Integrated physio-biochemical and transcriptomic analysis reveals the joint toxicity mechanisms of two typical antidepressants fluoxetine and sertraline on Microcystis aeruginosa.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are of increasing concern worldwide due to their ubiquitous occurrence and detrimental effects on aquatic organisms. However, little is known regarding their effects on the dominant bloom-forming cyanobacterium, Microcystis aeruginosa. Here, we investigated the individual and joint effects of two typical SSRIs fluoxetine (FLX) and sertraline (SER) on M. aeruginosa at physio-biochemical and molecular levels. Results showed that FLX and SER had strong growth inhibitory effects on M. aeruginosa with the 96-h median effect concentrations (EC50s) of 362 and 225 µg/L, respectively. Besides, the mixtures showed an additive effect on microalgal growth. Meanwhile, both individual SSRIs and their mixtures can inhibit photosynthetic pigment synthesis, cause oxidative damage, destroy cell membrane, and promote microcystin-leucine-arginine (MC-LR) synthesis and release. Moreover, the mixtures enhanced the damage to photosynthesis, antioxidant system, and cell membrane and facilitated MC-LR synthesis and release compared to individuals. Furthermore, transcriptomic analysis revealed that the dysregulation of the key genes related to transport, photosystem, protein synthesis, and non-ribosomal peptide structures was the fundamental molecular mechanism underlying the physio-biochemical responses of M. aeruginosa. These findings provide a better understanding of the toxicity mechanisms of SSRIs to microalgae and their risks to aquatic ecosystems.

Personality Affects Zebrafish Response to Sertraline.

Sertraline is widely prescribed to treat anxiety and depression. Sertraline acts by blocking serotonin, norepinephrine, and dopamine transporters systems and has been detected in surface waters globally, where it may impact fish behavior. We classified zebrafish personality on three behavioral axes, boldness, anxiety, and sociability, assigning fish as either high or low in each category. The fish were exposed to nominal concentrations of 0, 5, 50, 500, or 5000 ng/L sertraline (measured concentrations: <10, 21.3, 370, and 2200 ng/L, respectively) to assess changes in boldness, anxiety, and sociability after 7 and 28 days. We also measured shoaling behavior and response to an alarm cue, and determined the gut microbiome of a subset of fish. After 7 days there was no overall effect of sertraline on boldness, but there was an interaction between initial personality and sex, with a stronger impact on females classified as low-boldness personality. Sertraline reduced sociability in all treatments compared with the control, but there was again an interaction between sertraline and initial personality. Fish that were classified as low-sociability responded more strongly to sertraline. After 7 days, fish exposed to a nominal concentration of 5000 ng/L (2200 ng/L measured) showed higher anxiety than controls, with the overall pattern of initial behavior retained. After 28 days, similar patterns were observed, but with higher variation. There was only a weak association between the gut microbiome and personality. Overall, the study highlights the importance of considering initial behavior, which can affect response to pollutants. Our results may also be applicable to human studies and provide a mechanism to explain why different individuals respond differently to the drug. Environ Toxicol Chem 2024;43:132-146. © 2023 SETAC.

Delicate plasticity: Maladaptive responses to fish predation risk in Daphnia magna caused by sertraline pollution.

An emerging environmental pollutant may have a greater impact on phenotypic plasticity than its direct toxicity, causing maladaptive responses of organisms to their current environment. To better understand such ecological risks, we proposed a delicate plasticity hypothesis: if an emerging stressor acts on the fundamental processes underlying a specific adaptive plastic response, it is more likely to pose high risks to the phenotypic plasticity. Endocrine regulation is one of the critical processes of plasticity and is becoming a target for emerging pollutants. To test this hypothesis, we measured individual traits and the expression of endocrine-related genes in Daphnia magna in response to fish predation risk under exponentially increasing concentrations of the antidepressant sertraline, a selective serotonin reuptake inhibitor. The results showed that sertraline impaired most of the defense responses of D. magna at concentrations lower than the effective concentrations of its direct toxicity. The high risks of sertraline on inducible defenses were also visually reflected in the relationships between toxicity and plasticity strength, that is, most of the defense responses exponentially decayed with an increase in sertraline toxicity. In addition, the expression of genes involved in serotonin synthesis was significantly correlated with the expression of other endocrine-related genes and with changes in morphological traits. These results revealed that environmental sertraline pollution could disturb endocrine regulation and cause high risks to inducible defenses of D. magna, providing evidence supporting the delicate plasticity hypothesis.

