Exploring the dermotoxicity of the mycotoxin deoxynivalenol: combined morphologic and proteomic profiling of human epidermal cells reveals alteration of lipid biosynthesis machinery and membrane structural integrity relevant for skin barrier function.
Carcinoma, Squamous Cell
/ metabolism
Cell Line, Tumor
Cells, Cultured
Dose-Response Relationship, Drug
Epidermal Cells
/ drug effects
Fusarium
/ metabolism
Humans
Keratinocytes
/ drug effects
Lipids
/ biosynthesis
Mitochondria
/ drug effects
Proteomics
Secondary Metabolism
Trichothecenes
/ administration & dosage
Deoxynivalenol dermotoxicity
Klf4 transcription factor
Skin barrier
Unfolded protein response mitochondrial
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
15
12
2020
accepted:
01
04
2021
pubmed:
24
4
2021
medline:
8
1
2022
entrez:
23
4
2021
Statut:
ppublish
Résumé
Deoxynivalenol (vomitoxin, DON) is a secondary metabolite produced by Fusarium spp. fungi and it is one of the most prevalent mycotoxins worldwide. Crop infestation results not only in food and feed contamination, but also in direct dermal exposure, especially during harvest and food processing. To investigate the potential dermotoxicity of DON, epidermoid squamous cell carcinoma cells A431 were compared to primary human neonatal keratinocytes (HEKn) cells via proteome/phosphoproteome profiling. In A431 cells, 10 µM DON significantly down-regulated ribosomal proteins, as well as mitochondrial respiratory chain elements (OXPHOS regulation) and transport proteins (TOMM22; TOMM40; TOMM70A). Mitochondrial impairment was reflected in altered metabolic competence, apparently combined with interference of the lipid biosynthesis machinery. Functional effects on the cell membrane were confirmed by live cell imaging and membrane fluidity assays (0.1-10 µM DON). Moreover, a common denominator for both A431 and HEKn cells was a significant downregulation of the squalene synthase (FDFT1). In sum, proteome alterations could be traced back to the transcription factor Klf4, a crucial regulator of skin barrier function. Overall, these results describe decisive molecular events sustaining the capability of DON to impair skin barrier function. Proteome data generated in the study are fully accessible via ProteomeXchange with the accession numbers PXD011474 and PXD013613.
Identifiants
pubmed: 33890134
doi: 10.1007/s00204-021-03042-y
pii: 10.1007/s00204-021-03042-y
pmc: PMC8166681
doi:
Substances chimiques
Lipids
0
Trichothecenes
0
deoxynivalenol
JT37HYP23V
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2201-2221Références
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