Deoxynivalenol and intestinal inflammation : an in vitro assessment

(eng) Deoxynivalenol (DON, vomitoxin), the most prevalent trichothecene mycotoxin worldwide, contaminates numerous food items from cereal origin. DON adversely affects animal health with symptoms going from reduced nutritional efficiency and weight gain upon chronic low dose exposure, to emesis, leukocytosis and haemorrhage upon acute high level ingestion. Also human toxicoses related to DON ingestion have been reported. The gastro-intestinal tract is the primary site of DON exposure in terms of timing and amount, and could constitute both a target of and a barrier to DON toxicity. The objective of this research was to determine the impact of DON exposure on inflammatory parameters in human intestinal epithelial cells in vitro. Proliferating and differentiated Caco-2 cells, respectively representative of young/immature, and adult/mature human enterocytes were exposed to realistic intestinal concentrations of DON (50 to 5000 ng/ml) during 24h. The induction of intracellular inflammatory signalling pathways was observed through the activation of the Mitogen Activated Protein Kinases (ERK1/2, JNK and p38) and the transcription factor Nuclear Factor (NF)- κB. DON dose-dependently upregulated the production of the inflammatory mediators IL-8 and PGE-2. These phenomena occurred similarly in proliferating and differentiated cells and were dependent on ERK1/2, JNK and NF-κB activation. The simultaneous exposure to a mixture of inflammatory mediators (IL-1β, TNF-α, IFN-γ and LPS) representative of an acute inflammatory reaction caused synergic increases in IL-8 secretion. Continuous incubation with DON (50 ng/ml) during 21 days increased basal level of IL-8 and PGE-2 production. DON exposure furthermore caused a dose-dependent increase of the paracellular permeability of the Caco-2 monolayer together with a decrease in protein synthesis, with a possible link between these events being the diminished synthesis of the tight junction protein claudin-4. Also intestinal alkaline phosphatase expression, a marker of cellular differentiation, was reduced. The results of this research allow to conclude that DON induces inflammatory parameters in the intestinal epithelium, together with causing a weakening of the monolayer structure and functioning. These observations could be important for human health hazard evaluation regarding DON exposure.