Impact of sertraline on biohydrogen production from alkaline anaerobic fermentation of waste activated sludge: Focusing on microbial community and metabolism.

Nowadays, antidepressants are massively consumed worldwide, inevitably bringing about the concern for their latent hazard to the natural environment. This research focused on exploring the effect of sertraline (SET, a typical antidepressant) on hydrogen yields from alkaline anaerobic fermentation of waste activated sludge (WAS). The hydrogen accumulation reached the peak of 14.73 mL/g VSS (volatile suspended solids) at a SET dosage of 50 mg/kg TSS (total suspended solids), i.e., 1.90 times of that in the control fermenter. The data of Illumina high-throughput sequencing demonstrated that SET promoted the expression of genes regulating the membrane transport. Microbial community analysis suggested that some species that could degrade refractory substances were enriched after SET exposure. Finally, metabolic pathways of hydrogen production and consumption were found to be significantly affected with SET addition. This study would deepen the concept of typical antidepressants influencing energy recovery from WAS.

Is lactational sertraline exposure safe for maternal health and the reproductive/neurobehavioral development of the descendants? A study in rats.

Although sertraline is considered one of the safest antidepressants in the lactation period, there are still few studies that assess its impact on child development. Therefore, this experimental study aimed to clarify the effect of sertraline on the neurobehavioral and reproductive development of male rats. Thus, 30 lactating rats were divided into 3 experimental groups (n = 10/group): CO- received filtered water, S10 and S20 groups that received, respectively, 10 and 20 mg/kg/day of sertraline. Treatment was performed by gavage, from postnatal days (PND) 1-20. During this period, the reflex and somatic development of rats were observed, as well as maternal behavior. On PND 21, mothers were euthanized and the organs were weighed. On PND 21, 45, and 100, one male from each litter was euthanized for histological and immunohistochemical (PCNA and WT1) analysis of the reproductive organs. The growth of body weight, the anogenital distance (AGD), the time to puberty, sperm quality, sexual behavior, neurobehavior, and natural fertility were also verified. Statistical analysis: One-way ANOVA or Kruskal-Wallis test (p ≤ 0.05). The results showed that mothers in the S20 group had an increase in thyroid weight. The male offspring exposed to sertraline had lower body weight (PND 7), lower AGD (PND 7 and 14), and delay in reflex development, in addition to histological alterations in the testis (PND 21). In adulthood, sperm quality was altered, without compromising natural fertility. Therefore, the present study found important alterations in the reflex and reproductive development of male rats exposed to sertraline during lactation.

Prenatal exposure to sertraline, associated or not with stress, can negatively program somatic and neurobehavioral development of female rats, and dysregulate reproductive function in adulthood.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed to pregnant women for treating mental illnesses. Among the drugs of this class, sertraline (ST) is the antidepressant therapy recommended most frequently. Therefore, this study aimed to evaluate the impact of gestational ST treatment on reproductive parameters and toxicological target organs of rat female offspring, as well as on somatic, reflex and neurobehavioral development, in a model of maternal adversity. Pregnant Wistar rats received vehicle (filtered water) or ST hydrochloride (20 mg/Kg/day diluted in vehicle) by oral gavage, associated or not with restraint stress for 1 h/day from gestational days 13-20. F1 female offspring was evaluated on reproductive parameters, body weight and somatic and reflex milestones from postnatal day (PND) 1. On PNDs 25 and 72, the elevated-plus-maze test was performed, while toxicological target organs were evaluated on PNDs 42 and 80. In utero exposure to ST, regardless of exposure to stress, reduced body weight at birth and affected the somatic development and estrous cycle. The absolute and relative thyroid weights were increased in Stress/ST group during puberty and adulthood, while the percentage of ovarian structures and the absolute uterine weight were altered in this group on PND 80. Prenatal exposure only to ST reduced initial body weight gain, delayed fur development and increased anxiety-like behavior on PND 25. Thus, this experimental study suggests that intrauterine exposure to ST disrupts the fetal environment and can negatively program serotonin-regulated processes. Furthermore, it impacts thyroid weight when associated with stress.

