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Behavioural and metabolomic changes from chronic dietary exposure to low-level deoxynivalenol reveal impact on mouse well-being


The mycotoxin deoxynivalenol (DON) has a high global prevalence in grain-based products. Biomarkers of exposure are detectable in most humans and farm animals. Considering the acute emetic and chronic anorexigenic toxicity of DON, maximum levels for food and feed have been implemented by food authorities. The tolerable daily intake (TDI) is 1 µg/kg body weight (bw)/day for the sum of DON and its main derivatives, which was based on the no-observed adverse-effect level (NOAEL) of 100 µg DON/kg bw/day for anorexic effects in rodents. Chronic exposure to a low-DON dose can, however, also cause inflammation and imbalanced neurotransmitter levels. In the present study, we therefore investigated the impact of a 2-week exposure at the NOAEL in mice by performing behavioural experiments, monitoring brain activation by c-Fos expression, and analysing changes in the metabolomes of brain and serum. We found that DON affected neuronal activity and innate behaviour in both male and female mice. Metabolite profiles were differentiable between control and treated mice. The behavioural changes evidenced at NOAEL reduce the safety margin to the established TDI and may be indicative of a risk for human health.

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  1. Albelda N, Joel D (2012) Animal models of obsessive-compulsive disorder: exploring pharmacology and neural substrates. Neurosci Biobehav Rev 36:47–63

  2. Al-Hazmi MA, Waggas AM (2013) Neurophysiological and behavioral effects of mycotoxin deoxynivalenol and fumonisin. Afr J Microbiol Res 7:1371–1377

  3. Bonnet MS, Roux J, Mounien L, Dallaporta M, Troadec J-D (2012) Advances in deoxynivalenol toxicity mechanisms: the brain as a target. Toxins 4:1120–1138

  4. Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, Wishart DS, Xia J (2018) MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucl Acids Res 46:W486–W494

  5. Da Rocha MEB, Freire FDCO, Maia FEF, Guedes MIF, Rondina D (2014) Mycotoxins and their effects on human and animal health. Food Control 36:159–165

  6. Deacon RM (2006) Assessing nest building in mice. Nat Protoc 1:1117–1119

  7. Di Guida R, Engel J, Allwood JW, Weber RJ, Jones MR, Sommer U, Viant MR, Dunn WB (2016) Non-targeted UHPLC–MS metabolomic data processing methods: a comparative investigation of normalisation, missing value imputation, transformation and scaling. Metabolomics 12:93–107

  8. Dinel AL, Joffre C, Trifilieff P, Aubert A, Foury A, Le Ruyet P, Layé S (2014) Inflammation early in life is a vulnerability factor for emotional behavior at adolescence and for lipopolysaccharide-induced spatial memory and neurogenesis alteration at adulthood. J Neuroinflam 11:155–167

  9. EFSA (2015) Experimental study of deoxynivalenol biomarkers in urine. http://www.efsa.europa.eu/en/supporting/pub/818e

  10. EU (2006a) Commission Regulation (EC) No 1881/2006 of 19 December 2006 setting maximum levels for certain contaminants in foodstuffs. http://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX:02006R1881-20100701

  11. EU (2006b) Commission Recommendation of 17 August 2006 on the presence of deoxynivalenol, zearalenone, ochratoxin A, T-2 and HT-2 and fumonisins in products intended for animal feeding. http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1440504898051&uri=CELEX:32006H0576

  12. Fæste CK, Ivanova L, Sayyari A, Hansen U, Sivertsen T, Uhlig S (2018) Prediction of deoxynivalenol toxicokinetics in humans by in vitro-to-in vivo extrapolation and allometric scaling of in vivo animal data. Arch Toxicol 92:2195–2216

  13. Ferhat AT, Torquet N, Le Sourd AM, De Chaumont F, Olivo-Marin JC, Faure P, Bourgeron T, Ey E (2016) Recording mouse ultrasonic vocalizations to evaluate social communication. J Vis Exp 112:e53871

  14. Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, Befort K, Gaveriaux-Ruff C, Dierich D, LeMeur M, Valverde O, Maldonado R, Kieffer BL (2000) Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 25:195–200

  15. Fitzpatrick DW, Boyd KE, Wilson LM, Wilson JR (1988) Effect of the trichothecene deoxynivalenol on brain biogenic monoamines concentrations in rats and chickens. J Environ Sci Health B 23:159–170

  16. Flannery BM, He K, Pestka JJ (2013) Deoxynivalenol-induced weight loss in the diet-induced obese mouse is reversible and PKR-independent. Toxicol Lett 221:9–14

  17. Gaigé S, Bonnet MS, Tardivel C, Pinton P, Trouslard J, Jean A, Guzylack L, Troadec JD, Dallaporta M (2013) c-Fos immunoreactivity in the pig brain following deoxynivalenol intoxication: focus on NUCB2/nesfatin-1 expressing neurons. Neurotoxicology 34:135–149

