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  1. Article: Effects of okadaic acid, azaspiracid-1, yessotoxin and their binary mixtures on human intestinal Caco-2 cells.

    Alarcan, Jimmy / Braeuning, Albert

    EXCLI journal

    2024  Volume 23, Page(s) 509–522

    Abstract: Phycotoxins are responsible for foodborne intoxications. Symptoms depend on the ingested toxins but mostly imply gastro-intestinal and neurological disorders. Importantly, humans are exposed to combinations of several phycotoxins, resulting in possible ... ...

    Abstract Phycotoxins are responsible for foodborne intoxications. Symptoms depend on the ingested toxins but mostly imply gastro-intestinal and neurological disorders. Importantly, humans are exposed to combinations of several phycotoxins, resulting in possible mixture effects. Most previous studies, however, have been focused on single toxin effects. Thus, the aim of this study was to examine the effects of binary mixtures of three main phycotoxins, okadaic acid (OA), azaspiracid-1 (AZA1) and yessotoxin (YTX), on human intestinal Caco-2 cells. The focus was placed on cell viability studies and inflammation responses using a multi-parametric approach to assess cell population (nuclei staining), cell metabolism/viability (reductase activity and lysosomal integrity), and release of inflammation markers (e.g., interleukins). Mixture effects were evaluated using the concentration addition (CA) and independent action (IA) models. Our assays show that none of the toxins had an impact on the cell population in the tested concentration range. Only OA modulated reductase activity, while all three toxins had strong effects on lysosomal integrity. Furthermore, all toxins triggered the release of interleukin 8 (IL-8), with OA being most potent. Mixture effect analysis showed additivity in most cases. However, supra-additivity was observed in regards to IL-6 and IL-8 release for combinations implying high concentrations of OA. This study extends the knowledge on mixture effects of phycotoxins in human cells.
    Language English
    Publishing date 2024-04-22
    Publishing country Germany
    Document type Journal Article
    ISSN 1611-2156
    ISSN 1611-2156
    DOI 10.17179/excli2023-6884
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Effects of marine biotoxins on drug-metabolizing cytochrome P450 enzymes and their regulation in mammalian cells.

    Würger, Leonie T D / Alarcan, Jimmy / Braeuning, Albert

    Archives of toxicology

    2024  Volume 98, Issue 5, Page(s) 1311–1322

    Abstract: Marine biotoxins are a heterogenous group of natural toxins, which are able to trigger different types of toxicological responses in animals and humans. Health effects arising from exposure to marine biotoxins are ranging, for example, from ... ...

    Abstract Marine biotoxins are a heterogenous group of natural toxins, which are able to trigger different types of toxicological responses in animals and humans. Health effects arising from exposure to marine biotoxins are ranging, for example, from gastrointestinal symptoms to neurological effects, depending on the individual toxin(s) ingested. Recent research has shown that the marine biotoxin okadaic acid (OA) can strongly diminish the expression of drug-metabolizing cytochrome P450 (CYP) enzymes in human liver cells by a mechanism involving proinflammatory signaling. By doing so, OA may interfere with the metabolic barrier function of liver and intestine, and thus alter the toxico- or pharmacokinetic properties of other compounds. Such effects of marine biotoxins on drug and xenobiotic metabolism have, however, not been much in the focus of research yet. In this review, we present the current knowledge on the effects of marine biotoxins on CYP enzymes in mammalian cells. In addition, the role of CYP-regulating nuclear receptors as well as inflammatory signaling in the regulation of CYPs by marine biotoxins is discussed. Strong evidence is available for effects of OA on CYP enzymes, along with information about possible molecular mechanisms. For other marine biotoxins, knowledge on effects on drug metabolism, however, is scarce.
    MeSH term(s) Animals ; Humans ; Marine Toxins/toxicity ; Cytochrome P-450 Enzyme System/metabolism ; Okadaic Acid ; Liver ; Receptors, Cytoplasmic and Nuclear ; Mammals/metabolism
    Chemical Substances Marine Toxins ; Cytochrome P-450 Enzyme System (9035-51-2) ; Okadaic Acid (1W21G5Q4N2) ; Receptors, Cytoplasmic and Nuclear
    Language English
    Publishing date 2024-02-28
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-024-03694-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Uptake of microplastics and related health effects: a critical discussion of Deng et al., Scientific reports 7:46687, 2017.