Contrasting dose response relationships of neuroactive antidepressants on the behavior of C. elegans.

Antidepressant prescriptions are on a rise worldwide and this increases the concerns for the impacts of these pharmaceuticals on nontarget organisms. Antidepressants are neuroactive compounds that can affect organism's behavior. Behavior is a sensitive endpoint that may also propagate effects at a population level. Another interesting aspect of antidepressants is that they have shown to induce non-monotonic dose-response (NMDR) curves. While such NMDR relationships may have clear implications for the environmental risk, the resolution of current studies is often too coarse to be able to detect relevant NMDR. Therefore, the current study was performed into the behavioral effects (activity, feeding and chemotaxis) in Caenorhabditis elegans as the model organism of the selective serotonin reuptake inhibitors fluoxetine and sertraline and the acetylcholinesterase inhibiting pesticide chlorpyrifos, using a wide range of concentrations (ng/l to mg/l). In order to statistically examine the non-monotonicity, nonlinear regression models were applied to the results. The results showed a triphasic dose-response relationship for activity and chemotaxis after exposure to fluoxetine, but not to sertraline or chlorpyrifos. Effects of fluoxetine already occurred at low concentrations in the range of ng/l while sertraline only showed effects at concentrations in the µg/l range, similar to chlorpyrifos. The different responses between fluoxetine and sertraline, both SSRIs, indicate that response patterns may not always be extrapolated from chemicals with the same primary mode of action. The effects of fluoxetine at low concentrations, in a non-monotonic manner, confirm the relevance of examining such responses at low concentrations.

Reproductive Development of Male Rats Exposed In Utero to Stress and/or Sertraline.

Despite increased prescription of sertraline during pregnancy, little is known about its action on reproductive development. Therefore, this study aimed to investigate the impact that stress, associated or not with sertraline, causes on the reproductive development of male rats. Pregnant Wistar rats were divided into 4 groups (n = 16/group): CO-received filtered water; SE-received 20 mg/kg sertraline; ST-submitted to restraint stress and received filtered water; SS-submitted to restraint stress and received sertraline. The treatment was carried out from gestational days (GDs) 13-20. The animals were euthanized on GD 20 (n = 8/group), postnatal day (PND) 45 (n = 8/group), and PND 110 (n = 8/group). The testes and epididymis were analyzed histologically, and immunohistochemistry was performed on the testes by proliferating cell nuclear antigen (PCNA) and the Wilms tumor protein (Wt1). Sperm quality was also analyzed on PND 110. The evolution of body weight, anogenital distance (AGD), and puberty installation day were also verified. Statistical analysis: 2-way ANOVA or Kruskal-Wallis test (p ≤ .05). Fetal testes presented a large number of acidophilic cells in the sertraline-exposed groups. The SS group also showed a decrease in the nuclear volume of Leydig cells. This same group showed low expression of PCNA and Wt1, decreased weight of the testes and epididymis, lower AGD, and delayed puberty installation. The adulthood groups exposed to sertraline presented alterations in sperm morphology and motility. The results demonstrated that prenatal exposure to sertraline compromises the development of the rat reproductive system.

Transcriptome profiling reveals toxicity mechanisms following sertraline exposure in the brain of juvenile zebrafish (Danio rerio).

