Environmentally Relevant Levels of Antiepileptic Carbamazepine Altered Intestinal Microbial Composition and Metabolites in Amphibian Larvae
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PROVIDER: S-EPMC11241184 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:Toxicometabolomics and biotransformation product (bioTP) elucidation were carried out in single zebrafish (ZF) embryos exposed to carbamazepine (CBZ). Exposures were conducted in 96-well plates containing six CBZ concentrations ranging from 0.5 μg/L to 50 mg/L (n = 12 embryos per dose). In the 50 mg/L dose group, 33% of embryos developed edema during the exposure (120 hpf), while hatching was significantly delayed in three of the lower-dose groups (0.46, 3.85, and 445 μg/L) compared to the control at 48 hpf. Toxicometabolomic analysis together with random forest modeling revealed a total of 80 significantly affected metabolites (22 identified via targeted lipidomics and 58 via nontarget analysis). The wide range of doses enabled the observation of both monotonic and nonmonotonic dose responses in the metabolome, which ultimately produced a unique and comprehensive biochemical picture that aligns with existing knowledge on the mode of action of CBZ. The combination of high dose exposures and apical endpoint assessment in single embryos also enabled hypothesis generation regarding the target organ for the morphologically altering insult. In addition, two CBZ bioTPs were identified without additional exposure experiments. Overall, this work showcases the potential of toxicometabolomics and bioTP determination in single ZF embryos for rapid and comprehensive chemical hazard assessment.
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Project description:Thiamethoxam (THM) is one of the most widely used insecticides globally, which was designed to selectively target nicotinic acetylcholine receptors (nAChRs) in the insect nervous system and is generally considered safe for non-targeted organisms. However, increasing evidence has demonstrated its neurotoxicity in aquatic organisms, though the underlying mechanisms, especially at environmentally relevant concentrations, remain largely unclear. In this study, the swimming distance of zebrafish was significantly shortened by 14.06%-21.64% after exposure to THM at 10-1000 ng/L. This behavioral impairment may result from the damage to nervous and visual systems, as confirmed by notable apoptosis, histological analysis of the eyes, and differential expression of numerous genes. Molecular docking and biomarkers assays found that THM can bind with nAChR and multiple hormone receptors, with binding energies varying from -3.75 to -6.74 kcal/mol. Consequently, the concentrations of a neurotransmitter (acetylcholine) and related hormones (cortisol, triiodothyronine, thyroxine, and thyroid-stimulating hormone) were significantly affected. Further investigations using a weighted gene correlation network and metabolomics suggest that THM may enter the cell via endocytosis and bind with multiple hormone receptors, potentially activating the MAPK signaling pathway. This activation may disrupt purine and pyrimidine metabolism in the cell nucleus, ultimately leading to cell apoptosis and neurotoxicity. This study reveals that THM, even at environmentally relevant concentrations, poses neurological risks to zebrafish and underscore the need for urgent attention to the ecological impacts of THM in aquatic environments.
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Project description:The impact of pharmaceuticals on non-target organisms in the environment is of increasing concern and study. Pharmaceuticals and other pollutants are often present as mixtures in an environmental compartment. Studies on the toxicological implications of these drugs on fish, particularly as mixtures at environmentally relevant concentrations, are very limited. Thus, this study aimed to evaluate the chronic effects of the anticonvulsant drug carbamazepine (CBZ) and progesterone (P4) at environmentally relevant concentrations, individually and in binary mixtures, applying a suite of biomarkers at the molecular level in zebrafish (Danio rerio). The effects on biotransformation enzymes 7-ethoxyresorufin O-deethylase (EROD) and glutathione-S-transferase (GST), antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidases (GPxSe and GPxTOT), and glutathione reductase (GR), and markers of damage, such as DNA strand breaks (DNAsb), lactate dehydrogenase (LDH), lipid peroxidation (LPO), and vitellogenin-like proteins (VTG), were evaluated. Analyses of the biochemical markers indicated that a synergistic dose-ratio-dependent effect of CBZ and P4 in zebrafish occurs after chronic exposure regarding VTG, biotransformation enzymes (EROD, GST), and oxidative stress marker (DNAsb). The results suggest a synergistic effect regarding VTG, thus indicating a high risk to the reproductive success of fish if these pharmaceuticals co-occur.
