Unmasking Spatial Heterogeneity in Phytotoxicology Mechanisms Induced by Carbamazepine by Mass Spectrometry Imaging and Multiomics Analyses.

Previous studies have highlighted the toxicity of pharmaceuticals and personal care products (PPCPs) in plants, yet understanding their spatial distribution within plant tissues and specific toxic effects remains limited. This study investigates the spatial-specific toxic effects of carbamazepine (CBZ), a prevalent PPCP, in plants. Utilizing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), CBZ and its transformation products were observed predominantly at the leaf edges, with 2.3-fold higher concentrations than inner regions, which was confirmed by LC-MS. Transcriptomic and metabolic analyses revealed significant differences in gene expression and metabolite levels between the inner and outer leaf regions, emphasizing the spatial location's role in CBZ response. Notably, photosynthesis-related genes were markedly downregulated, and photosynthetic efficiency was reduced at leaf edges. Additionally, elevated oxidative stress at leaf edges was indicated by higher antioxidant enzyme activity, cell membrane impairment, and increased free fatty acids. Given the increased oxidative stress at the leaf margins, the study suggests using in situ Raman spectroscopy for early detection of CBZ-induced damage by monitoring reactive oxygen species levels. These findings provide crucial insights into the spatial toxicological mechanisms of CBZ in plants, forming a basis for future spatial toxicology research of PPCPs.

Derivation of water quality criteria for paraquat, bisphenol A and carbamazepine using quantitative structure-activity relationship and species sensitivity distribution (QSAR-SSD).

The risk assessment of an expanding array of emerging contaminants in aquatic ecosystems and the establishment of water quality criteria rely on species sensitivity distribution (SSD), necessitating ample multi-trophic toxicity data. Computational methods, such as quantitative structure-activity relationship (QSAR), enable the prediction of specific toxicity data, thus mitigating the need for costly experimental testing and exposure risk assessment. In this study, robust QSAR models for four aquatic species (Rana pipiens, Crassostrea virginica, Asellus aquaticus, and Lepomis macrochirus) were developed using leave-one-out (LOO) screening variables and the partial least squares algorithm to predict toxicity data for paraquat, bisphenol A, and carbamazepine. These predicted data can be integrated with experimental data to construct SSD models and derive hazardous concentration for 5 % of species (HC5) for the criterion maximum concentration. The chronic water quality criterion for paraquat, bisphenol A, and carbamazepine were determined at 6.7, 11.1, and 3.5 µg/L, respectively. The QSAR-SSD approach presents a viable and cost-effective method for deriving water quality criteria for other emerging contaminants.

Effects of species of origin and mode of induction of microsomes on carbamazepine-induced cell toxicity.

Standardization and validation of in vitro drug metabolism is essential for pre-clinical drug development as well as for in vitro toxicity assays including the lymphocyte toxicity assay (LTA) and the in vitro platelet toxicity assay (iPTA). Use of isolated liver microsomes (MIC) in in vitro testing has been utilized for a long time; however, the effect of species of origin and induction agents on the metabolic capacities of MIC is not adequately evaluated. In this study we investigated the impact of species of origin and induction agent on the capacity of MICs to bioactivate carbamazepine (CBZ) using cytotoxicity as a gross endpoint to measure the levels of cytotoxic metabolites generated by each type of MICs. Jurkat E6.1 cell line was used and MICs from human, rat, mouse, minipig and rabbit origin as well as rat MICs that is either non-induced or induced by phenobarbitone (PHB), dexamethasone (DEXA), 3-methylcholanthrene (3MC), clofibrate (CLOF) and isoniazid (INH) were investigated. MICs from minipig and rat MICs induced with 3MC exhibited the highest capacity to produce cytotoxic metabolites of CBZ. These findings will help optimize and standardize in vitro toxicity assays and provide guidance to pre-clinical investigation of drugs.

The responses and tolerance of photosynthetic system in Chlorella vulgaris to the pharmaceutical pollutant carbamazepine.

