Abstract
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.
Highlights
Skin structural integrity is essential for the maintenance of barrier function
DON induced proteome alterations in A431 cells point toward regulation of transcription factor KLF4
As for other toxins, proteomic profiling after incubation with DON has been previously performed and it greatly contributed to enhance our understanding of the molecular events sustaining the immunomodulatory function of the toxin (Nogueira da Costa et al 2011a, b; Pan et al 2013), as well as its effect at intestinal
Summary
Skin structural integrity is essential for the maintenance of barrier function. at cellular level, the plasma membrane represents the interface with the extracellular environment and, as such, its structure and stability are essential for cellular homeostasis. For food contaminants in general and for mycotoxins in particular, dermal exposure through contaminated food commodities during harvest and processing is becoming a topic of great interest (Doi and Uetsuka 2014), and it poses concerns in addition to the classical oral administration route (Katrine et al 2017). DON is classified in the trichothecene structural group and acts at molecular level via inhibition of protein synthesis (Cundliffe et al 1974; Ueno 1977). This event is initiated by binding to the A-site of the 60S large ribosomal subunit (Dellafiora et al 2017; Garreau de Loubresse et al 2014) and leads to the impairment of the peptidyl-transferase activity of the organelle. DON is known to impair the intestinal barrier system; it targets cell–cell-junctional proteins and mucous layer hampering in this way gut functionality (Beisl et al 2020, 2021; Pinton and Oswald 2014; Robert et al 2017; Wang et al 2020)
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