Skip to main content
SpringerLink
Log in

Potential roles for calcium-sensing receptor (CaSR) and transient receptor potential ankyrin-1 (TRPA1) in murine anorectic response to deoxynivalenol (vomitoxin)

  • Genotoxicity and Carcinogenicity
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Food contamination by the trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) has the potential to adversely affect animal and human health by suppressing food intake and impairing growth. In mice, the DON-induced anorectic response results from aberrant satiety hormone secretion by enteroendocrine cells (EECs) of the gastrointestinal tract. Recent in vitro studies in the murine STC-1 EEC model have linked DON-induced satiety hormone secretion to activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor, and transient receptor potential ankyrin-1 (TRPA1), a TRP channel. However, it is unknown whether similar mechanisms mediate DON’s anorectic effects in vivo. Here, we tested the hypothesis that DON-induced food refusal and satiety hormone release in the mouse are linked to activation of CaSR and TRPA1. Oral treatment with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate (AITC)) suppressed food intake in mice, and the agonist’s effects were suppressed by pretreatment with corresponding antagonists NPS-2143 or ruthenium red (RR), respectively. Importantly, NPS-2143 or RR inhibited both DON-induced food refusal and plasma elevations of the satiety hormones cholecystokinin (CCK) and peptide YY3–36 (PYY3–36); cotreatment with both antagonists additively suppressed both anorectic and hormone responses to DON. Taken together, these in vivo data along with prior in vitro findings support the contention that activation of CaSR and TRPA1 contributes to DON-induced food refusal by mediating satiety hormone exocytosis from EEC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  • Azcona-Olivera JI, Ouyang Y et al (1995) Induction of cytokine mRNAs in mice after oral exposure to the trichothecene vomitoxin (deoxynivalenol): relationship to toxin distribution and protein synthesis inhibition. Toxicol Appl Pharmacol 133(1):109–120

    Article  CAS  PubMed  Google Scholar 

  • Chakravarti B, Chattopadhyay N, Brown EM (2012) Signaling through the extracellular calcium-sensing receptor (CaSR). Adv Exp Med Biol 740:103–142

    Article  CAS  PubMed  Google Scholar 

  • Challis B, Pinnock S, Coll A et al (2003) Acute effects of PYY3–36 on food intake and hypothalamic neuropeptide expression in the mouse. Biochem Biophys Res Commun 311(4):915–919

    Article  CAS  PubMed  Google Scholar 

  • Della-Fera MA, Baile CA (1980) CCK-octapeptide injected in CSF decreases meal size and daily food intake in sheep. Peptides 1(1):51–54

    Article  CAS  PubMed  Google Scholar 

  • Doihara H, Nozawa K, Kawabata-Shoda E, Kojima R, Yokoyama T, Ito H (2009a) Molecular cloning and characterization of dog TRPA1 and AITC stimulate the gastrointestinal motility through TRPA1 in conscious dogs. Eur J Pharmacol 617(1–3):124–129

    Article  CAS  PubMed  Google Scholar 

  • Doihara H, Nozawa K, Kawabata-Shoda E, Kojima R, Yokoyama T, Ito H (2009b) TRPA1 agonists delay gastric emptying in rats through serotonergic pathways. Naunyn Schmiedebergs Arch Pharmacol 380(4):353–357

    Article  CAS  PubMed  Google Scholar 

  • D’Souza-Li L (2006) The calcium-sensing receptor and related diseases. Arq Bras Endocrinol Metabol 50(4):628–639

    Article  PubMed  Google Scholar 

  • Ebenezer I, De La Riva C, Baldwin B (1990) Effects of the CCK receptor antagonist MK-329 on food intake in pigs. Physiol Behav 47(1):145–148

    Article  CAS  PubMed  Google Scholar 

  • EFSA (2013) Statement on the risks for public health related to a possible increase of the maximum level of deoxynivalenol for certain semi-processed cereal products. EFSA J 11(12):3490

    Google Scholar 

  • Flannery BM, Wu W, Pestka JJ (2011) Characterization of deoxynivalenol-induced anorexia using mouse bioassay. Food Chem Toxicol 49(8):1863–1869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flannery BM, Clark ES, Pestka JJ (2012) Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY. Toxicol Sci 130(2):289–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Girardet C, Bonnet MS, Jdir R et al (2011) The food-contaminant deoxynivalenol modifies eating by targeting anorexigenic neurocircuitry. PLoS One 6(10):e26134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hörsten S, Hoffmann T, Alfalah M et al (2004) PP, PYY and NPY: synthesis, storage, release and degradation. Neuropept Y relat reptides 162:23–44