Screening for sensitive toxicological indicators and understanding algal tolerance to pharmaceutical contaminants (PhCs) are essential for assessing PhCs risk and their removal by microalgae. Carbamazepine (CBZ) showed adverse effects on microalgae, but the specific toxicity mechanisms on the most sensitive algal photosynthetic system (PS) remain limited. This study delved into the impact of CBZ exposure on the growth, cell viability, pigment content, and PS of Chlorella vulgaris. The findings revealed a notable inhibition of C. vulgaris growth by CBZ, with an IC50 value of 27.2 mg/L at 96 h. CBZ exposure induced algal membrane damage and cell viability. Intriguingly, CBZ drastically diminished intracellular pigment levels, notably showing "low promotion and high inhibition" of chlorophyll b (Chl b) by 72 h. Moreover, the study identified a decreased number of active reaction centers (RCs) within algal PSII alongside inhibited electron transport from QA to QB on the PSII receptor side, leading to PSII disruption. As an adaptive response to CBZ stress, C. vulgaris stimulated its Chl b synthesis, increased non-photochemical quenching (NPQ), and adapted its tolerance to bright light. Additionally, the alga attempted to compensate for the CBZ-induced reduction in electron transfer efficiency at the PSII receptor side and light energy utilization by increasing its electron transfer from downstream. Principal component analysis (PCA) further verified that the parameters on non-photochemical dissipation, electron transport, and integrative performance were the most sensitive algal toxicological indicators for CBZ exposure, and algal PS has energy protection capability through negative feedback regulation. However, prolonged exposure to high doses of CBZ will eventually result in permanent damage to the algal PS. Hence, attention should be paid to the concentration of CBZ in the effluent and the exposure time, while methods to mitigate algal photodamage should be appropriately sought for algal treatment of dense effluents.

Bio-electrochemical degradation of carbamazepine (CBZ): A comprehensive study on effectiveness, degradation pathway, and toxicological assessment.

Recent attention on the detrimental effects of pharmaceutically active compounds (PhACs) in natural water has spurred researchers to develop advanced wastewater treatment methods. Carbamazepine (CBZ), a widely recognized anticonvulsant, has often been a primary focus in numerous studies due to its prevalence and resistance to breaking down. This study aims to explore the effectiveness of a bio-electrochemical system in breaking down CBZ in polluted water and to assess the potential harmful effects of the treated wastewater. The results revealed bio-electro degradation process demonstrated a collaborative effect, achieving the highest CBZ degradation compared to electrodegradation and biodegradation techniques. Notably, a maximum CBZ degradation efficiency of 92.01% was attained using the bio-electrochemical system under specific conditions: Initial CBZ concentration of 60 mg/L, pH level at 7, 0.5% (v/v) inoculum dose, and an applied potential of 10 mV. The degradation pathway established by identifying intermediate products via High-Performance Liquid Chromatography-Mass Spectrometry, revealed the complete breakdown of CBZ without any toxic intermediates or end products. This finding was further validated through in vitro and in vivo toxicity assays, confirming the absence of harmful remnants after the degradation process.

Occurrence of pharmaceutically active compounds in groundwater and their effects to the human health.

Groundwater contamination by pharmaceutically active compounds (PhACs) has been considered a public health concern worldwide. Alongside the potential toxicological risk of these organic substances, many countries still rely on groundwater for drinking water supply. Thus, this study identified a priority list of seven licit PhACs, comprising acetaminophen (ACT), tramadol (TRA), carbamazepine (CBZ), erythromycin (ERY), sulfamethoxazole (SMX), metformin (MET), and oxazepam (OXZ). Consumption, concentration, and human toxicity in silico results were collected from open access databases. These three indicators were analyzed separately and grouped through a general risk index. The consumption index (data from the USA and Brazil) indicated that ACT, TRA, and MET are the most consumed. Monitoring samples from the USA and Europe (n = 816) indicated that OXZ and ERY stand out as the higher occurrence index considering both regions, but the ranking for each region showed considerable differences. When assessing toxicological risk, an index ≥ 0.5 was attributed to CBZ, MET, OXZ, SMX, and TRA. The general risk indicated the need to be attentive to MET, OXZ, and TRA as they presented ≥ 0.5 index values for at least two indicators.

Insight into the generation of toxic by-products during UV/H2O2 degradation of carbamazepine: Mechanisms, N-transformation and toxicity.

