Peptide YY3-36 and 5-hydroxytryptamine mediate emesis induction by trichothecene deoxynivalenol (vomitoxin)

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 effe...

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Bibliographic Details
Published in:Toxicological sciences 2013-05, Vol.133 (1), p.186-195
Main Authors: Wu, Wenda, Bates, Melissa A, Bursian, Steven J, Flannery, Brenna, Zhou, Hui-Ren, Link, Jane E, Zhang, Haibin, Pestka, James J
Format: Article
Language:English
Subjects:
Animals
Antiemetics - administration & dosage
Antiemetics - pharmacology
Antiemetics - therapeutic use
Benzamides - administration & dosage
Benzamides - pharmacology
Benzamides - therapeutic use
Cholecystokinin - antagonists & inhibitors
Cholecystokinin - blood
Cholecystokinin - metabolism
Devazepide - administration & dosage
Devazepide - pharmacology
Devazepide - therapeutic use
Disease Models, Animal
Dose-Response Relationship, Drug
Female
Granisetron - administration & dosage
Granisetron - pharmacology
Granisetron - therapeutic use
Mink
Peptide Fragments - antagonists & inhibitors
Peptide Fragments - blood
Peptide Fragments - metabolism
Peptide YY - antagonists & inhibitors
Peptide YY - blood
Peptide YY - metabolism
Piperazines - administration & dosage
Piperazines - pharmacology
Piperazines - therapeutic use
Serotonin - blood
Serotonin - metabolism
Serotonin Antagonists - administration & dosage
Serotonin Antagonists - pharmacology
Serotonin Antagonists - therapeutic use
Time Factors
Trichothecenes - blood
Trichothecenes - toxicity
Vomiting - blood
Vomiting - chemically induced
Vomiting - metabolism
Vomiting - prevention & control
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Summary: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.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kft033