    Article  Google Scholar 

  • Karra E, Batterham RL (2010) The role of gut hormones in the regulation of body weight and energy homeostasis. Mol Cell Endocrinol 316(2):120–128

    Article  CAS  PubMed  Google Scholar 

  • Kim MJ, Son HJ, Song SH, Jung M, Kim Y, Rhyu MR (2013) The TRPA1 agonist, methyl syringate suppresses food intake and gastric emptying. PLoS One 8(8):e71603. doi:10.1371/journal.pone.0071603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohno D, Nakata M, Maejima Y et al (2008) Nesfatin-1 neurons in paraventricular and supraoptic nuclei of the rat hypothalamus coexpress oxytocin and vasopressin and are activated by refeeding. Endocrinology 149(3):1295–1301

    Article  CAS  PubMed  Google Scholar 

  • le Roux CW, Batterham RL, Aylwin SJ et al (2006) Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinol 147(1):3–8

    Article  Google Scholar 

  • Liou AP (2013) Digestive physiology of the pig symposium: G protein-coupled receptors in nutrient chemosensation and gastrointestinal hormone secretion. J Anim Sci 91(5):1946–1956

    Article  CAS  PubMed  Google Scholar 

  • Liu K, Samuel M, Ho M, Harrison RK, Paslay JW (2010) NPPB structure-specifically activates TRPA1 channels. Biochem Pharmacol 80(1):113–121

    Article  CAS  PubMed  Google Scholar 

  • Maresca M (2013) From the gut to the brain: journey and pathophysiological effects of the food-associated trichothecene mycotoxin deoxynivalenol. Toxins (Basel) 5(4):784–820

    Article  CAS  Google Scholar 

  • Moran-Ramos S, Tovar AR, Torres N (2012) Diet: friend or foe of enteroendocrine cells—how it interacts with enteroendocrine cells. Adv Nutr 3(1):8–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagata K, Duggan A, Kumar G, Garcia-Anoveros J (2005) Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci 25(16):4052–4061

    Article  CAS  PubMed  Google Scholar 

  • Nemeth EF, Delmar EG, Heaton WL et al (2001) Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J Pharmacol Exp Ther 299(1):323–331

    CAS  PubMed  Google Scholar 

  • Nilius B, Owsianik G, Voets T et al (2007) Transient receptor potential cation channels in disease. Physiol Rev 87(1):165–217

    Article  CAS  PubMed  Google Scholar 

  • Nilius B, Appendino G, Owsianik G (2012) The transient receptor potential channel TRPA1: from gene to pathophysiology. Pflugers Arch 464(5):425–458

    Article  CAS  PubMed  Google Scholar 

  • Pestka JJ (2010a) Deoxynivalenol: mechanisms of action, human exposure, and toxicological relevance. Arch Toxicol 84(9):663–679

    Article  CAS  PubMed  Google Scholar 

  • Pestka JJ (2010b) Toxicological mechanisms and potential health effects of deoxynivalenol and nivalenol. World Mycotox J 3(4):323–347

    Article  CAS  Google Scholar 

  • Reimann F, Tolhurst G, Gribble FM (2012) G-protein coupled receptors in intestinal chemosensation. Cell Metab 15(4):421–431

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MW (2006) Central nervous system regulation of food intake. Obesity 14(S2):1S–8S

    Article  CAS  PubMed  Google Scholar 

  • Sloth B, Holst JJ, Flint A et al (2007) Effects of PYY1–36 and PYY3–36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. Am J Physiol Endocrinol Metab 292(4):E1062–E1068

    Article  CAS  PubMed  Google Scholar 

  • Steinert RE, Feinle-Bisset C, Geary N et al (2013) Digestive physiology of the pig symposium: secretion of gastrointestinal hormones and eating control. J Anim Sci 91(5):1963–1973

    Article  CAS  PubMed  Google Scholar 

  • Talavera K, Gees M, Karashima Y et al (2009) Nicotine activates the chemosensory cation channel TRPA1. Nat Neurosci 12(10):1293–1299