Carbamazepine (CBZ) is a widely used anticonvulsant drug that has been detected in aquatic environments. This study investigated the toxicity of its by-products (CBZ-BPs), which may surpass CBZ. Unlike the previous studies, this study offered a more systematic approach to identifying toxic BPs and inferring degradation pathways. Furthermore, quadrupole time-of-flight (QTOF) and density functional theory (DFT) calculations were employed to analyze CBZ-BP structures and degradation pathways. Evaluation of total organic carbon (TOC) and total nitrogen (TN) mineralization rates, revealed carbon (C) greater susceptibility to mineralization compared with nitrogen (N). Furthermore, three rules were established for CBZ decarbonization and N removal during degradation, observing the transformation of aromatic compounds into aliphatic hydrocarbons and stable N-containing organic matter over time. Five potentially highly toxic BPs were screened from 14 identified BPs, with toxicity predictions guiding the selection of commercial standards for quantification and true toxicity testing. Additionally, BP207 emerged as the most toxic, supported by the predictive toxicity accumulation model (PTAM). Notably, highly toxic BPs feature an acridine structure, indicating its significant contribution to toxicity. These findings offered valuable insights into the degradation mechanisms of emerging contaminants and the biosafety of aquatic environments during deep oxidation.

Effect of zeolites on the reduction of the ecotoxicity of carbamazepine in the environment.

In this study, the impact of calcination of zeolites on the ecotoxicity of carbamazepine solutions in two matrices, water and synthetic sewage, was assessed. Two types of zeolites were tested: natural zeolite, in the form of a zeolite rock consisting mainly of clinoptilolite, and a synthetic zeolite type 5 A. Additionally, zeolites were calcined at a temperature of 200 °C. The kinetics of carbamazepine adsorption in aqueous solutions and in synthetic sewage matrix was determined. Higher adsorption capacity was obtained for carbamazepine aqueous solutions as well as zeolites after the calcination process. Considering type of zeolite, the highest and fastest uptake of carbamazepine was observed for natural zeolite after calcination. In the case of ecotoxicity, carbamazepine solutions before adsorption was the most toxic towards Raphidocelis subcapitata, next Aliivibrio fischeri and Daphnia magna, regardless to the matrix type. The differentiation in toxicity regarding the type of matrix was observed, in the case of algae and bacteria, higher toxicity was demonstrated by carbamazepine solutions in the water matrix, while in the case of crustaceans-the sewage matrix. After the adsorption process, the toxicity of carbamazepine solutions on zeolites decreased by 34.5-60.9 % for R. subcapitata, 33-39 % for A. fischeri and 55-60 % for D. magna, thus confirming the effectiveness of the proposed method of carbamazepine immobilization.

Molecular, behavioral, and growth responses of juvenile yellow catfish (Tachysurus fulvidraco) exposed to carbamazepine.

Carbamazepine (CBZ) is an anticonvulsant medication used to treat epilepsy and bipolar disorder. Due to its persistence and low removal rate in wastewater treatment plants, it is frequently detected in the environment, raising concerns regarding its potential adverse effects on aquatic organisms and ecosystems. In this study, we aimed to assess the impact of CBZ on the behavior and growth of juvenile yellow catfish Tachysurus fulvidraco, a native and economically important species in China. Fish were exposed to CBZ at three concentrations of 1, 10, or 100 µg/L for 14 days. The fish exposed to 10 and 100 µg/L of CBZ exhibited decreased feeding, and a significant increase in cannibalistic tendencies was observed in fish exposed to 100 µg/L CBZ. Acetylcholinesterase activity was increased in the brain of fish exposed to 100 µg/L CBZ. CBZ also inhibited the growth of yellow catfish. To better elucidate mechanisms of toxicity, transcriptomics was conducted in both the brain and liver. In the brain, gene networks associated with neurotransmitter dysfunction were altered by CBZ, as well as networks associated with mitochondrial dysfunction and metabolism. In the liver, gene networks associated with the immune system were altered by CBZ. The current study improves comprehension of the sub-lethal effects of CBZ and reveals novel insight into molecular and biochemical pathways disrupted by CBZ, identifying putative key events associated with reduced growth and altered behavior. This study emphasizes the necessity for improved comprehension of the effects of pharmaceutical contaminants on fish at environmentally relevant levels.

Carbamazepine transmits immune effect by activation of gut-liver axis and TLR signaling pathway from parental zebrafish to offspring.