  18. Girardet C, Bonnet MS, Jdir R, Sadoud M, Thirion S, Tardivel C, Roux J, Lebrun B, Mounien L, Trouslard J, Jean A, Dallaporta M, Troadec JD (2011a) Central inflammation and sickness-like behavior induced by the food contaminant deoxynivalenol: a PGE2-independent mechanism. Toxicol Sci 124:179–191

  19. Girardet C, Bonnet MS, Jdir R, Sadoud M, Thirion S, Tardivel C, Roux J, Lebrun B, Wanaverbecq N, Mounien L, Trouslard J, Jean A, Dallaporta M, Troadec JD (2011b) The food-contaminant deoxynivalenol modifies eating by targeting anorexigenic neurocircuitry. PLoS ONE 6:e26134

  20. Gonzalez-Riano C, Garcia A, Barbas C (2016) Metabolomics studies in brain tissue: a review. J Pharm Biomed Anal 130:141–168

  21. Hasan TF, Hasan H (2011) Anorexia nervosa: a unified neurological perspective. Int J Med Sci 8:679–703

  22. Hayes DJ, Northoff G (2012) Common brain activations for painful and non-painful aversive stimuli. BMC Neurosci 13:60–77

  23. Ivanova L, Tartor H, Grove S, Kristoffersen A, Uhlig S (2018) Workflow for the targeted and untargeted detection of small metabolites in fish skin mucus. Fishes 3:21–33

  24. Knutsen HK, Alexander J, Barregård L, Bignami M, Brüschweiler B, Ceccatelli S, Cottrill B, Dinovi M, Grasl-Kraupp B, Hogstrand C, Hoogenboom L, Nebbia CS, Oswald IP, Petersen A, Rose M, Roudot A-C, Schwerdtle T, Vleminckx C, Vollmer G, Wallace H, De Saeger S, Eriksen GS, Farmer P, Fremy J-M, Gong YY, Meyer K, Naegeli H, Parent-Massin D, Rietjens I, Van Egmond H, Altieri A, Eskola M, Gergelova P, Bordajandi LR, Benkova B, Dörr B, Gkrillas A, Gustavsson N, Van Manen M, Edler L (2017) Risks to human and animal health related to the presence of deoxynivalenol and its acetylated and modified forms in food and feed. EFSA J 15:4718

  25. Kouadio JH, Moukha S, Brou K, Gnakri D (2013) Lipid metabolism disorders, lymphocytes cells death, and renal toxicity induced by very low levels of deoxynivalenol and fumonisin B1 alone or in combination following 7 days oral administration to mice. Toxicol Int 20:218–224

  26. Luna RA, Foster JA (2015) Gut brain axis: diet microbiota interactions and implications for modulation of anxiety and depression. Curr Opin Biotechnol 32:35–41

  27. Lutz PE, Ayranci G, Chu-Sin-Chung P, Matifas A, Koebel P, Filliol D, Befort K, Ouagazzal AM, Kieffer BL (2014) Distinct mu, delta, and kappa opioid receptor mechanisms underlie low sociability and depressive-like behaviors during heroin abstinence. Neuropsychopharmacology 39:2694–2705

  28. Manduca A, Lassalle O, Sepers M, Campolongo P, Cuomo V, Marsicano G, Kieffer B, Vanderschuren LJ, Trezza V, Manzoni OJ (2016) Interacting cannabinoid and opioid receptors in the nucleus accumbens core control adolescent social play. Front Behav Neurosci 10:211–226

  29. Moreno N, Gonzalez A (2006) The common organization of the amygdaloid complex in tetrapods: new concepts based on developmental, hodological and neurochemical data in anuran amphibians. Prog Neurobiol 78:61–90

  30. Nagl V, Schatzmayr G (2015) Deoxynivalenol and its masked forms in food and feed. Curr Opin Food Sci 5:43–49

  31. Ngampongsa S, Ito K, Kuwahara M, Kumagai S, Tsubone H (2011) Arrhythmias and alterations in autonomic nervous function induced by deoxynivalenol (DON) in unrestrained rats. J Toxicol Sci 36:453–460

  32. Niesink RJ, Van Ree JM (1989) Involvement of opioid and dopaminergic systems in isolation-induced pinning and social grooming of young rats. Neuropharmacology 28:411–418

  33. Ossenkopp KP, Hirst M, Rapley WA (1994) Deoxynivalenol (vomitoxin)-induced conditioned taste aversions in rats are mediated by the chemosensitive area postrema. Pharmacol Biochem Behav 47:363–367

  34. Paul ED, Lowry CA (2013) Functional topography of serotonergic systems supports the Deakin/Graeff hypothesis of anxiety and affective disorders. J Psychopharmacol 27:1090–1106