Sertraline (SER) is one of the most commonly detected antidepressants in the aquatic environment that can negatively affect aquatic organisms at low concentrations. Despite some knowledge on its acute toxicity to fish, the effects of chronic SER exposure remain poorly understood along with any underlying mechanisms of SER-induced toxicity. To address this knowledge gap, the effects of chronic exposure to three SER concentrations from low to high were investigated in zebrafish. Juvenile zebrafish were exposed to three concentrations of 1, 10, or 100 µg/L of SER for 28 d, after which indicators of oxidative stress and neurotoxicity in the brain were measured. Superoxide dismutase (SOD) activity was significantly enhanced by SER at 1 up to 100 µg/L, and catalase (CAT) activity was significantly induced by SER at 1 or 10 µg/L. The activity of acetylcholinesterase (AChE) was significantly induced by 10 and 100 µg/L of SER, and the serotonin (5-HT) level was significantly increased by all three concentrations of SER. To ascertain mechanisms of SER-induced toxicity, transcriptomics was conducted in the brain of zebrafish following 100 µg/L SER exposure. The molecular signaling pathways connected with circadian system and the immune system were significantly altered in the zebrafish brain. Based on transcriptomic data, the expression levels of six circadian clock genes were measured, and three genes were significantly altered in relative abundance in fish from all experimental treatments with SER, including cryptochrome circadian regulator 2 (cry2), period circadian clock 2 (per2), and period circadian clock 3 (per3). We hypothesize that the circadian system may be related to SER-induced neurotoxicity and oxidative stress in the central nervous system. This study reveals potential mechanisms and key events (i.e., oxidative stress and neurotoxicity) associated with SER-induced toxicity, and improves understanding of the molecular and biochemical pathways putatively perturbed by SER.

Hypersensitivity of Zebrafish htr2b Mutant Embryos to Sertraline Indicates a Role for Serotonin Signaling in Cardiac Development.

ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are antidepressants prescribed in 10% of pregnancies in the United States. Maternal use of SSRIs has been linked to an elevated rate of congenital heart defects, but the exact mechanism of pathogenesis is unknown. Previously, we have shown a decrease in cardiomyocyte proliferation, left ventricle size, and reduced cardiac expression of the serotonin receptor 5-HT 2B in offspring of mice exposed to the SSRI sertraline during pregnancy, relative to offspring of untreated mice. These results suggest that disruption of serotonin signaling leads to heart defects. Supporting this conclusion, we show here that zebrafish embryos exposed to sertraline develop with a smaller ventricle, reduced cardiomyocyte number, and lower cardiac expression of htr2b relative to untreated embryos. Moreover, zebrafish embryos homozygous for a nonsense mutation of htr2b ( htr2bsa16649 ) were sensitized to sertraline treatment relative to wild-type embryos. Specifically, the ventricle area was reduced in the homozygous htr2b mutants treated with sertraline compared with wild-type embryos treated with sertraline and homozygous htr2b mutants treated with vehicle control. Whereas long-term effects on left ventricle shortening fraction and stroke volume were observed by echocardiography in adult mice exposed to sertraline in utero, echocardiograms of adult zebrafish exposed to sertraline as embryos were normal. These results implicate the 5-HT 2B receptor functions in heart development and suggest zebrafish are a relevant animal model that can be used to investigate the connection between maternal SSRI use and elevated risk of congenital heart defects.

Sertraline as a new potential anthelmintic against Haemonchus contortus: toxicity, efficacy, and biotransformation.

Haemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.

Meta-transcriptomic profiling of functional variation of freshwater microbial communities induced by an antidepressant sertraline hydrochloride.

Sertraline hydrochloride (Ser-HCl) is an effective and commonly used antidepressant drug, which is also frequently detected in aquatic environments. Our previous research showed that Ser-HCl changes the community composition of aquatic microbiome, but the understanding of the expression of functional pathways in microbial communities is still incomplete; to address this knowledge gap, we used meta-transcriptomics analysis to evaluate the toxicity of Ser-HCl to natural aquatic microbial communities cultured in laboratory microcosms. Meta-transcriptomic results show that a 15-day exposure to 50 µg/L Ser-HCl significantly changed the functional expression activity of aquatic microbial communities. Pathways related to lipid metabolism, energy metabolism, membrane transport function, and genetic information processing in the aquatic microbial community were severely inhibited under Ser-HCl treatment, but metabolism of cofactors and vitamins to alleviate biological toxicity after Ser-HCl exposure was enhanced. Our study thus reveals details of the effects of sertraline on the functioning of aquatic microbiome. Due to the extensive use of Ser-HCl and its strong biological activity, it should not continue to be an overlooked pollutant. Therefore, more attention should be paid to the negative effects of such biologically active drugs on the expression of aquatic microbiome.