Carbamazepine (CBZ) has been identified in the aquatic environment as an emerging contaminant. Its immune effect across generations at environmentally relevant concentrations is little known. We aim to elucidate the effects of CBZ on the immune system in zebrafish (Danio rerio), hypothesizing the effects caused by CBZ exposure in the parental generation can be passed on to its offspring, leading to impairment of innate immune function and defense against pathogen weakened. A suite of bioassays (including a test with added lipopolysaccharide) was used to measure the effects of environmentally relevant levels of CBZ (1, 10, and 100 µg/l) on zebrafish at multiple biological levels, and across 2 successive generations (21 days exposure for F0; 5 and 21 days exposure or nonexposure for F1). The results showed that CBZ affected homeostasis in the immune system, caused liver vacuolization, increased the inflammation-related microbiota proportion in gut, and decreased reproduction, by induction of oxidative stress and modulation of Toll-like receptors (TLR) signaling pathway on gut-liver axis. The effects of exposure to CBZ over 21 days in F0 could be passed to the next generation. Intergenerational effects on TLR and antioxidant defense system were also observed in nonexposed F1 at 5 days post-fertilization (5 dpf), but diminished at 21 dpf. The finding provided evidence to unravel immune response by gut-liver axis mediated and oxidative stress under 4 test conditions. The study has raised a potential concern about the multigenerational immune effects of environmental pollutants and calls for a focus on the risk of synergetic pathogen infection.

Omics techniques reveal the toxicity mechanisms of three antiepileptic drugs to juvenile zebrafish (Danio rerio) brain and liver.

Epilepsy, a neurological disorder, is characterized by seizures that are an appearance of excessive brain activity and is symptomatically treated with antiepileptic drugs (AEDs). Oxcarbazepine (OCBZ), lamotrigine (LTG), and carbamazepine (CBZ) are widely used AEDs in clinics and are very often detected in aquatic environments. However, neither the sub-lethal effects nor the specific mechanisms of these AEDs' action on the fish are well understood. In this study, juvenile zebrafish were exposed to a sub-lethal concentration (100 µg/L) of OCBZ, LTG, and CBZ for 28 d, after which indicators of oxidative stress (i.e. superoxide dismutase (SOD) activity, catalase (CAT) activity, and malondialdehyde (MDA) level) and neurotoxicity (i.e. acetylcholinesterase (AChE) activity, γ-aminobutyric acid (GABA) level, and glutamic acid (Glu) level) were measured. Brain SOD activity was significantly increased by three AEDs, while brain CAT activity was significantly inhibited by LTG and CBZ. Liver SOD activity was significantly enhanced by CBZ, and liver CAT activity was significantly induced by OCBZ and LTG. Liver MDA level was significantly increased by three AEDs. Brain AChE activity was significantly increased by LTG and CBZ, and brain GABA level was significantly enhanced by three AEDs. However, there were no significant alterations in the levels of MDA and Glu in zebrafish brain. To ascertain mechanisms of AEDs-induced toxicity, brain transcriptomics and liver metabolomics were conducted in zebrafish. The brain transcriptomics results showed that lots of differentially expressed genes (DEGs) were enriched in the sensory system, the immune system, the digestive system, the metabolic processes, and others in three AEDs treated groups. The metabolomics data indicated dysregulation of glycerophospholipid signaling and lipid homeostasis in zebrafish liver after three AEDs exposure. The overall results of this study improve understanding of the sub-lethal effects and potential molecular mechanisms of action of AEDs in fish.

Bioaccumulation and molecular effects of carbamazepine and methylmercury co-exposure in males of Dreissena polymorpha.