    Braeuning, Albert

    Archives of toxicology

    2018  Volume 93, Issue 1, Page(s) 219–220

    MeSH term(s) Animals ; Biological Transport ; Biomarkers ; Environmental Monitoring ; Mice ; Plastics ; Water Pollutants, Chemical
    Chemical Substances Biomarkers ; Plastics ; Water Pollutants, Chemical
    Language English
    Publishing date 2018-11-23
    Publishing country Germany
    Document type Editorial ; Comment
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-018-2367-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Mixture prioritization and testing: the importance of toxicokinetics.

    Braeuning, Albert / Marx-Stoelting, Philip

    Archives of toxicology

    2021  Volume 95, Issue 5, Page(s) 1863–1864

    MeSH term(s) Animals ; Computer Simulation ; Models, Biological ; Toxicokinetics
    Language English
    Publishing date 2021-03-17
    Publishing country Germany
    Document type Editorial
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-021-03026-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Particulate iron oxide food colorants (E 172) during artificial digestion and their uptake and impact on intestinal cells.

    Sieg, Holger / Schaar, Caroline / Fouquet, Nicole / Böhmert, Linda / Thünemann, Andreas F / Braeuning, Albert

    Toxicology in vitro : an international journal published in association with BIBRA

    2024  Volume 96, Page(s) 105772

    Abstract: Iron oxide of various structures is frequently used as food colorant (E 172). The spectrum of colors ranges from yellow over orange, red, and brown to black, depending on the chemical structure of the material. E 172 is mostly sold as solid powder. ... ...

    Abstract Iron oxide of various structures is frequently used as food colorant (E 172). The spectrum of colors ranges from yellow over orange, red, and brown to black, depending on the chemical structure of the material. E 172 is mostly sold as solid powder. Recent studies have demonstrated the presence of nanoscaled particles in E 172 samples, often to a very high extent. This makes it necessary to investigate the fate of these particles after oral uptake. In this study, 7 differently structured commercially available E 172 food colorants (2 x Yellow FeO(OH), 2 x Red Fe
    MeSH term(s) Humans ; Food Coloring Agents/toxicity ; Caco-2 Cells ; Scattering, Small Angle ; X-Ray Diffraction ; Dust ; Digestion ; Ferric Compounds
    Chemical Substances ferric oxide (1K09F3G675) ; Food Coloring Agents ; Dust ; Ferric Compounds
    Language English
    Publishing date 2024-01-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 639064-x
    ISSN 1879-3177 ; 0887-2333
    ISSN (online) 1879-3177
    ISSN 0887-2333
    DOI 10.1016/j.tiv.2024.105772
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Metabolism-Disrupting Chemicals Affecting the Liver: Screening, Testing, and Molecular Pathway Identification.

    Fritsche, Kristin / Ziková-Kloas, Andrea / Marx-Stoelting, Philip / Braeuning, Albert

    International journal of molecular sciences

    2023  Volume 24, Issue 3

    Abstract: The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, ...