  35. Paxinos G, Franklin KBL (2012) The mouse brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego

  36. Payros D, Alassane-Kpembi I, Pierron A, Loiseau N, Pinton P, Oswald IP (2016) Toxicology of deoxynivalenol and its acetylated and modified forms. Arch Toxicol 90:2931–2957

  37. Peng Z, Chen L, Xiao J, Zhou X, Nüssler AK, Liu L, Liu J, Yang W (2017) Review of mechanisms of deoxynivalenol-induced anorexia: the role of gut microbiota. J Appl Toxicol 37:1021–1029

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

  39. Pestka JJ, Islam Z, Amuzie CJ (2008) Immunochemical assessment of deoxynivalenol tissue distribution following oral exposure in the mouse. Toxicol Lett 178:83–87

  40. Pinton P, Oswald IP (2014) Effect of deoxynivalenol and other Type B trichothecenes on the intestine: a review. Toxins 6:1615–1643

  41. Prado WA, Roberts MH (1985) An assessment of the antinociceptive and aversive effects of stimulating identified sites in the rat brain. Brain Res 340:219–228

  42. Prelusky DB, Yeung JM, Thompson BK, Trenholm HL (1992) Effect of deoxynivalenol on neurotransmitters in discrete regions of swine brain. Arch Environ Contam Toxicol 22:36–40

  43. Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301:805–809

  44. Schatzmayr G, Zehner F, Täubel M, Schatzmayr D, Klimitsch A, Loibner AP, Binder EM (2006) Microbiologicals for deactivating mycotoxins. Mol Nutr Food Res 50:543–551

  45. Sundheim L, Lillegaard IT, Fæste CK, Brantsæter AL, Brodal G, Eriksen GS (2017) Deoxynivalenol exposure in Norway, risk assessments for different human age groups. Toxins 9:46–53

  46. Tardivel C, Airault C, Djelloul M, Guillebaud F, Barbouche R, Troadec J-D, Gaigé S, Dallaporta M (2015) The food born mycotoxin deoxynivalenol induces low-grade inflammation in mice in the absence of observed-adverse effects. Toxicol Lett 232:601–611

  47. Terciolo C, Maresca M, Pinton P, Oswald IP (2018) Review article: role of satiety hormones in anorexia induction by Trichothecene mycotoxins. Food Chem Toxicol 121:701–714

  48. Tominaga M, Momonaka Y, Yokose C, Tadaishi M, Shimizu M, Yamane T, Oishi Y, Kobayashi-Hattori K (2016) Anorexic action of deoxynivalenol in hypothalamus and intestine. Toxicon 118:54–60

  49. Vanderschuren LJ, Achterberg EJ, Trezza V (2016) The neurobiology of social play and its rewarding value in rats. Neurosci Biobehav Rev 70:86–105

  50. Wu W, Zhang H (2014) Role of tumor necrosis factor-α and interleukin-1β in anorexia induction following oral exposure to the trichothecene deoxynivalenol (vomitoxin) in the mouse. J Toxicol Sci 39:875–886

  51. Yalcin I, Bohren Y, Waltisperger E, Sage-Ciocca D, Yin JC, Freund-Mercier MJ, Barrot M (2011) A time-dependent history of mood disorders in a murine model of neuropathic pain. Biol Psychiatry 70:946–953

  52. Yamamoto T (2007) Brain regions responsible for the expression of conditioned taste aversion in rats. Chem Senses 32:105–109

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The authors would like to thank Dr. Ipek Yalcin for helpful advice about behavioural experiments and Dr. Pierre Veinante for critical reading of the manuscript. We would also like to thank Dr. Hege Divon at the Norwegian Veterinary Institute (NVI) for funding the consumables and chemical analyses used in the study through FUNtox, a strategic institute program on Fungi and Mycotoxins in a “One Health” perspective. Furthermore, we are very thankful to Dr. Silvio Uhlig in the chemistry section of the NVI for his support in the chemical and metabolomics analyses.


This project was funded through the bilateral PHC AURORA-program by the Research Council of Norway (Grant Number NFR255406) and Campus France, and in addition the CNRS, the University of Strasbourg and the Norwegian Veterinary Institute.

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Correspondence to Christiane K. Faeste or Dominique Massotte.

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This article does not contain clinical studies or patient data. This article does not contain any studies with human participants performed by any of the authors. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Faeste, C.K., Pierre, F., Ivanova, L. et al. Behavioural and metabolomic changes from chronic dietary exposure to low-level deoxynivalenol reveal impact on mouse well-being. Arch Toxicol 93, 2087–2102 (2019). https://doi.org/10.1007/s00204-019-02470-1

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  • Deoxynivalenol
  • Chronic administration in mice
  • Anxiety
  • Innate behaviour
  • Brain activation