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Project description:Viruses contribute to the mortality of marine microbes, consequentially altering biological species composition and system biogeochemistry. Although it is well established that host cells provide metabolic resources for virus replication, the extent to which infection reshapes host metabolism at a global level and the effect of this alteration on the cellular material released following viral lysis is less understood. To address this knowledge gap, the growth dynamics, metabolism and extracellular lysate of roseophage-infected Sulfitobacter sp. 2047 was studied using a variety of techniques, including liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics. Quantitative estimates of the total amount of carbon and nitrogen sequestered into particulate biomass indicate that phage infection redirects ∼75% of nutrients into virions. Intracellular concentrations for 82 metabolites were measured at seven time points over the infection cycle. By the end of this period, 71% of the detected metabolites were significantly elevated in infected populations, and stable isotope-based flux measurements showed that these cells had elevated metabolic activity. In contrast to simple hypothetical models that assume that extracellular compounds increase because of lysis, a profile of metabolites from infected cultures showed that >70% of the 56 quantified compounds had decreased concentrations in the lysate relative to uninfected controls, suggesting that these small, labile nutrients were being utilized by surviving cells. These results indicate that virus-infected cells are physiologically distinct from their uninfected counterparts, which has implications for microbial community ecology and biogeochemistry.
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Project description:To investigate the effects of glucocorticoids on the gene expression profiles in zebrafish, we performed a microarray-based transcriptomic study using larvae exposed to three representative glucocoriticoids at environmentally relevant high and low concentrations. Transcriptiomic profiel of developing zebrafish larvae exposed to dexamethasone, prednisolone or triamcinolone at 50 pM to 50 nM from 3 hours post-fertilisation to 5 days post-fertilisation were analyzed using G2519F Agilent Zebrafish Whole Genome Oligo Microarray Ver3.0, 4x44K.
2017-07-01 | GSE93227 | GEO
Project description:Copper (Cu) pollution in coastal areas is a worldwide threat for aquatic communities. This study aims to demonstrate the usefulness of the DNA metabarcoding analysis in order to describe the ecotoxicological effect of Cu at environmental concentrations on marine periphyton. Additionally, the study investigates if Cu-induced changes in community structure co-occurs with changes in community functioning (i.e., photosynthesis and community tolerance to Cu). Periphyton was exposed for 18 days to five Cu concentrations, between 0.01 and 10 μM, in a semi-static test. Diversity and community structure of prokaryotic and eukaryotic organisms were assessed by 16S and 18S amplicon sequencing, respectively. Community function was studied as impacts on algal biomass and photosynthetic activity. Additionally, we studied Pollution-Induced Community Tolerance (PICT) using photosynthesis as the endpoint. Sequencing results detected an average of 9,504 and 1,242 OTUs for 16S and 18S, respectively, reflecting the high biodiversity of marine periphytic biofilms. Eukaryotes represent the most Cu-sensitive kingdom, where effects were seen already at concentrations as low as 0.01 μM. The structure of the prokaryotic part of the community was impacted at slightly higher concentrations (0.06 μM), which is still in the range of the Cu concentrations observed in the area (0.08 μM). The current environmental quality standard for Cu of 0.07 μM therefore does not seem to be sufficiently protective for periphyton. Cu exposure resulted in a more Cu-tolerant community, which was accompanied by a reduced total algal biomass, increased relative abundance of diatoms and a reduction of photosynthetic activity. Cu exposure changed the network of associations between taxa in the communities. A total of 23 taxa, including taxa within Proteobacteria, Bacteroidetes, Stramenopiles, and Hacrobia, were identified as being particularly sensitive to Cu. DNA metabarcoding is presented as a sensitive tool for community-level ecotoxicological studies that allows to observe impacts simultaneously on a multitude of pro- and eukaryotic taxa, and therefore to identify particularly sensitive, non-cultivable taxa.