    Article  CAS  PubMed  Google Scholar 

  • Tapia R, Velasco I (1997) Ruthenium red as a tool to study calcium channels, neuronal death and the function of neural pathways. Neurochem Int 30(2):137–147

    Article  CAS  PubMed  Google Scholar 

  • Terranegra A, Ferraretto A, Dogliotti E et al (2010) Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor. J Mol Endocrinol 45(4):245–256

    Article  CAS  PubMed  Google Scholar 

  • Wada M, Furuya Y, Sakiyama J et al (1997) The calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J Clin Invest. 100(12):2977–2983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Chandra R, Samsa LA et al (2011) Amino acids stimulate cholecystokinin release through the Ca2+-sensing receptor. Am J Physiol Gastrointest Liver Physiol 300(4):G528–G537

    Article  CAS  PubMed  Google Scholar 

  • Ward BK, Magno AL, Walsh JP et al (2012) The role of the calcium-sensing receptor in human disease. Clin Biochem 45(12):943–953

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Flannery BM, Sugita-Konishi Y et al (2012) Comparison of murine anorectic responses to the 8-ketotrichothecenes 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, fusarenon X and nivalenol. Food Chem Toxicol 50(6):2056–2061

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Bates MA, Bursian SJ et al (2013a) Comparison of emetic potencies of the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon X, and nivalenol. Toxicol Sci 131(1):279–291

    Article  CAS  PubMed  Google Scholar 

  • Wu W, Bates MA, Bursian SJ et al (2013b) Peptide YY3–36 and 5-hydroxytryptamine mediate emesis induction by trichothecene deoxynivalenol (vomitoxin). Toxicol Sci 133(1):186–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu W, Zhou HR, He K et al (2014a) Role of cholecystokinin in anorexia induction following oral exposure to the 8-ketotrichothecenes deoxynivalenol, 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, fusarenon X, and nivalenol. Toxicol Sci 138(2):278–289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu W, Zhou HR, Bursian SJ et al (2014b) Comparison of anorectic and emetic potencies of deoxynivalenol (vomitoxin) to the plant metabolite deoxynivalenol-3-glucoside and synthetic deoxynivalenol derivatives EN139528 and EN139544. Toxicol Sci 142(1):167–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu W, Zhou HR, Pan X et al (2015a) Comparison of anorectic potencies of the trichothecenes T-2 Toxin, HT-2 Toxin and satratoxin G to the ipecac alkaloid emetine. Toxicol Rep 2:238–251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu W, Zhou HR, Bursian SJ et al (2015b). Emetic responses to T-2 toxin, HT-2 toxin and emetine correspond to plasma elevations of peptide YY and 5-hydroxytryptamine. Arch Toxicol [Epub ahead of print]

  • Montell C (2005) The TRP superfamily of cation channels. Sci STKE 272:re3

    Google Scholar 

  • Zhang DM, Bula W, Stellar E (1986) Brain cholecystokinin as a satiety peptide. Physiol Behav 36(6):1183–1186

    Article  CAS  PubMed  Google Scholar 

  • Zhou HR, Pestka JJ (2015) 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 145(2):407–417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge the assistance of Dr. Erica Clark and Melissa Bates. This study was supported by USDA NIFA Award (2011-0635), by USDA Wheat and Barley SCAB Initiative Award 59-0206-9-058, and by Public Health Service Grant ES03553 from the National Institutes of Health. Wenda Wu was supported by National Natural Science Foundation of China (31402268), Fundamental Research Funds for the Central Universities (KJQN201526), Natural Science Foundation of Jiangsu Province of China (BK20140691), National Natural Science Foundation of China (31572576), and Priority Academic Development Program of Jiangsu Higher Education Institutions.

Author information

Authors and Affiliations

  1. College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, People’s Republic of China

    Wenda Wu

  2. Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, 48824, USA

    Wenda Wu, Hui-Ren Zhou & James J. Pestka

  3. Center for Integrative Toxicology, Michigan State University, 234 G.M. Trout Building, East Lansing, MI, 48824-1224, USA

    James J. Pestka

  4. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, 48824, USA

    James J. Pestka

Authors
  1. Wenda Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui-Ren Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James J. Pestka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James J. Pestka.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, W., Zhou, HR. & 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 91, 495–507 (2017). https://doi.org/10.1007/s00204-016-1687-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-016-1687-x

Keywords

Search

Navigation