainly at the lowest exposure concentrations and shortest duration. The lowest concentration to show an effect was 3.45 µg/L fluoxetine with a 2-h exposure period and is about 3.71 times higher than environmental concentrations. Our results highlight rapid disruption of another foot-mediated behavior in aquatic snails by SSRI-type antidepressants. We discuss these and other reported nonmonotonic dose responses caused by antidepressants in terms of the various possible physiological mechanisms of action in nontarget aquatic species.


Assuntos
Antidepressivos/toxicidade , Inibidores de Captação de Serotonina/toxicidade , Inibidores da Recaptação de Serotonina e Norepinefrina/toxicidade , Caramujos/efeitos dos fármacos , Animais , Fluoxetina/toxicidade , Paroxetina/toxicidade , Sertralina/toxicidade , Caramujos/fisiologia , Cloridrato de Venlafaxina/toxicidade
20.
Aquat Toxicol ; 182: 20-30, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27842272

RESUMO

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) are widely prescribed for the treatment of depression and anxiety disorders. Consequently, these compounds are frequently identified in global waterways where they may pose a hazard to aquatic biota. Evidence demonstrates these compounds to be capable of influencing the behaviour of fish, but the relevance of many reported behavioural endpoints is unclear and the value of some findings has been questioned. Since these compounds act on neuroendocrine-mediated pathways in vertebrates, the present study explored how exposure to two representative SSRIs (fluoxetine and sertraline) and an SNRI (venlafaxine) affect circadian rhythms in fish. Male mosquitofish (Gambusia holbrooki) were exposed to 1, 10 and 100µg/L concentrations of these compounds individually and when present as a full mixture, for a period of one week. Neither fluoxetine nor sertraline had an impact on diurnal activity patterns when fish were exposed to these compounds alone at any concentration, whereas venlafaxine significantly disrupted normal circadian rhythmicity but only at 100µg/L. When fish were exposed to the full mixture, significantly altered diurnal activity patterns were rapidly observed at nominal concentrations of 1 and 100µg/L, but there was no effect at 10µg/L. This sort of non-monotonic dose relationship is not altogether unusual for fish exposed to antidepressants, but it poses a problem when attempting to evaluate potential risks to the aquatic environment. To evaluate the possibility for misinterpretation when collecting behavioural data over short temporal scales, the data for each day of the experiment was analysed separately. The outcomes demonstrate the importance of longer periods of data collection, which may be necessary to capture the full range of natural behavioural variability that exists both amongst and within individual fish. More importantly, these findings may help reveal why discrepancies are commonly being reported in the literature with regards behavioural effects in fish exposed to antidepressants. It is thus suggested that research be aimed at documenting behavioural variability in fish species used in toxicity testing, to establish guidelines for quality control and where possible inform the development of standardised methodologies so that behavioural analysis can be more appropriately applied to the broad field of aquatic toxicology.


Assuntos
Antidepressivos/toxicidade , Comportamento Animal/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Ciprinodontiformes/fisiologia , Testes de Toxicidade/métodos , Animais , Fluoxetina/toxicidade , Inibidores de Captação de Serotonina/toxicidade , Sertralina/toxicidade , Cloridrato de Venlafaxina/toxicidade , Poluentes Químicos da Água/toxicidade
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