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Toxicology. 2020 Feb 7;433-434:152405. doi: 10.1016/j.tox.2020.152405. [Epub ahead of print]

The Fusarium mycotoxin, 2-Amino-14,16-dimethyloctadecan-3-ol (AOD) induces vacuolization in HepG2 cells.

Author information

1
Chemistry and Toxinology Research Group, Norwegian Veterinary Institute, 0454, Oslo, Norway. Electronic address: Anita.Solhaug@vetinst.no.
2
Department of Molecular Cell Biology, Institute for Cancer Research, the Norwegian Radium Hospital, Oslo University Hospital, 0379, Oslo, Norway.
3
Department of Environmental Health, Division of Infection Control and Environment and Health, Norwegian Institute of Public Health, 0403, Oslo, Norway.
4
Chemistry and Toxinology Research Group, Norwegian Veterinary Institute, 0454, Oslo, Norway.
5
Department of Biosciences, University of Oslo, 0316 Oslo Norway.

Abstract

The mycotoxin 2-Amino-14,16-dimethyloctadecan-3-ol (AOD) has been isolated from cultures of the fungus Fusarium avenaceum, one of the most prevalent Fusarium species. AOD is an analogue of sphinganine and 1-deoxysphinganine, important intermediates in the de novo biosynthesis of cellular sphingolipids. Here we studied cellular effects of AOD using the human liver cell line HepG2 as a model system. AOD (10 μM) induced a transient accumulation of vacuoles in the cells. The effect was observed at non-cytotoxic concentrations and was not linked to cell death processes. Proteomic analyses indicated that protein degradation and/or vesicular transport may be a target for AOD. Further studies revealed that AOD had only minor effects on the initiation rate of macropinocytosis and autophagy. However, the AOD-induced vacuoles were lysosomal-associated membrane protein-1 (LAMP-1) positive, suggesting that they most likely originate from lysosomes or late endosomes. Accordingly, both endosomal and autophagic protein degradation were inhibited. Further studies revealed that treatment with concanamycin A or chloroquine completely blocked the AOD-induced vacuolization, suggesting that the vacuolization is dependent of acidic lysosomes. Overall, the results strongly suggest that the increased vacuolization is due to an accumulation of AOD in lysosomes or late endosomes thereby disturbing the later stages of the endolysosomal process.

KEYWORDS:

Emerging mycotoxins; Endosomes; Lysosomes; Sphingolipids; Vacuolization

PMID:
32044396
DOI:
10.1016/j.tox.2020.152405

Conflict of interest statement

Declaration of Competing Interest The authors declare that there are no conflicts of interest

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