    Abstract The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, so-called metabolic endocrine disrupters, or metabolism-disrupting chemicals (MDCs). Among different metabolism-related diseases, obesity and non-alcoholic fatty liver disease (NAFLD) constitute a growing health problem, which has been associated with a western lifestyle combining excessive caloric intake and reduced physical activity. In the past years, awareness of chemical exposure as an underlying cause of metabolic endocrine effects has continuously increased. Within this review, we have collected and summarized evidence that certain environmental MDCs are capable of contributing to metabolic diseases such as liver steatosis and cholestasis by different molecular mechanisms, thereby contributing to the metabolic syndrome. Despite the high relevance of metabolism-related diseases, standardized mechanistic assays for the identification and characterization of MDCs are missing. Therefore, the current state of candidate test systems to identify MDCs is presented, and their possible implementation into a testing strategy for MDCs is discussed.
    MeSH term(s) Humans ; Non-alcoholic Fatty Liver Disease/diagnosis ; Metabolic Syndrome ; Metabolic Diseases ; Obesity ; Endocrine Disruptors/toxicity
    Chemical Substances Endocrine Disruptors
    Language English
    Publishing date 2023-01-31
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24032686
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Impact of perfluoroalkyl substances (PFAS) and PFAS mixtures on lipid metabolism in differentiated HepaRG cells as a model for human hepatocytes.

    Sadrabadi, Faezeh / Alarcan, Jimmy / Sprenger, Heike / Braeuning, Albert / Buhrke, Thorsten

    Archives of toxicology

    2023  Volume 98, Issue 2, Page(s) 507–524

    Abstract: Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants with various adverse health effects in humans including disruption of lipid metabolism. Aim of the present study was to elucidate the molecular mechanisms of PFAS-mediated effects ... ...

    Abstract Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants with various adverse health effects in humans including disruption of lipid metabolism. Aim of the present study was to elucidate the molecular mechanisms of PFAS-mediated effects on lipid metabolism in human cells. Here, we examined the impact of a number of PFAS (PFOS, PFOA, PFNA, PFDA, PFHxA, PFBA, PFHxS, PFBS, HFPO-DA, and PMPP) and of some exposure-relevant PFAS mixtures being composed of PFOS, PFOA, PFNA and PFHxS on lipid metabolism in human HepaRG cells, an in vitro model for human hepatocytes. At near cytotoxic concentrations, the selected PFAS and PFAS mixtures induced triglyceride accumulation in HepaRG cells and consistently affected the expression of marker genes for steatosis, as well as PPARα target genes and genes related to lipid and cholesterol metabolism, pointing to common molecular mechanisms of PFAS in disrupting cellular lipid and cholesterol homeostasis. PPARα activation was examined by a transactivation assay in HEK293T cells, and synergistic effects were observed for the selected PFAS mixtures at sum concentrations higher than 25 µM, whereas additivity was observed at sum concentrations lower than 25 µM. Of note, any effect observed in the in vitro assays occurred at PFAS concentrations that were at least four to five magnitudes above real-life internal exposure levels of the general population.
    MeSH term(s) Humans ; Lipid Metabolism ; PPAR alpha/genetics ; HEK293 Cells ; Hepatocytes ; Lipids ; Fluorocarbons/toxicity ; Cholesterol ; Alkanesulfonic Acids/toxicity ; Environmental Pollutants/toxicity
    Chemical Substances PPAR alpha ; Lipids ; Fluorocarbons ; Cholesterol (97C5T2UQ7J) ; Alkanesulfonic Acids ; Environmental Pollutants
    Language English
    Publishing date 2023-12-20
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-023-03649-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Comparative Analysis of Transcriptional Responses to Genotoxic and Non-Genotoxic Agents in the Blood Cell Model TK6 and the Liver Model HepaRG.

    Kreuzer, Katrin / Sprenger, Heike / Braeuning, Albert

    International journal of molecular sciences

    2022  Volume 23, Issue 7

    Abstract: Transcript signatures are a promising approach to identify and classify genotoxic and non-genotoxic compounds and are of interest as biomarkers or for future regulatory application. Not much data, however, is yet available about the concordance of ... ...