Dreissena polymorpha is a bivalve promising for biomonitoring in freshwater ecosystems thanks to its abundance and high filtration activity allowing rapid uptake of toxicants and identification of their negative effects. Nonetheless, we still lack knowledge on its molecular responses to stress under realistic scenario, e.g. multi-contamination. Carbamazepine (CBZ) and Hg are ubiquitous pollutants sharing molecular toxicity pathways, e.g. oxidative stress. A previous study in zebra mussels showed their co-exposure to cause more alterations than single exposures, but molecular toxicity pathways remained unidentified. D. polymorpha was exposed 24 h (T24) and 72 h (T72) to CBZ (6.1 ± 0.1 µg L-1), MeHg (430 ± 10 ng L-1) and the co-exposure (6.1 ± 0.1 µg L-1CBZ and 500 ± 10 ng L-1 MeHg) at concentrations representative of polluted areas (~10× EQS). RedOx system at the gene and enzyme level, the proteome and the metabolome were compared. The co-exposure resulted in 108 differential abundant proteins (DAPs), as well as 9 and 10 modulated metabolites at T24 and T72, respectively. The co-exposure specifically modulated DAPs and metabolites involved in neurotransmission, e.g. dopaminergic synapse and GABA. CBZ specifically modulated 46 DAPs involved in calcium signaling pathways and 7 amino acids at T24. MeHg specifically modulated 55 DAPs involved in the cytoskeleton remodeling and hypoxia-induced factor 1 pathway, without altering the metabolome. Single and co-exposures commonly modulated proteins and metabolites involved in energy and amino acid metabolisms, response to stress and development. Concomitantly, lipid peroxidation and antioxidant activities were unchanged, supporting that D. polymorpha tolerated experimental conditions. The co-exposure was confirmed to cause more alterations than single exposures. This was attributed to the combined toxicity of CBZ and MeHg. Altogether, this study underlined the necessity to better characterize molecular toxicity pathways of multi-contamination that are not predictable on responses to single exposures, to better anticipate adverse effects in biota and improve risk assessment.

Combined exposure of polystyrene microplastics and carbamazepine induced transgenerational effects on the reproduction of Daphnia magna.

Polystyrene microplastics (PS MPs) and carbamazepine (CBZ) are frequently detected in freshwater ecosystems. However, the transgenerational effects of PS MPs and CBZ on the reproduction of aquatic organisms and the corresponding mechanisms are still unclear. In the present study, Daphnia magna was used to evaluate the reproductive toxicity in two consecutive generations (F0, F1). The molting and reproduction parameters, the expression of reproduction, and the toxic metabolism genes were examined after 21-day exposure. A significantly enhanced toxicity was observed in the presence of 5 µm PS MPs and CBZ. Chronic exposure results showed that the 5 µm PS MPs alone, CBZ alone, and their mixtures exerted significant reproductive toxicity of D. magna. The results of RT-qPCR showed transcripts of genes related to reproduction (cyp314, ecr-b, cut, vtg1, vtg2, dmrt93b) and toxic metabolism (cyp4, gst) were altered in both the F0 and F1. In addition, for the F0, gene transcriptional changes of reproduction were not fully translated into physiological performance, probably due to the compensatory responses caused by the low dose of PS MPs alone, CBZ alone, and their mixtures. Whereas for the F1, the trade-off between reproduction and toxic metabolism at gene levels was observed, which translated into a significant reduction in the total neonate number of F1. These findings suggest that long-term exposure to MPs and CBZ can cause serious reproduction damage to aquatic animals, which needs to be given sufficient attention.

Individual and combined effects of amoxicillin and carbamazepine to the marine copepod Tigriopus fulvus.

Pharmaceuticals can be considered a global threat to aquatic ecosystems due to their pseudo-persistence and their potential toxicity towards non-target species. Amoxicillin (AMX) and carbamazepine (CBZ) and their mixture (1:1) were investigated on the marine copepod Tigriopus fulvus (Fischer, 1860) considering both acute and chronic endpoints. While acute and chronic exposure did not directly affect survival, reproductive endpoints were affected like the mean egg hatching time that was significantly longer than the negative control for treatments with AMX (0.789 ± 0.079 µg/L), CBZ (8.88 ± 0.89 µg/L), and AMX and CMZ as a mixture (1.03 ± 0.10 µg/L and 0.941 ± 0.094 µg/L), in that order.

Carbamazepine, venlafaxine, tramadol, and their main metabolites: Toxicological effects on zebrafish embryos and larvae.

