Response of intestinal HT-29 cells to the trichothecene mycotoxin deoxynivalenol and its sulfated conjugates. (1st October 2018)

• Record Type: Journal Article
• Authors: Del Favero, Giorgia; Woelflingseder, Lydia; Braun, Dominik; Puntscher, Hannes; Kütt, Mary-Liis; Dellafiora, Luca; Warth, Benedikt; Pahlke, Gudrun; Dall'Asta, Chiara; Adam, Gerhard; Marko, Doris
• Is Part Of: Toxicology letters. Volume 295(2018)
• Page Start: 424
• Page End: 437
• Publication Date: 2018-10-01
• Subjects: DON deoxynivalenol -- DON-3-Sulf deoxynivalenol-3-sulfate -- DON-15-Sulf deoxynivalenol-15-sulfate -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- Keap-1 kelch-like ECH-associated protein 1 -- Nrf-2 nuclear factor (erythroid-derived 2)-like 2 -- γ-GCL gamma-glutamate-cysteine ligase -- NQO-1 NAD(P)H dehydrogenase quinine 1 -- IL-8 interleukin 8 -- COX-2 cyclooxygenase 2; Deoxynivalenol-3-sulfate -- Deoxynivalenol-15-sulfate -- Cell proliferation -- Food contaminant -- Mycotoxins -- Cytotoxicity; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2018.07.007
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Toxicity of trichothecene mycotoxin deoxynivalenol (DON) and its sulfated metabolites differ in HT-29 cells. Combined in vitro / in silico approach was used to explore the differential pathways activated by DON-3-sulfate and DON-15-sulfate in comparison to the parent compound in intestinal cells. Highlights: DON-3-Sulf and DON-15-Sulf are taken up by HT-29 cells, but less compared to DON. In silico modelling shows reduced fit of DON-sulfates to the ribosomal pocket. DON-3-Sulf and DON-15-Sulf mediate a proliferative stimulus in HT-29 cells and modulate autophagy. Abstract: The sulfated forms of the Fusarium toxin deoxynivalenol (DON), deoxynivalenol-3-sulfate (DON-3-Sulf) and deoxynivalenol-15-sulfate (DON-15-Sulf) were recently described, however little is known about their mechanism of action in mammalian cells. DON-3-Sulf and DON-15-Sulf were taken up by HT-29 colon carcinoma cells, although to a lesser extent compared to DON. All three compounds were found to enhance the intracellular ROS level in the dichlorofluorescein assay (≥ 1μM), even though substantial differences were observed in their cytotoxic potential. In silico modelling highlighted that DON-sulfates do not share the classical mechanism of action of DON, being unable to fit into the ribosomal pocket and trigger the classical ribotoxic stress response. However, DON-3-Sulf and DON-15-Sulf sustained a distinctive proliferative stimulus in HT-29 and activated autophagy. The mechanisms of action of DON-3-Sulf and DON-15-Sulf suggest a potential interplay between the onset of ribosomal inhibition and autophagy activation as an alternative and/or complementary mode of action for DON and its sulfated analogues.