Deoxynivalenol (DON), the most naturally-occurring trichothecenes, may affect animal and human health by causing vomiting as a hallmark of food poisoning. Deoxynivalenol-3-glucoside (D3G) usually co-occurs with DON as its glucosylated form and is another emerging food safety issue in recent years. However, the toxicity of D3G is not fully understood compared to DON, especially in emetic potency. The goals of this research were to (1) compare emetic effects to D3G by oral and intraperitoneal (IP) routes and relate emetic effects to brain-gut peptides glucose-dependent insulinotropic polypeptide (GIP) and substance P (SP) in mink; (2) determine the roles of calcium-sensing receptor (CaSR) and transient receptor potential (TRP) channel in D3G's emetic effect. Both oral and IP exposure to D3G elicited marked emetic events. This emetic response corresponded to an elevation of GIP and SP. Blocking the GIP receptor (GIPR) diminished emetic response induction by GIP and D3G. The neurokinin 1 receptor (NK-1R) inhibitor Emend® restrained the induction of emesis by SP and D3G. Importantly, CaSR antagonist NPS-2143 or TRP channel antagonist ruthenium red dose-dependently inhibited both D3G-induced emesis and brain-gut peptides GIP and SP release; cotreatment with both antagonists additively suppressed both emetic and brain-gut peptide responses to D3G. To summarize, our findings demonstrate that activation of CaSR and TRP channels contributes to D3G-induced emesis by mediating brain-gut peptide exocytosis in mink.

College of Life Science Yangtze University Jingzhou 434025 China

Department of Chemistry Faculty of Science University of Hradec Kralove 50003 Hradec Kralove Czech Republic

MOE Joint International Research Laboratory of Animal Health and Food Safety College of Veterinary Medicine Nanjing Agricultural University Nanjing 210095 China

School of Animal Husbandry and Veterinary Medicine Jiangsu Vocational College of Agriculture and Forestry Jurong 212400 China

See more in PubMed

You L., Zhao Y., Kuca K., Wang X., Oleksak P., Chrienova Z., Nepovimova E., Jaćević V., Wu Q., Wu W. Hypoxia, oxidative stress, and immune evasion: A trinity of the trichothecenes T-2 toxin and deoxynivalenol (DON) Arch. Toxicol. 2021;95:1899–1915. doi: 10.1007/s00204-021-03030-2. PubMed DOI

EFSA Scientific opinion on the risk to human and animal health related to the presence of deoxynivalenol and its acetylated and modified forms in food and feed. EFSA J. 2017;15:345. PubMed PMC

Zhang L., Ma R., Zhu M., Zhang N., Liu X., Wang Y., Qin T., Zheng L., Liu Q., Zhang W., et al. Effect of deoxynivalenol on the porcine acquired immune response and potential remediation by a novel modified HSCAS adsorbent. Food Chem. Toxicol. 2020;138:111187. doi: 10.1016/j.fct.2020.111187. PubMed DOI

Mishra S., Srivastava S., Dewangan J., Divakar A., Rath S.K. Global occurrence of deoxynivalenol in food commodities and exposure risk assessment in humans in the last decade: A survey. Crit. Rev. Food Sci. Nutr. 2020;60:1346–1374. doi: 10.1080/10408398.2019.1571479. PubMed DOI

Zhao L., Zhang L., Xu Z., Liu X., Chen L., Dai J., Karrow N., Sun L. Occurrence of Aflatoxin B-1, deoxynivalenol and zearalenone in feeds in China during 2018–2020. J. Anim. Sci. Biotechnol. 2021;12:74. doi: 10.1186/s40104-021-00603-0. PubMed DOI PMC

Deng Y., You L., Nepovimova E., Wang X., Musilek K., Wu Q., Wu W., Kuca K. Biomarkers of deoxynivalenol (DON) and its modified form DON-3-glucoside (DON-3G) in humans. Trends Food Sci. Technol. 2021;110:551–558. doi: 10.1016/j.tifs.2021.02.038. DOI

Biomin BIOMIN Mycotoxin Survey Q3 2021 Results. [(accessed on 6 March 2022)]. Available online: https://www.biomin.net/science-hub/biomin-mycotoxin-survey-q3-2021-results/

Liu M., Zhao L., Gong G., Zhang L., Shi L., Dai J., Han Y., Wu Y., Khalil M., Sun L. Invited review: Remediation strategies for mycotoxin control in feed. J. Anim. Sci. Biotechnol. 2022;13:19. doi: 10.1186/s40104-021-00661-4. PubMed DOI PMC

Zhou H., Guog T., Dai H., Yu Y., Zhang Y., Ma L. Deoxynivalenol: Toxicological profiles and perspective views for future research. World Mycotoxin J. 2020;13:179–188. doi: 10.3920/WMJ2019.2462. DOI