Pharmaceutical compounds and their metabolites are found in natural and wastewater. However, investigation of their toxic effects on aquatic animals has been neglected, especially for metabolites. This work investigated the effects of the main metabolites of carbamazepine, venlafaxine and tramadol. Zebrafish embryos were exposed (0.1-100 µg/L) for 168hpf exposures to each metabolite (carbamazepine-10,11-epoxide, 10,11-dihydrocarbamazepine, O-desmethylvenlafaxine, N-desmethylvenlafaxine, O-desmethyltramadol, N-desmethyltramadol) or the parental compound. A concentration-response relationship was found for the effects of some embryonic malformations. Carbamazepine-10,11-epoxide, O-desmethylvenlafaxine and tramadol elicited the highest malformation rates. All compounds significantly decreased larvae responses on a sensorimotor assay compared to controls. Altered expression was found for most of the 32 tested genes. In particular, abcc1, abcc2, abcg2a, nrf2, pparg and raraa were found to be affected by all three drug groups. For each group, the modelled expression patterns showed differences in expression between parental compounds and metabolites. Potential biomarkers of exposure were identified for the venlafaxine and carbamazepine groups. These results are worrying, indicating that such contamination in aquatic systems may put natural populations at significant risk. Furthermore, metabolites represent a real risk that needs more scrutinising by the scientific community.

Analyzing the potential environmental impact of NIOSH list of hazardous drugs (group 2).

For the first time, several pharmaceuticals have been defined as priority substances in the new proposal of the revision of the Water Framework Directive (WFD). Consequently, environmental quality standards have been determined for several drugs. This is the case with the antiepileptic carbamazepine, which is considered as hazardous in healthcare settings by The National Institute for Occupational Safety and Health (NIOSH). This organism considers as such drugs that have shown teratogenicity, carcinogenicity, genotoxicity or other developmental, reproductive, or organ toxicity at low doses in studies with animals or humans. This study has been focused on the non-carcinogenic drugs classified in group 2, and their presence in the environment. This group contains many different therapeutic agents such as antineoplastics, psychoactive drugs, immunosuppressants and antivirals, among others. Of the 116 drugs included in the list, 26 have been found in aquatic environmental matrices. Certain drugs have received most attention (e.g., the antiepileptic carbamazepine, progesterone and the antidepressant paroxetine) while others completely lack environmental monitoring. Carbamazepine, fluconazole, paroxetine and warfarin have been found in invertebrates' tissues, whereas carbamazepine, oxazepam and paroxetine have been found in fish tissues. The main aim of the NIOSH's hazardous drug list is to inform healthcare professionals about adequate protection measures to prevent occupational exposure to these pharmaceuticals. However, this list contains useful information for other professionals and researchers such as environmental scientists. The paucity of relevant environmental data of certain hazardous pharmaceuticals might be important to help in the prioritization of compounds that may demand further research.

Chronic exposure to environmentally relevant concentrations of carbamazepine interferes with anxiety response of adult female zebrafish through GABA /5-HT pathway and HPI axis.

Carbamazepine (CBZ) is one of the widely distributed pharmaceutical residues in aquatic environments, yet few researches have addressed its chronic effect on the anxiety of fish, and the mechanisms possibly involved remained elusive. In this study, adult female zebrafish (Danio rerio) were exposed to environmental relevant concentrations of CBZ (CBZ-low, 10 µg/L; CBZ-high, 100 µg/L) for 28 days. After exposure, CBZ-high didn't affect the anxiety of fish. However, the onset time to the higher half of the tank was delayed and the total duration in the lower half of the tank was increased in CBZ-low fish, suggesting an increased anxiety. Further investigation indicated that CBZ-low significantly decreased the gamma-aminobutyric acid (GABA) level in the brain, while increased the serotonin (5-HT) level in the brain and cortisol level in plasma. Accordingly, the mRNA levels of genes in GABA (gad2, abat, gabrb2, gabrg2, gria1a and slc12a2) pathway and HPI (crha, actha, pc1 and pc2) axis were also altered. Despite the upregulation of tph2 was consistent with increased 5-HT level in the brain, significantly downregulated htr1aa and htr1b may indicate attenuated 5-HT potency. Although CBZ-high significantly reduced GABA level in the brain and increased cortisol level in plasma, the effects were dramatically alleviated than that of CBZ-low. Consistently, the expression of genes in HPI (crha, actha, pc1 and pc2) axis and GABA (gad2 and abat) pathway were also altered by CBZ-high, probably due to inconspicuous anxiety response of CBZ-high. Briefly, our data suggested that low concentration of CBZ disrupted zebrafish anxiety by interfering with neurotransmission and endocrine system, thereby bringing about adverse ecological consequences.

