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. 2013 May;133(1):186-95.
doi: 10.1093/toxsci/kft033. Epub 2013 Mar 1.

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

Wenda Wu  1 , Melissa A Bates, Steven J Bursian, Brenna Flannery, Hui-Ren Zhou, Jane E Link, Haibin Zhang, James J Pestka
Affiliations

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

Wenda Wu et al. Toxicol Sci. 2013 May.

Abstract

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.

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Figures

Fig. 1.
Fig. 1.
Emesis induction in mink corresponds to elevation in plasma DON. (A) Experimental design for DON-induced plasma PYY3–36 and 5-HT release; (B) mean cumulative emetic events (total retches and vomits) in mink following ip exposure to DON. Data are averages for both responders and nonresponders. The numbers of animals responding/tested at 15, 30, 60, and 120min were 6/16, 9/12, 8/8, and 4/4, respectively, for 0.1mg/kg bw DON group and 11/16, 12/12, 8/8, and 4/4, respectively, for 0.25mg/kg bw DON group. The mean latency time to onset of emesis for the 0.1 and 0.25mg/kg DON groups were 17±2 and 12±2min, respectively. (C) Kinetics of plasma DON concentration. Data represent mean ± SEM (n = 4 per group). A two-way ANOVA using Bonferroni t-test was used to assess significant differences in cumulative emetic events and kinetics of DON concentration in plasma. *p < 0.05 indicates statistically significant differences in emetic events or DON concentration compared with the control. ŧ p < 0.05 indicates a statistically significant difference in emetic events relative to the 0-min time point or significant difference in DON concentration relative to the 120-min time point within a given dose.
Fig. 2.
Fig. 2.
Emesis induction corresponds to elevation in plasma PYY3–36. (A) Kinetics of DON-induced plasma PYY3–36 concentration. Data are the mean ± SEM (n = 4 per group). A two-way ANOVA using Bonferroni t-test was used to assess significant differences in kinetics of PYY3–36 concentration in plasma. Asterisk indicates statistically significant differences in PYY3–36 concentration compared with the control at p < 0.05. (B) Relationship between total emetic events and PYY3–36 levels at 60min in DON-treated mink. Cumulative emetic events significantly correlated with PYY3–36 (Spearman rank-order correlation coefficient = 0.651, p < 0.05).
Fig. 3.
Fig. 3.
PYY3–36 mediates DON-induced emesis. Experimental design for Y2 receptor antagonist in DON-induced emesis; (B) suppression of DON- and PYY-induced emesis by Y2 receptor antagonists. Emetic events include vomiting (gray) and retching (black) episodes. ND = not detected. Data represent mean ± SEM (n = 4 per group). A one-way ANOVA using Tukey’s test or t-test was used to analyze significant differences between treatments and the respective controls. *p < 0.05 indicates statistically significant differences in emetic events between Y2 receptor antagonist treatment groups and only DON or PYY treatment group. These results and frequency, latency, and duration times are presented in tabular form in Supplementary data.
Fig. 4.
Fig. 4.
Emesis induction corresponds to elevations in plasma 5-HT. (A) Kinetics of DON-induced plasma 5-HT. Data are the mean ± SEM (n = 4 per group). A two-way ANOVA using Bonferroni t-test was used to assess significant differences in kinetics of 5-HT concentration in plasma. Asterisk indicates statistically significant differences in 5-HT concentration compared with the control at p < 0.05. (B) Relationship between total emetic events and plasma 5-HT at 60min. Cumulative emetic events significantly correlated with plasma 5-HT (Spearman rank-order correlation coefficient = 0.623, p < 0.05).
Fig. 5.
Fig. 5.
5-HT mediates DON-induced emesis. (A) Experimental design for 5-HT3 receptor antagonist in DON- and cisplatin-induced emesis; (B) suppression of emesis by 5-HT3 receptor antagonist, granisetron. Emetic events include vomiting (gray) and retching (black) episodes. ND = not detected. Data represent mean ± SEM (n = 4 per group). A one-way ANOVA using Tukey’s test or t-test was used to analyze significant differences between treatments and the respective controls. Asterisk indicates statistically significant differences in emetic events between 5-HT3 receptor antagonist treatment groups and only DON or cisplatin treatment group at p < 0.05. These results and frequency, latency, and duration times are presented in tabular form in Supplementary data.
Fig. 6.
Fig. 6.
PYY-induced emesis is mediated through 5-HT. (A) Experimental design; (B) suppression of PYY-induced emesis by 5-HT3 receptor antagonist granisetron. Emetic events include vomiting (gray) and retching (black) episodes. ND = not detected. Data represent mean ± SEM (n = 4 per group). A one-way ANOVA using Tukey’s test or t-test was used to analyze significant differences between treatments and the respective controls. Asterisk indicates statistically significant differences in emetic events between 5-HT3 receptor antagonist treatment group and only PYY treatment group at p < 0.05. These results and frequency, latency, and duration times are presented in tabular form in Supplementary data.
Fig. 7.
Fig. 7.
Putative mechanisms for DON-induced emesis. The results presented here suggest that DON could act by inducing PYY release (e.g., L cells) and 5-HT release (e.g., EC cells). These might activate neuropeptide Y2 receptor (NPY2R) and 5-HT3 receptors (5-HT3R), respectively, in the peripheral and central nervous systems, ultimately inducing emesis via the CPG. The potential exists for significant crosstalk (dotted line)ss whereby PYY induces 5-HT release at peripheral and central sites.
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