Pestka J.J. Deoxynivalenol: Mechanisms of action, human exposure, and toxicological relevance. Arch. Toxicol. 2010;84:663–679. doi: 10.1007/s00204-010-0579-8. PubMed DOI

Wu F., Groopman J.D., Pestka J.J. Public health impacts of foodborne mycotoxins. Annu. Rev. Food Sci. Technol. 2014;5:351–372. doi: 10.1146/annurev-food-030713-092431. PubMed DOI

Suzuki T., Iwahashi Y. Low Toxicity of Deoxynivalenol-3-Glucoside in Microbial Cells. Toxins. 2015;7:187–200. doi: 10.3390/toxins7010187. PubMed DOI PMC

JECFA . Deoxynivalenol. WHO Press; Geneva, Switzerland: 2011. Evaluation of certain contaminants in food: 72nd report of the joint FAO/WHO expert committee on food additives; pp. 37–48. (WHO Technical Report Series, No. 959).

Freire L., Sant’Ana A.S. Modified mycotoxins: An updated review on their formation, detection, occurrence, and toxic effects. Food Chem. Toxicol. 2018;111:189–205. doi: 10.1016/j.fct.2017.11.021. PubMed DOI

Payros D., Alassane-Kpembi I., Pierron A., Loiseau N., Pinton P., Oswald I.P. Toxicology of deoxynivalenol and its acetylated and modified forms. Arch. Toxicol. 2016;90:2931–2957. doi: 10.1007/s00204-016-1826-4. PubMed DOI

Vidal A., Claeys L., Mengelers M., Vanhoorne V., Vervaet C., Huybrechts B., De Saeger S., De Boevre M. Humans significantly metabolize and excrete the mycotoxin deoxynivalenol and its modified form deoxynivalenol-3-glucoside within 24 hours. Sci. Rep. 2018;8:5255. doi: 10.1038/s41598-018-23526-9. PubMed DOI PMC

Gratz S.W., Duncan G., Richardson A.J. Human fecal microbiota metabolize deoxynivalenol and deoxynivalenol-3-glucoside and may be responsible for urinary de-epoxy deoxynivalenol. Appl. Environ. Microbiol. 2013;79:1821–1825. doi: 10.1128/AEM.02987-12. PubMed DOI PMC

Gratz S.W., Currie V., Richardson A.J., Duncan G., Holtrop G., Farquharson F., Louis P., Pinton P., Oswald I.P. Porcine Small and Large Intestinal Microbiota Rapidly Hydrolyze the Masked Mycotoxin Deoxynivalenol-3-Glucoside and Release Deoxynivalenol in Spiked Batch Cultures In Vitro. Appl. Microbiol. Biotechnol. 2018;84:e02106–e02117. doi: 10.1128/AEM.02106-17. PubMed DOI PMC

Wu W., Zhou H.R., Bursian S.J., Pan X., Link J.E., Berthiller F., Adam G., Krantis A., Durst T., Pestka J.J. Comparison of ano-rectic and emetic potencies of deoxynivalenol (vomitoxin) to the plant metabolite deoxynivalenol-3-glucoside and synthetic de-oxynivalenol derivatives EN139528 and EN139544. Toxicol. Sci. 2014;142:167–181. doi: 10.1093/toxsci/kfu166. PubMed DOI PMC

Wu W., Zhou H.R., Bursian S.J., Link J.E., Pestka J.J. Emetic responses to T-2 toxin, HT-2 toxin and emetine correspond to plasma elevations of peptide YY3-36 and 5-hydroxytryptamine. Arch. Toxicol. 2016;90:997–1007. doi: 10.1007/s00204-015-1508-7. PubMed DOI PMC

Wu W., Bates M.A., Bursian S.J., Link J.E., Flannery B.M., Sugita-Konishi Y., Watanabe M., Zhang H., Pestka J.J. Comparison of emetic potencies of the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon X, and nivalenol. Toxicol. Sci. 2013;131:279–291. doi: 10.1093/toxsci/kfs286. PubMed DOI PMC

Wu W., Zhou H.R., Pestka J.J. Potential roles for calcium-sensing receptor (CaSR) and transient receptor potential ankyrin-1 (TRPA1) in murine anorectic response to deoxynivalenol (vomitoxin) Arch. Toxicol. 2017;91:495–507. doi: 10.1007/s00204-016-1687-x. PubMed DOI

Wu W., Zhou H.R., Bursian S.J., Link J.E., Pestka J.J. Calcium-sensing receptor and transient receptor ankyrin-1 mediate emesis induction by deoxynivalenol (vomitoxin) Toxicol. Sci. 2017;155:32–42. doi: 10.1093/toxsci/kfw191. PubMed DOI PMC