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Project description:The application of fatty acid (FA) isotopic analysis has great potential in elucidating food web structure, but it has not experienced the same wide-spread use as amino acid isotopic analyses. The failure to adopt FA isotopic methods is almost certainly linked to a lack of reliable information on trophic fractionation of FA, particularly in higher predators. In this work, we attempt to address this shortfall, through comparison of FA δ13C values in captive Atlantic pollock (Pollachius virens) liver and their known diets. Since catabolism is likely the main cause of fractionation and it may vary with dietary fat content, we investigated the impact of dietary fat concentration on isotopic discrimination in FA. We fed Atlantic pollock three formulated diets with similar FA isotopic compositions but different fat concentrations (5-9% of diet), representative of the range found in natural prey, for 20 weeks. At the conclusion of the study, δ13C values of liver FA were very similar to the FA within the corresponding diets, with most discrimination factors < 1. For all FA except 22:6n-3, dietary fat had no effect on discrimination factors. Only for 22:6n-3 did fish fed the highest fat diet have lower δ13C values than the diet consumed. Thus, these FA-specific discrimination factors can be applied to evaluate diets in marine fish consuming natural diets and will serve as additional and valuable biomarkers in fish feeding ecology.
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Project description:Misregulation of Wnt signaling is common in human cancer. The development of small molecule inhibitors against the Wnt receptor, frizzled (FZD), may have potential in cancer therapy. During small molecule screens, we observed binding of carbamazepine to the cysteine-rich domain (CRD) of the Wnt receptor FZD8 using surface plasmon resonance (SPR). Cellular functional assays demonstrated that carbamazepine can suppress FZD8-mediated Wnt/β-catenin signaling. We determined the crystal structure of the complex at 1.7 Å resolution, which reveals that carbamazepine binds at a novel pocket on the FZD8 CRD. The unique residue Tyr52 discriminates FZD8 from the closely related FZD5 and other FZDs for carbamazepine binding. The first small molecule-bound FZD structure provides a basis for anti-FZD drug development. Furthermore, the observed carbamazepine-mediated Wnt signaling inhibition may help to explain the phenomenon of bone loss and increased adipogenesis in some patients during long-term carbamazepine treatment.
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Project description:N,N-Diethyl-meta-toluamide (DEET) is a synthetic insect repellent invented in 1946 by the US Department of Agriculture for use by military personnel and now used worldwide as evidenced by its detection at various levels in human urine, serum, semen, and cord serum (1–5). While the neurological effects of DEET have been widely investigated (6–8), its effects on the germline and reproductive health are less understood. Here we used the nematode Caenorhabditis elegans, a genetically and cytologically tractable model system that shares a high degree of conservation of its genes and biochemical pathways with humans and is highly predictive of mammalian reprotoxicity, to study how DEET affects the germline (9–12). We found that exposure to environmentally relevant levels of DEET causes activation of p53/CEP-1-dependent germ cell apoptosis and alters recombination by inducing elevated levels of meiotic DNA double-strand breaks (DSBs) and crossovers (COs) resulting in chromosome abnormalities and missegregation. RNA sequencing (RNA-seq) analysis links DEET induced alterations in the expression of genes related to oxidation and reduction (redox) processes and chromatin structure to reduced mitochondrial function, altered DSB repair progression, and impaired early embryonic cell division. Our work shows that exposure to environmentally relevant levels of DEET interferes with gene expression, leading to increased oxidative stress and altered chromatin structure resulting in detectable germline effects that can pose a risk to reproductive health.
2024-02-07 | GSE242682 | GEO
Project description:Scrapie and chronic wasting disease (CWD) are prion diseases of particular environmental concern as they are horizontally transmissible and can remain infectious after years in the environment. Recent evidence suggests that the N-terminus of PrPSC, the infectious conformation of the prion protein, plays an important role in the mechanism of sorption to soil particles. We hypothesize that, in a prion-infected animal carcass, a portion of the N-terminus of PrPSc could be cleaved by proteinases in the brain at ordinary temperatures. Hamster (HY transmissible mink encephalopathy-infected), transgenic mice (CWD-infected), and elk (CWD-infected) brain homogenates were incubated at 22 and 37 degrees C for up to 1 month and then analyzed by Western blot using N-terminal and middle region monoclonal anti-PrP antibodies. For all three systems, there was a very faint or undetectable N-terminal PrP signal after 35 days at both temperatures, which indicates that full-length PrPSc might be rare in the brain matter of animal carcasses. Future studies on prion-soil interactions should therefore consider N-terminal-degraded PrPSc in addition to the full-length form. Both mouse and elk CWD PrPSc demonstrated greater resistance to degradation than HY TME PrPSc. This indicates that the transgenic mouse-CWD model is a good surrogate for natural CWD prions, but that other rodent prion models might not accurately represent CWD prion fate in the environment.
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