Effects of common antiepileptic drugs on teleost fishes.

Antiepileptic drugs (AEDs) are globally prescribed to treat epilepsy and many other psychiatric disorders in humans. Their high consumption, low metabolic rate in the human body and low efficiency of wastewater treatment plants (WWTPs) in eliminating these chemicals results in the frequent occurrence of these pharmaceutical drugs in aquatic systems. Therefore, aquatic organisms, including ecologically and economically important teleost fishes, may be inadvertently exposed to these chemicals. Due to their physiological similarity with humans, fishes may be particularly vulnerable to AEDs. Almost all AED drugs are detectable in natural aquatic ecosystems, but diazepam (DZP) and carbamazepine (CBZ) are among the most widely detected AEDs to date. Recent studies suggest that these drugs have a substantial capacity to induce neurotoxicity and behavioral abnormality in fishes. Here we review the current state of knowledge regarding the potential mode of action of DZP and CBZ as well as that of some other AEDs on teleosts and put observable behavioral effects into a mechanistic context. We find that following their intended mode of action in humans, AEDs also disrupt the GABAergic, glutamatergic and serotonergic systems as well as parasympathetic neurotransmitters in fishes. Moreover, AEDs have non-specific modes of action in teleosts ranging from estrogenic activity to oxidative stress. These physiological changes are often accompanied by dose-dependent disruptions of anxiety, locomotor activity, social behaviors, food uptake, and learning and memory, but DZP and CBZ consistently induced anxiolytic effects. Thereby, AED exposure severely compromises individual fitness across teleost fish species, which may lead to population and ecosystem impairment. We also showcase promising avenues for future research by highlighting where we lack data when it comes to effects of certain AEDs, AED concentrations and behavioral endpoints.

Response of hepatic biochemical parameters and neurotoxicity to carbamazepine and ibuprofen in Oreochromis mossambicus.

Globally, the prevalence and pollution of pharmaceutical drugs in aquatic environments have been steadily increasing. This study sought to evaluate the effects of 14 days of exposure to environmental-relevant doses (ibuprofen 0.5, 5, and 50 µg/L, and carbamazepine 0.005, 1, and 10 µg/L) of the nonsteroidal anti-inflammatory drugs ibuprofen and carbamazepine in the freshwater fish Oreochromis mossambicus. The results showed a significant (P < 0.05) decrease in O. mossambicus superoxide dismutase, catalase, biotransformation enzymes, glutathione-s-transferase, glutathione peroxidase, oxidative stress lipid peroxidation, protein carbonyl activity, cellular damage metallothionine, reduced glutathione, immunological activities, and respiratory burst activity. Consequently, the acquired data revealed that O. mossambicus treated with ibuprofen and carbamazepine shows more significant alterations in metabolic depression, biochemical parameters, and oxidative stress. In addition, increased neurotoxic effects were observed in ibuprofen and carbamazepine treated O. mossambicus.

Mixtures of environmental pharmaceuticals in marine organisms: Mechanistic evidence of carbamazepine and valsartan effects on Mytilus galloprovincialis.

Unravelling the adverse outcomes of pharmaceuticals mixture represents a research priority to characterize the risk for marine ecosystems. The present study investigated, for the first time, the interactions between two of the most largely detected pharmaceuticals in marine species: carbamazepine (CBZ) and valsartan (VAL), elucidating mechanisms that can modulate bioaccumulation, excretion and the onset of toxicity. Mytilus galloprovincialis were exposed to environmental levels of CBZ and VAL dosed alone or in combination: measurement of drug bioaccumulation was integrated with changes in the whole transcriptome and responsiveness of various biochemical and cellular biomarkers. Interactive and competing mechanisms between tested drugs were revealed by the much higher CBZ accumulation in mussels exposed to this compound alone, while an opposite trend was observed for VAL. A complex network of responses was observed as variations of gene expression, functional effects on neurotransmission, cell cycle, immune responses and redox homeostasis. The elaboration of results through a quantitative Weight of Evidence model summarized a greater biological reactivity of CBZ compared to VAL and antagonistic interactions between these compounds, resulting in a reduced effect of the antiepileptic when combined with valsartan. Overall, new perspectives are highlighted for a more comprehensive risk assessment of environmental mixtures of pharmaceuticals.