    Abstract Transcript signatures are a promising approach to identify and classify genotoxic and non-genotoxic compounds and are of interest as biomarkers or for future regulatory application. Not much data, however, is yet available about the concordance of transcriptional responses in different cell types or tissues. Here, we analyzed transcriptomic responses to selected genotoxic food contaminants in the human p53-competent lymphoblastoid cell line TK6 using RNA sequencing. Responses to treatment with five genotoxins, as well as with four non-genotoxic liver toxicants, were compared with previously published gene expression data from the human liver cell model HepaRG. A significant overlap of the transcriptomic changes upon genotoxic stress was detectable in TK6 cells, whereas the comparison with the HepaRG model revealed considerable differences, which was confirmed by bioinformatic data mining for cellular upstream regulators or pathways. Taken together, the study presents a transcriptomic signature for genotoxin exposure in the human TK6 blood cell model. The data demonstrate that responses in different cell models have considerable variations. Detection of a transcriptomic genotoxin signature in blood cells indicates that gene expression analyses of blood samples might be a valuable approach to also estimate responses to toxic exposure in target organs such as the liver.
    MeSH term(s) Blood Cells ; DNA Damage ; Humans ; Liver ; Mutagens/adverse effects ; Transcriptome
    Chemical Substances Mutagens
    Language English
    Publishing date 2022-03-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms23073420
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Firefly luciferase inhibition: a widely neglected problem.

    Braeuning, Albert

    Archives of toxicology

    2015  Volume 89, Issue 1, Page(s) 141–142

    MeSH term(s) Enzyme Inhibitors/pharmacology ; Genes, Reporter ; Inhibitory Concentration 50 ; Luciferases, Firefly/antagonists & inhibitors ; Luciferases, Firefly/genetics ; Research Design ; Stilbenes/pharmacology
    Chemical Substances Enzyme Inhibitors ; Stilbenes ; Luciferases, Firefly (EC 1.13.12.7) ; resveratrol (Q369O8926L)
    Language English
    Publishing date 2015-01
    Publishing country Germany
    Document type Editorial
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-014-1423-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: β-catenin signaling, the constitutive androstane receptor and their mutual interactions.

    Braeuning, Albert / Pavek, Petr

    Archives of toxicology

    2020  Volume 94, Issue 12, Page(s) 3983–3991

    Abstract: Aberrant signaling through β-catenin is an important determinant of tumorigenesis in rodents as well as in humans. In mice, xenobiotic activators of the constitutive androstane receptor (CAR), a chemo-sensing nuclear receptor, promote liver tumor growth ... ...

    Abstract Aberrant signaling through β-catenin is an important determinant of tumorigenesis in rodents as well as in humans. In mice, xenobiotic activators of the constitutive androstane receptor (CAR), a chemo-sensing nuclear receptor, promote liver tumor growth by means of a non-genotoxic mechanism and, under certain conditions, select for hepatocellular tumors which contain activated β-catenin. In normal hepatocytes, interactions of β-catenin and CAR have been demonstrated with respect to the induction of proliferation and drug metabolism-related gene expression. The molecular details of these interactions are still not well understood. Recently it has been hypothesized that CAR might activate β-catenin signaling, thus providing a possible explanation for some of the observed phenomena. Nonetheless, many aspects of the molecular interplay of the two regulators have still not been elucidated. This review briefly summarizes our current knowledge about the interplay of CAR and β-catenin. By taking into account data and observations obtained with different mouse models and employing different experimental approaches, it is shown that published data also contain substantial evidence that xenobiotic activators of CAR do not activate, or do even inhibit signaling through the β-catenin pathway. The review highlights new aspects of possible ways of interaction between the two signaling cascades and will help to stimulate scientific discussion about the crosstalk of β-catenin signaling and the nuclear receptor CAR.
    MeSH term(s) Animals ; Cell Transformation, Neoplastic/chemically induced ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Humans ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Liver Neoplasms/chemically induced ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Receptors, Cytoplasmic and Nuclear/agonists ; Receptors, Cytoplasmic and Nuclear/metabolism ; Risk Assessment ; Risk Factors ; Wnt Signaling Pathway ; Xenobiotics/toxicity ; beta Catenin/metabolism
    Chemical Substances Receptors, Cytoplasmic and Nuclear ; Xenobiotics ; beta Catenin ; constitutive androstane receptor (438XLITDI3)
    Language English
    Publishing date 2020-10-24
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-020-02935-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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