Liou A.P. Digestive physiology of the pig symposium: G protein-coupled receptors in nutrient chemosensation and gastrointestinal hormone secretion. J. Anim. Sci. 2013;91:1946–1956. doi: 10.2527/jas.2012-5910. PubMed DOI

Reimann F., Tolhurst G., Gribble F.M. G-protein coupled receptors in intestinal chemosensation. Cell Metab. 2012;15:421–431. doi: 10.1016/j.cmet.2011.12.019. PubMed DOI

Zhou H.R., Pestka J.J. Deoxynivalenol (vomitoxin)-induced cholecystokinin and glucagon-like peptide-1 release in the STC-1 enteroendocrine cell model is mediated by calcium-sensing receptor and transient receptor potential ankyrin-1 channel. Toxicol. Sci. 2015;145:407–417. doi: 10.1093/toxsci/kfv061. PubMed DOI PMC

Naylor R.J., Rudd J.A. Mechanisms of chemotherapy/radiotherapy-induced emesis in animal models. Oncology. 1996;53:8–17. doi: 10.1159/000227634. PubMed DOI

Horn C.C., Wallisch W.J., Homanics G.E., Williams J.P. Why is the neurobiology of nausea and vomiting so important? Appetite. 2008;50:430–434. doi: 10.1016/j.appet.2007.09.015. PubMed DOI PMC

Johnston K.D., Lu Z., Rudd J.A. Looking beyond 5-HT(3) receptors: A review of the wider role of serotonin in the pharmacology of nausea and vomiting. Eur. J. Pharmacol. 2014;722:13–25. doi: 10.1016/j.ejphar.2013.10.014. PubMed DOI

Koga T., Fukuda H. Descending pathway from the central pattern generator of vomiting. Neuroreport. 1997;8:2587–2590. doi: 10.1097/00001756-199707280-00033. PubMed DOI

Navari R.M., Aapro M. Antiemetic Prophylaxis for Chemotherapy-Induced Nausea and Vomiting. N. Engl. J. Med. 2016;374:1356–1367. doi: 10.1056/NEJMra1515442. PubMed DOI

Finan B., Douros J.D. GLP-1/GIP/glucagon receptor triagonism gets its try in humans. Cell Metab. 2022;34:3–4. doi: 10.1016/j.cmet.2021.12.010. PubMed DOI

Kim D.Y., Piao J., Hong H.S. Substance-P inhibits cardiac microvascular endothelial dysfunction caused by high glucose-induced oxidative stress. Antioxidants. 2021;10:1084. doi: 10.3390/antiox10071084. PubMed DOI PMC

Meleine M., Melchior C., Prinz P., Penfornis A., Coffin B., Stengel A., Ducrotté P., Gourcerol G. Gastrointestinal peptides during chronic gastric electrical stimulation in patients with intractable vomiting. Neuromodulation. 2017;20:774–782. doi: 10.1111/ner.12645. PubMed DOI

Jin Z., Daksla N., Gan T.J. Neurokinin-1 antagonists for postoperative nausea and vomiting. Drugs. 2021;81:1171–1179. doi: 10.1007/s40265-021-01532-y. PubMed DOI

Tian L., Qian W., Qian Q., Zhang W., Cai X. Gingerol inhibits cisplatin-induced acute and delayed emesis in rats and minks by regulating the central and peripheral 5-HT, SP, and DA systems. J. Nat. Med. 2020;74:353–370. doi: 10.1007/s11418-019-01372-x. PubMed DOI PMC

Forsyth D.M., Yoshizawa T., Morooka N., Tuite J. Emetic and refusal activity of deoxynivalenol to swine. Appl. Environ. Microbiol. 1977;34:547–552. doi: 10.1128/aem.34.5.547-552.1977. PubMed DOI PMC

Yue J., Guo D., Gao X., Wang J., Nepovimova E., Wu W., Kuca K. Deoxynivalenol (Vomitoxin)-induced anorexia is induced by the release of intestinal hormones in mice. Toxins. 2021;13:512. doi: 10.3390/toxins13080512. PubMed DOI PMC

Zhang J., Jia H., Wang Q., Zhang Y., Wu W., Zhang H. Role of peptide YY3-36 and glucose-dependent insulinotropic polypeptide in anorexia induction by trichothecences T-2 toxin, HT-2 toxin, diacetoxyscirpenol, and neosolaniol. Toxicol. Sci. 2017;159:203–210. doi: 10.1093/toxsci/kfx128. PubMed DOI

Zhang J., Zhang H., Liu S.L., Wu W., Zhang H. Comparison of anorectic potencies of type A trichothecenes T-2 toxin, HT-2 toxin, diacetoxyscirpenol, and neosolaniol. Toxins. 2018;10:179. doi: 10.3390/toxins10050179. PubMed DOI PMC

