title: Co-exposure to low doses of the food contaminants deoxynivalenol and nivalenol has a synergistic inflammatory effect on intestinal explants.
abstract: The global incidence of Fusarium head blight and attendant cereal grains multi-contamination by the trichothecene mycotoxins deoxynivalenol (DON) and nivalenol (NIV) are increasing as a possible result of climate change and inadequate agricultural practices. At the molecular level, these mycotoxins bind to the ribosome, activate the mitogen-activated protein kinase and induce a local and systemic inflammation. DON is of public health concern owing to the narrow margin between exposure and tolerable daily intake. The intestinal inflammatory response to DON, NIV and their mixture was analyzed to determine thresholds for their intestinal pro-inflammatory effects and characterize the type and magnitude of their interaction. Fully differentiated three-dimensional porcine jejunal explants were exposed to increasing doses of DON and NIV alone or in combination; the expression levels of IL-1α, IL-1β, IL-8, IL-17A and IL-22 were measured by RT-PCR. Doses as low as 0.16 µM DON or 0.73 µM NIV significantly increase the intestinal expression levels of the tested inflammation-related genes. These doses are lower than those previously reported for other intestinal toxicity endpoints. The combined pro-inflammatory activity of DON and NIV was synergistic for all the tested genes with combination index value range of 0.23-0.8. Our results indicate that (1) inflammation is a very sensitive endpoint for the intestinal toxicity of the trichothecenes and (2) co-exposure to DON and NIV has a greater inflammatory effect than induced by mycotoxins alone. This synergy should be taken into account considering the frequent co-occurrence of DON and NIV in the diet.
authors.affiliation: Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-PURPAN, UPS 180 Chemin de Tournefeuille, BP93173, 31027, Toulouse Cedex 03, France.|Hôpital d'Instruction des Armées, Camp Guézo, 01BP517, Cotonou, Bénin.
authors.forename: Imourana
authors.initials: I
authors.lastname: Alassane-Kpembi
authors.affiliation: Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-PURPAN, UPS 180 Chemin de Tournefeuille, BP93173, 31027, Toulouse Cedex 03, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Puel
authors.affiliation: Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-PURPAN, UPS 180 Chemin de Tournefeuille, BP93173, 31027, Toulouse Cedex 03, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-PURPAN, UPS 180 Chemin de Tournefeuille, BP93173, 31027, Toulouse Cedex 03, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cossalter
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.|PD Science LLC, Paramus, NJ, 07652-1754, USA.
authors.forename: Ting-Chao
authors.initials: TC
authors.lastname: Chou
authors.affiliation: Toxalim (Research Center in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-PURPAN, UPS 180 Chemin de Tournefeuille, BP93173, 31027, Toulouse Cedex 03, France. Isabelle.Oswald@toulouse.inra.fr.
authors.forename: Isabelle P
authors.initials: IP
authors.lastname: Oswald
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004751:Enteritis / Q000139:chemically induced / Q000473:pathology; D005506:Food Contamination; D005786:Gene Expression Regulation / Q000187:drug effects; D007579:Jejunal Diseases / Q000139:chemically induced / Q000473:pathology; D007583:Jejunum / Q000187:drug effects* / Q000473:pathology; D009183:Mycotoxins / Q000008:administration & dosage / Q000633:toxicity; D009924:Organ Culture Techniques / Q000379:methods; D013552:Swine; D018675:Toxicity Tests / Q000379:methods; D014255:Trichothecenes / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D016207:Cytokines; D009183:Mycotoxins; D014255:Trichothecenes; C038405:nivalenol; C007262:deoxynivalenol
keywords: Benchmark dose; Deoxynivalenol; Intestine; Low-dose synergy; Nivalenol; Pro-inflammatory cytokine