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Deoxynivalenol and human epidermal cells: proteomic profiling indicates alterations of cell membrane integrity and barrier function - phosphoproteomics

ABSTRACT: The possibility to combine untargeted proteomic workflows to more classical experimental approaches is continuously opening new insights in all branches of biological sciences. Deoxynivalenol (vomitoxin, DON) is a secondary metabolite produced by Fusarium spp. fungi and it is one of the most recurrent mycotoxins worldwide. DON is known to inhibit protein synthesis and as such to interact with the different cell types in multiple and complex ways. For the purpose of this study epidermoid squamous cell carcinoma cells A431 and primary human HEKn cells were incubated with DON for 24 h and toxin dependent alteration of the proteome profile was observed in nuclear and cytoplasmic fractions. In A431 cells, DON significantly down-regulated ribosomal proteins, as well as mitochondrial respiratory chain elements (OXPHOS regulation) and transport proteins (TOMM22; TOMM40; TOMM70A). In line with the impairment of the mitochondrial function, altered metabolic capability was indicated, with particular target of the lipid synthesis machinery. Functional effect of the mycotoxin on cell membranes was confirmed by live cell imaging and by membrane fluidity assay. Downregulation of the squalene synthase (FDFT1) was consistent in both cell types and the effects of the toxin on cell membranes and cholestherol biosyhtesis were found as common denominator for both A431 and HEKn. Overall we described crucial molecular events pointing toward the capability of DON to impair skin barrier function. Data generated in the study are fully accessible via ProemeXchange with the accession numbers PXD011474 and PXD013613.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epidermal Cell

DISEASE(S): Squamous Cell Carcinoma

SUBMITTER: Christopher Gerner

LAB HEAD: Christopher Gerner

PROVIDER: PXD016153 | Pride | 2021-06-01

REPOSITORIES: Pride

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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.

Del Favero Giorgia G Janker Lukas L Neuditschko Benjamin B Hohenbichler Julia J Kiss Endre E Woelflingseder Lydia L Gerner Christopher C Marko Doris D

Archives of toxicology 20210423 6

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. ...[more]

PMID: 33890134

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Project description:Deoxynivalenol (DON) is a type B trichothecene mycotoxin that is commonly found in cereals and grains worldwide. The presence of this fungal secondary-metabolite raises public-health concerns at both the agriculture and food industry level. The toxicity of DON is mainly characterized by its ability to inhibit ribosomal protein biosynthesis. Recently, we have shown that DON has a negative impact on gut integrity, a feature also noticed for Campylobacter (C.) jejuni. We further demonstrated that DON increased the load of C. jejuni in the gut and inner organs. In contrast, feeding the less toxic DON metabolite deepoxy-deoxynivalenol (DOM-1) to broilers reduced the Campylobacter load in vivo. Consequently, it can be hypothesized that DON and DOM-1 have a direct or indirect effect on the growth profile of C. jejuni. The aim of the present study was to further resolve the nature of this interaction in vitro by co-incubation and RNA-sequencing. The co-incubation of C. jejuni with DON resulted in significantly higher bacterial growth rates from 30 h of incubation onwards. On the contrary, the co-incubation of C. jejuni with DOM-1 reduced the CFU counts, indicating that this DON metabolite might contribute to reduce the burden of C. jejuni in birds, altogether confirming in vivo data. Furthermore, the transcriptomic profile of C. jejuni following incubation with either DON or DOM-1 differed. Co-incubation of C. jejuni with DON significantly increased the expression of multiple genes which are critical for Campylobacter growth, particularly members of the Flagella gene family, frr (ribosome-recycling factor), PBP2 futA-like (Fe3+ periplasmic binding family) and PotA (ATP-binding subunit). These organelles are required for pathogenicity-related phenotypes including motility, biofilm formation, host cell interactions, and host colonization, which may explain the high Campylobacter load in the intestine of DON-fed broiler chickens. On the contrary, DOM-1 downregulated the Flagella gene family and upregulated ribosomal proteins. The results highlight the adaptive mechanisms involved in the transcriptional response of C. jejuni to DON and its metabolite DOM-1, based on the following effects: (a) ribosomal proteins; (b) flagellar proteins; (c) engagement of different metabolic pathways. The results provide insight into the response of an important intestinal microbial pathogen against DON and lead to a better understanding of the luminal or environmental acclimation mechanisms in chickens.

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