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Investigation of age-related differences in toxicokinetic processes of deoxynivalenol and deoxynivalenol-3-glucoside in weaned piglets

  • Toxicokinetics and Metabolism
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Abstract

Age-related differences in toxicokinetic processes of deoxynivalenol (DON) and deoxynivalenol-3-glucoside (DON3G) were studied. DON3G [55.7 µg/kg bodyweight (BW)] and an equimolar dose of DON (36 µg/kg BW) were administered to weaned piglets (4 weeks old) by single intravenous and oral administration in a double two-way cross-over design. Systemic and portal blood was sampled at different time points pre- and post-administration and plasma concentrations of DON, DON3G and their metabolites were quantified using validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) and liquid chromatography–high-resolution mass spectrometry (LC–HRMS) methods. Data were processed using tailor-made compartmental toxicokinetic (TK) models to accurately estimate TK parameters. Results were statistically compared to data obtained in a previous study on 11-week-old pigs using identical experimental conditions. Significant age-related differences in intestinal and systemic exposure to both DON and DON3G were noted. Most remarkably, a significant difference was found for the absorbed fraction of DON3G, after presystemic hydrolysis to DON, in weaned piglets compared to 11-week-old piglets (83% vs 16%, respectively), assumed to be mainly attributed to the higher intestinal permeability of weaned piglets. Other differences in TK parameters could be assigned to a higher water/fat body ratio and longer gastrointestinal transit time of weaned piglets. Results may further refine current risk assessment concerning DON and DON3G in animals. Additionally, since piglets possibly serve as a human paediatric surrogate model, results may be extrapolated to human infants.

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References

  • Alcorn J, McNamara PJ (2002) Ontogeny of hepatic and renal systemic clearance pathways in infants: Part I. Clin Pharmacokinet 41:959–998

    CAS  PubMed  Google Scholar 

  • Arunachalam C, Doohan FM (2013) Trichothecene toxicity in eukaryotes: cellular and molecular mechanisms in plants and animals. Toxicol Lett 217:149–158

    CAS  PubMed  Google Scholar 

  • Avantaggiato G, Havenaar R, Visconti A (2004) Evaluation of the intestinal absorption of deoxynivalenol and nivalenol by an in vitro gastrointestinal model, and the binding efficacy of activated carbon and other adsorbent materials. Food Chem Toxicol 42:817–824

    CAS  PubMed  Google Scholar 

  • Berthiller F, Krska R, Domig KJ et al (2011) Hydrolytic fate of deoxynivalenol-3-glucoside during digestion. Toxicol Lett 206:264–267

    CAS  PubMed  PubMed Central  Google Scholar 

  • Boudry G, Péron V, Le Huërou-Luron I et al (2004) Weaning induces both transient and long-lasting modifications of absorptive, secretory, and barrier properties of piglet intestine. J Nutr 134:2256–2262

    CAS  PubMed  Google Scholar 

  • Broekaert N, Devreese M, Demeyere K et al (2016) Comparative in vitro cytotoxicity of modified deoxynivalenol on porcine intestinal epithelial cells. Food Chem Toxicol 95:103–109

    CAS  PubMed  Google Scholar 

  • Broekaert N, Devreese M, van Bergen T et al (2017) In vivo contribution of deoxynivalenol-3-β-d-glucoside to deoxynivalenol exposure in broiler chickens and pigs: oral bioavailability, hydrolysis and toxicokinetics. Arch Toxicol 91:699–712

    CAS  PubMed  Google Scholar 

  • Butte NF, Hopkinson JM, Wong WW et al (2000) Body composition during the first 2 years of life: An updated reference. Pediatr Res 47:578–585

    CAS  PubMed  Google Scholar 

  • Catteuw A, Broekaert N, De Baere S et al (2019) Insights into in vivo absolute oral bioavailability, biotransformation, and toxicokinetics of zearalenone, α-zearalenol, β-zearalenol, zearalenone-14-glucoside, and zearalenone-14-sulfate in pigs. J Agric Food Chem 67:3448–3458

