devazepide and deoxynivalenol

Deoxynivalenol (DON, vomitoxin), a trichothecene mycotoxin produced by Fusarium sp. that frequently occurs in cereal grains, has been associated with human and animal food poisoning. Although a common hallmark of DON-induced toxicity is the rapid onset of emesis, the mechanisms for this adverse effect are not fully understood. Recently, our laboratory has demonstrated that the mink (Neovison vison) is a suitable small animal model for investigating trichothecene-induced emesis. The goal of this study was to use this model to determine the roles of two gut satiety hormones, peptide YY3-36 (PYY3-36) and cholecystokinin (CCK), and the neurotransmitter 5-hydroxytryptamine (5-HT) in DON-induced emesis. Following ip exposure to DON at 0.1 and 0.25mg/kg bw, emesis induction ensued within 15-30min and then persisted up to 120min. Plasma DON measurement revealed that this emesis period correlated with the rapid distribution and clearance of the toxin. Significant elevations in both plasma PYY3-36 (30-60min) and 5-HT (60min) but not CCK were observed during emesis. Pretreatment with the neuropeptide Y2 receptor antagonist JNJ-31020028 attenuated DON- and PYY-induced emesis, whereas the CCK1 receptor antagonist devezapide did not alter DON's emetic effects. The 5-HT3 receptor antagonist granisetron completely suppressed induction of vomiting by DON and the 5-HT inducer cisplatin. Granisetron pretreatment also partially blocked PYY3-36-induced emesis, suggesting a potential upstream role for this gut satiety hormone in 5-HT release. Taken together, the results suggest that both PYY3-36 and 5-HT play contributory roles in DON-induced emesis.

Topics: Animals; Antiemetics; Benzamides; Cholecystokinin; Devazepide; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Granisetron; Mink; Peptide Fragments; Peptide YY; Piperazines; Serotonin; Serotonin Antagonists; Time Factors; Trichothecenes; Vomiting

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin known to commonly contaminate grain-based foods, suppresses growth of experimental animals, thus raising concerns over its potential to adversely affect young children. Although this growth impairment is believed to result from anorexia, the initiating mechanisms for appetite suppression remain unknown. Here, we tested the hypothesis that DON induces the release of satiety hormones and that this response corresponds to the toxin's anorectic action. Acute ip exposure to DON had no effect on plasma glucagon-like peptide-1, leptin, amylin, pancreatic polypeptide, gastric inhibitory peptide, or ghrelin; however, the toxin was found to robustly elevate peptide YY (PYY) and cholecystokinin (CCK). Specifically, ip exposure to DON at 1 and 5mg/kg bw induced PYY by up to 2.5-fold and CCK by up to 4.1-fold. These responses peaked within 15-120 min and lasted up to 120 min (CCK) and 240 min (PPY), corresponding with depressed rates of food intake. Direct administration of exogenous PYY or CCK similarly caused reduced food intake. Food intake experiments using the NPY2 receptor antagonist BIIE0246 and the CCK1A receptor antagonist devazepide, individually, suggested that PYY mediated DON-induced anorexia but CCK did not. Orolingual exposure to DON induced plasma PYY and CCK elevation and anorexia comparable with that observed for ip exposure. Taken together, these findings suggest that PYY might be one critical mediator of DON-induced anorexia and, ultimately, growth suppression.

Topics: Administration, Oral; Animals; Anorexia; Appetite Depressants; Appetite Regulation; Arginine; Behavior, Animal; Benzazepines; Chemokines, CC; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Eating; Female; Food Contamination; Injections, Intraperitoneal; Mice; Mycotoxins; Peptide YY; Receptors, Cholecystokinin; Receptors, Neuropeptide Y; Satiation; Time Factors; Trichothecenes