Environmentally relevant concentrations of sertraline disrupts behavior and the brain and liver transcriptome of juvenile yellow catfish (Tachysurus fulvidraco): Implications for the feeding and growth axis.

Sertraline (SER) is one of the most prevalent antidepressants detected in aquatic environments, but its impact on fish behavior and growth remain poorly understood. As such, behavior and growth were assessed in yellow catfish (Tachysurus fulvidraco) following SER exposure. SER induced shoaling, reduced food consumption and growth, and increased cannibalism at environmentally relevant concentrations. To ascertain toxicity mechanisms, acetylcholinesterase (AChE) activity and transcripts related to growth and feeding were measured. AChE activity was increased in fish exposed to 10 and 100 µg/L SER. Transcript levels of neuropeptide Y, somatostatin, growth hormone, and insulin growth factor 1 were reduced in the brain following SER exposure. RNA-seq conducted in brain and liver revealed that gene networks associated with feeding and growth (i.e. leptin expression networks in the brain and insulin signaling pathways in the liver) were altered, proposed to be associated with the decreased food intake and growth. The brain also accumulated SER, which may relate to neurobehavioral responses. Lastly, the main metabolite of SER, norsertraline, was detected in the liver, and may also relate to toxicity. This study uncovers mechanisms and key events proposed to lead to impaired behavior and growth after exposure to some antidepressants.

Molecular and behavioral responses of zebrafish embryos/larvae after sertraline exposure.

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.

Toxicity Profile, Pharmacokinetic, and Drug-Drug Interaction Study of Citalopram and Sertraline Following Oral Delivery in Rat: An LC-MS/MS Method for the Simultaneous Determination in Plasma.

The burden of depression and other mental disorders is on the rise globally, and successful treatment sometimes requires modifications of drugs and/or dose regimens. The development of novel analytical methods for the determination of antidepressant drugs in biological fluids is thus urgently required. Herein, a sensitive, robust, and rapid liquid chromatographic coupled tandem mass spectrometric method was developed and validated for the determination of citalopram (CIT) and sertraline (SER) in rat plasma after oral administration. The analytes of interest and internal standard (duloxetine (DUL)) were extracted from 100 µL of plasma with solid-phase extraction on an Oasis HLB cartridge followed by the separation with gradient elution with water containing 0.1% formic acid and acetonitrile on an Agilent Eclipse Plus ODS (4.6 × 100 mm, 3.5 µm) column at flow rate 0.2 mL min-1. The triple quadrupole mass spectrometry was applied via electrospray ionization source for detection. The fragmentation pattern of the protonated CIT, SER, and DUL was elucidated using multiple reaction monitoring of the transitions of m/z 325.2 to 109, 306.1 to 158.9, and 298.1 to 154.1 as [M + H]+ for CIT, SER, and DUL, respectively. The proposed method has been validated as per US-FDA bioanalytical guidelines in terms of linearity, accuracy, precision, matrix effects, stability, selectivity, and recovery. The method was linear over the concentration range of 1-2000 and 1-1000 ng mL-1 with the lower limit of detection of 0.12 and 0.19 ng mL-1 for CIT and SER, respectively. The interday and intraday precisions and accuracy expressed by the relative standard deviation and the relative standard error were both lower than 11.1% and 2.1%, respectively. The proposed method was successfully applied for the pharmacokinetics and drug monitoring studies of CIT and SER in rat plasma after a single oral dose of 120 mg kg-1 of CIT and SER. Coadministration of SER with CIT has affected the peak plasma concentrations, maximum plasma concentration time, area under the concentration-time curve, and oral clearance of CIT. Molecular modeling study showed that SER could competitively inhibit CYP2D6, the main enzyme involved in CIT metabolism. A possible drug-drug interaction in psychiatric patients undergoing chronic SER and CIT treatment is therefore worthy of more attention in an effort to avoid side effects and serotonin syndrome.

Effects of selective serotonin reuptake inhibitor sertraline on hybrid striped bass predatory behavior and brain chemistry.

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.

The role of hepatic cytochrome P450s in the cytotoxicity of sertraline.

