Identification of key pathways involved in the toxic response of the cyanobacterial toxin cylindrospermopsin in human hepatic HepaRG cells
| Autor: | Ludovic Le Hégarat, Antoine Huguet, Rachelle Lanceleur, Valérie Fessard, Hélène Quenault |
|---|---|
| Přispěvatelé: | Laboratoire de Fougères, Bâtiment Bioagropolis, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Laboratoire de Fougères - ANSES, Laboratoire de Ploufragan - Plouzané |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
hepatotoxicity DNA damage Bacterial Toxins xénobiotique xenobiotic cyanobactérie Pharmacology cyanobacteria Cell Line 03 medical and health sciences chemistry.chemical_compound Alkaloids 0302 clinical medicine Cytochrome P-450 Enzyme System test in-vitro Humans toxicité Uracil toxin Cyanobacteria Toxins hepaRG cell hépatotoxicité Cell Cycle Hepatotoxin toxicity toxicologie General Medicine Cell cycle Cell redox homeostasis Glutathione 3. Good health in-vitro test toxine 030104 developmental biology chemistry Apoptosis 030220 oncology & carcinogenesis [SDV.TOX]Life Sciences [q-bio]/Toxicology Toxicity Hepatocytes Cylindrospermopsin Transcriptome Metabolic Networks and Pathways Drug metabolism DNA Damage toxicology cellule hepaRG |
| Zdroj: | Toxicology in Vitro Toxicology in Vitro, Elsevier, 2019, 58, pp.69-77. ⟨10.1016/j.tiv.2019.03.023⟩ |
| ISSN: | 0887-2333 |
| Popis: | International audience; The hepatotoxin cylindrospermopsin (CYN) has been involved in cases of poisoning in humans following ingestion. As its liver toxicity process is complex, we studied the transcriptomic profile of HepaRG cells exposed to CYN. The affected pathways were confirmed through the expression of key genes and the investigation of toxicity markers. In addition, CYP450 activities and cell redox homeostasis were investigated following acute and repeated exposure. CYN induced the down-regulation of genes involved in xenobiotic metabolism and cell cycle progression. There was cell cycle disturbance characterised by an accumulation of G1/S and G2/M cells and an increase in phospho-H3-positive cells. This was linked to the induction of DNA damage demonstrated by an increase in γH2AX-positive cells as well as an accumulation of sub-G1 cells indicating apoptosis but not involving caspase-3. While glutathione (GSH) content sharply decreased following acute exposure to CYN, it increased following repeated exposure, reflecting an adaptive response of cell redox homeostasis. However, our data also suggested that CYN induced the down-regulation of phase I and II metabolism gene products, and CYP450 activities were affected following both acute and repeated exposure to CYN. Our study indicated that repeated exposure of liver cells to low concentrations of CYN may affect their detoxification capacities. |
| Databáze: | OpenAIRE |
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