Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside

Abstract

Natural food contaminants such as mycotoxins are an important problem for human health. Deoxynivalenol (DON) is one of the most common mycotoxins detected in cereals and grains. Its toxicological effects mainly concern the immune system and the gastrointestinal tract. This toxin is a potent ribotoxic stressor leading to MAP kinase activation and inflammatory response. DON frequently co-occurs with its glucosylated form, the masked mycotoxin deoxynivalenol-3-β-D-glucoside (D3G). The toxicity of this later compound remains unknown in mammals. This study aimed to assess the ability of D3G to elicit a ribotoxic stress and to induce intestinal toxicity. The toxicity of D3G and DON (0-10 µM) was studied in vitro, on the human intestinal Caco-2 cell line, and ex vivo, on porcine jejunal explants. First, an in silico analysis revealed that D3G, contrary to DON, was unable to bind to the A-site of the ribosome peptidyl transferase center, the main targets for DON toxicity. Accordingly, D3G did not activate JNK and P38 MAPKs in treated Caco-2 cells and did not alter viability and barrier function on cells, as measured by the trans-epithelial electrical resistance. Treatment of intestinal explants for 4 h with 10 µM DON induced morphological lesions and up-regulated the expression of pro-inflammatory cytokines as measured by qPCR and pan-genomic microarray analysis. By contrast, expression profile of D3G-treated explants was similar to that of controls, and these explants did not show histomorphology alteration. In conclusion, our data demonstrated that glucosylation of DON suppresses its ability to bind to the ribosome and decreases its intestinal toxicity.

Deoxynivalenol and Its Modified Forms: Are There Major Differences?

“…As hypothesized, DON3G had no effect on TEER values, which is line with previous results in which Caco-2 cells were exposed to 10 µM DON3G for 8 days [34]. Although there was a slight decrease in TEER after exposure to 8.4 µM DOM-1 for 12 and 24 h, DOM-1 did not significantly influence TEER values over the entire concentration range tested.…”

“…The results of the comparable experiment with DON3G and DOM-1 confirmed that DON3G had no effect on CXCL8 secretion, which was previously reported by measuring the CXCL8 mRNA expression [34]. …”

“…These data suggest that the bacterial metabolite DOM-1 could be cytotoxic for intestinal epithelial cells at high concentrations. Furthermore, recently published data observed no cytotoxic effects of DON3G (0.05 µM to 10 µM) after 48 h exposure in proliferating Caco-2 cells, whereas differentiated Caco-2 cells showed no cytotoxicity up to 100 µM for 8 days [34]. …”

“…Recent elegant in silico and in vitro experiments indicated that DON3G is apparently poorly absorbed by intestinal cells and fails to bind to the A-site of the ribosome peptidyl transferase center, and hence is not able to induce the activation of mitogen activated protein kinases (MAPK), which is the main pathway resulting in the typical ribotoxic stress considered as main molecular mechanism of DON-induced cell injury and inflammation [34]. …”

Behaviour of durum wheat cultivars towards deoxynivalenol content: A multi-year assay in Italy

“…D3G is also defined as masked form of DON. This compound has a lower acute toxicity compared to his parent mycotoxin particularly in the binding to the ribosome and its intestinal toxicity (Pierron et al, 2016). However, it can be hydrolysed by several intestinal bacteria releasing free DON and this fact is of great toxicological concern (Berthiller et al, 2011).…”