Sertraline, an antidepressant, is commonly used to manage mental health symptoms related to depression, anxiety disorders, and obsessive-compulsive disorder. The use of sertraline has been associated with rare but severe hepatotoxicity. Previous research demonstrated that mitochondrial dysfunction, apoptosis, and endoplasmic reticulum stress were involved in sertraline-associated cytotoxicity. In this study, we reported that after a 24-h treatment in HepG2 cells, sertraline caused cytotoxicity, suppressed topoisomerase I and IIα, and damaged DNA in a concentration-dependent manner. We also investigated the role of cytochrome P450 (CYP)-mediated metabolism in sertraline-induced toxicity using our previously established HepG2 cell lines individually expressing 14 CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrated that CYP2D6, 2C19, 2B6, and 2C9 metabolize sertraline, and sertraline-induced cytotoxicity was significantly decreased in the cells expressing these CYPs. Western blot analysis demonstrated that the induction of É£H2A.X (a hallmark of DNA damage) and topoisomerase inhibition were partially reversed in CYP2D6-, 2C19-, 2B6-, and 2C9-overexpressing HepG2 cells. These data indicate that DNA damage and topoisomerase inhibition are involved in sertraline-induced cytotoxicity and that CYPs-mediated metabolism plays a role in decreasing the toxicity of sertraline.

Immunotoxicities of microplastics and sertraline, alone and in combination, to a bivalve species: size-dependent interaction and potential toxication mechanism.

Although coexposure to pharmaceuticals and microplastics (MPs) may frequently occur, the synergistic impact of MPs and antidepressants on marine species still remains poorly understood. In this study, the immunotoxicities of polystyrene MPs (diameters 500 nm and 30 µm) and sertraline (Ser), alone and in combination, were investigated in a bivalve mollusk Tegillarca granosa. Results showed that both MPs and Ser significantly suppressed the immune responses of T. granosa. In addition, though the toxic effect of Ser was not affected by microscale MPs, an evident synergistic immuno-toxic effect was observed between Ser and nanoscale MPs, which indicates a size-dependent interaction between the two. To further ascertain the underlying toxication mechanisms, the intracellular content of reactive oxygen species, apoptosis status, ATP content, pyruvate kinase activity, plasma cortisol level, and in vivo concentrations of neurotransmitters and cytochrome P450 1A1 were analysed. A transcriptomic analysis was also performed to reveal global molecular alterations following Ser and/or MPs exposure. The obtained results indicated that the presence of nanoscale MPs may enhance the immunotoxicity of Ser by (i) inducing apoptosis of haemocytes and, hence, reducing the THC; (ii) constraining the energy availability for phagocytosis; and (iii) hampering the detoxification of Ser.

The teratogenic effects of sertraline in mice.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs), which include paroxetine (Paxil), sertraline (Zoloft), fluoxetine (Prozac), citalopram (Celexa), and escitalopram (Lexapro), are the most common antidepressants prescribed to pregnant women. There is considerable debate in the literature regarding the developmental toxicities of SSRIs individually, and as a class. METHODS: It is considered unethical to perform developmental toxicity studies on pregnant women, but rodent and nonrodent species provide laboratory-controlled experimental models to examine the toxicity of SSRI exposure during pregnancy. The Embryo-Fetal Developmental Toxicity Study was conducted with sertraline in mice, Crl:CD1 (lCR), during the period of organogenesis. RESULTS: Increased resorption rates, lower fetal weight, and increased percentage of fetuses with visceral and skeletal abnormalities were found in the intermediate and high sertraline dose groups. In addition to incomplete ossification of treated animals, eleven sertraline exposed fetuses, two in group 2 (5 mg/kg), five in group 3 (25 mg/kg), and four in group 4 (60 mg/kg), had cleft palate (CP). This malformation was not observed in any controls. Only the highest dose of sertraline was found to be maternally toxic, as evidenced by significantly lower weight gain during pregnancy. CONCLUSION: These data indicate that in utero exposure to sertraline at 25 and 60 mg/kg was embryotoxic, teratogenic, and fetotoxic in mice. The incidence of CP observed in groups 3 and 4 (2.99% and 2.5%, respectively) were higher than the maximum range value noted in historical controls and indicate sertraline is a teratogen in ICR mice.