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

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Abstract

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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References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  Google Scholar 

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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

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

  • 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

  • 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

  • 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

    Article  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

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

    Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  • 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

    Article  CAS  Google Scholar 

  • 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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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Acknowledgements

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.

Funding

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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  1. Florian Pierre

    Present address: Institut Européen de Chimie et Biologie, Pessac, France

Authors and Affiliations

  1. Toxinology Research Group, Norwegian Veterinary Institute, Oslo, Norway

    Christiane K. Faeste

  2. Centre de la Recherche Nationale Scientifique, University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, 8 Allée du Général Rouvillois, 67000, Strasbourg, France

    Florian Pierre & Dominique Massotte

  3. Section of Chemistry, Norwegian Veterinary Institute, Oslo, Norway

    Lada Ivanova

  4. Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Oslo, Norway

    Amin Sayyari

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  1. Christiane K. Faeste
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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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