Sheng K., Zhang H., Yue J., Gu W., Gu C., Zhang H., Wu W. Anorectic response to the trichothecene T-2 toxin correspond to plasma elevations of the satiety hormone glucose-dependent insulinotropic polypeptide and peptide YY3-36. Toxicology. 2018;402–403:28–36. doi: 10.1016/j.tox.2018.04.007. PubMed DOI

Sheng K., Lu X., Yue J., Gu W., Gu C., Zhang H., Wu W. Role of neurotransmitters 5-hydroxytryptamine and substance P in anorexia induction following oral exposure to the trichothecene T-2 toxin. Food Chem. Toxicol. 2019;123:1–8. doi: 10.1016/j.fct.2018.10.041. PubMed DOI

Jia H., Wu W., Lu X., Zhang J., He C.H., Zhang H.B. Role of glucagon-like peptide-1 and gastric inhibitory peptide in anorexia induction following oral exposure to the trichothecene mycotoxin deoxynivalenol (Vomitoxin) Toxicol. Sci. 2017;159:16–24. doi: 10.1093/toxsci/kfx112. PubMed DOI

Yamamoto K., Asano K., Tasaka A., Ogura Y., Kim S., Ito Y., Yamatodani A. Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats. Br. J. Pharmacol. 2014;171:2888–2899. doi: 10.1111/bph.12629. PubMed DOI PMC

Urva S., Coskun T., Loghin C., Cui X., Beebe E., O’Farrell L., Briere D.A., Benson C., Nauck M.A., Haupt A. The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists. Diabetes Obes. Metab. 2020;22:1886–1891. doi: 10.1111/dom.14110. PubMed DOI PMC

Sun X., Xu L., Guo F., Luo W., Gao S., Luan X. Neurokinin-1 receptor blocker CP-99 994 improved emesis induced by cisplatin via regulating the activity of gastric distention responsive neurons in the dorsal motor nucleus of vagus and enhancing gastric motility in rats. Neurogastroenterol. Motil. 2017;29:1–11. doi: 10.1111/nmo.13096. PubMed DOI

Prelusky D.B., Trenholm H.L. The efficacy of various classes of anti-emetics in preventing deoxynivalenol-induced vomiting in swine. Nat. Toxins. 1993;1:296–302. doi: 10.1002/nt.2620010508. PubMed DOI

Liu M., Zhang L., Chu X., Ma R., Wang Y., Liu Q., Zhang N., Karrow N., Sun L. Effects of deoxynivalenol on the porcine growth performance and intestinal microbiota and potential remediation by a modified HSCAS binder. Food Chem. Toxicol. 2020;141:111373. doi: 10.1016/j.fct.2020.111373. PubMed DOI

Koivisto A.P., Belvisi M.G., Gaudet R., Szallasi A. Advances in TRP channel drug discovery: From target validation to clinical studies. Nat. Rev. Drug Discov. 2022;21:41–59. doi: 10.1038/s41573-021-00268-4. PubMed DOI PMC

Moran M.M. TRP channels as potential drug targets. Annu. Rev. Pharmacol. Toxicol. 2018;58:309–330. doi: 10.1146/annurev-pharmtox-010617-052832. PubMed DOI

Nilius B., Szallasi A. Transient receptor potential channels as drug targets: From the science of basic research to the art of medicine. Pharmacol. Rev. 2014;66:676–814. doi: 10.1124/pr.113.008268. PubMed DOI

Gorvin C.M. Molecular and clinical insights from studies of calcium-sensing receptor mutations. J. Mol. Endocrinol. 2019;63:R1–R16. doi: 10.1530/JME-19-0104. PubMed DOI

Tuffour A., Kosiba A.A., Zhang Y., Peprah F.A., Gu J., Shi H. Role of the calcium-sensing receptor (CaSR) in cancer metastasis to bone: Identifying a potential therapeutic target. Biochim. Biophys. Acta Rev. Cancer. 2021;1875:188528. doi: 10.1016/j.bbcan.2021.188528. PubMed DOI

Berthiller F., Dall′Asta C., Schuhmacher R., Lemmens M., Adam G., Krska R. Masked mycotoxins: Determination of a deoxynivalenol glucoside in artificially and naturally contaminated wheat by liquid chromatography-tandem mass spectrometry. J. Agric. Food Chem. 2005;53:3421–3425. doi: 10.1021/jf047798g. PubMed DOI

Wu W., Bates M.A., Bursian S.J., Flannery B., Zhou H.R., Link J.E., Zhang H., Pestka J.J. Peptide YY3-36 and 5-hydroxytryptamine mediate emesis induction by trichothecene deoxynivalenol (vomitoxin) Toxicol. Sci. 2013;133:186–195. doi: 10.1093/toxsci/kft033. PubMed DOI PMC