    CAS  PubMed  Google Scholar 

  • Dänicke S, Brezina U (2013) Kinetics and metabolism of the Fusarium toxin deoxynivalenol in farm animals: consequences for diagnosis of exposure and intoxication and carry over. Food Chem Toxicol 60:58–75

    PubMed  Google Scholar 

  • Dänicke S, Brüssow KP, Valenta H et al (2005) On the effects of graded levels of Fusarium toxin contaminated wheat in diets for gilts on feed intake, growth performance and metabolism of deoxynivalenol and zearalenone. Mol Nutr Food Res 49:932–943

    PubMed  Google Scholar 

  • Dänicke S, Valenta H, Döll S (2004) On the toxicokinetics and the metabolism of deoxynivalenol (DON) in the pig. Arch Anim Nutr 58:169–180. https://doi.org/10.1080/00039420410001667548

    Article  CAS  PubMed  Google Scholar 

  • Devreese M, Croubels S, De Baere S et al (2018) Comparative toxicokinetics and plasma protein binding of ochratoxin A in four avian species. J Agric Food Chem 66:2129–2135

    CAS  PubMed  Google Scholar 

  • Dobson P, Lanthaler K, Oliver S, Kell D (2009) Implications of the dominant role of transporters in drug uptake by cells (supplementary material). Curr Top Med Chem 9:163–181. https://doi.org/10.2174/156802609787521616

    Article  CAS  PubMed  Google Scholar 

  • EFSA (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 

  • EMA (2005) Guideline on the need for non-clinical testing in juvenile animals on human pharmaceuticals for paediatric indications. EMEA/CHMP/SWP/169215/2005

  • EMA (1995) ICH Q2 Validation of analytical procedure. CPMP/ICH/381/95

  • Eriksen GS, Pettersson H (2003) Metabolism and toxicity of trichothecenes. Acta Univ Agric Sueciae Agrar 400:1401–6249

    Google Scholar 

  • EU (2010) Directive 2010/63/EU on the protection of animals used for scientific purposes. Off J Eur Union L 276/33:0–47

  • Fæste CK, Ivanova L, Sayyari A et al (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

    PubMed  Google Scholar 

  • Friend DW, Trenholm HL, Prelusky DB et al (2010) Effect of deoxynivalenol (DON)-contaminated diet fed to growing-finishing pigs on their performance at market weight, nitrogen retention and DON excretion. Can J Anim Sci 66:1075–1085

    Google Scholar 

  • Fӕste CK, Pierre F, Ivanova L et al (2019) Behavioural and metabolomic changes from chronic dietary exposure to low-level deoxynivalenol reveal impact on mouse well-being. Arch Toxicol 93:2087–2102

    Google Scholar 

  • Gasthuys E, Vandecasteele T, De Bruyne P et al (2016) The potential use of piglets as human pediatric surrogate for preclinical pharmacokinetic and pharmacodynamic drug testing. Curr Pharm Des 22:4069–4085

    CAS  PubMed  Google Scholar 

  • Goyarts T, Dänicke S (2006) Bioavailability of the Fusarium toxin deoxynivalenol (DON) from naturally contaminated wheat for the pig. Toxicol Lett 163:171–182

    CAS  PubMed  Google Scholar 

  • Heinritz SN, Mosenthin R, Weiss E (2013) Use of pigs as a potential model for research into dietary modulation of the human gut microbiota. Nutr Res Rev 26:191–209

    PubMed  Google Scholar 

  • Ivanova L, Fæste CK, Solhaug A (2018) Role of P-glycoprotein in deoxynivalenol-mediated in vitro toxicity. Toxicol Lett 284:21–28

    CAS  PubMed  Google Scholar 

  • KB (2013) Royal decision on Belgian animal welfare legislation. Belgisch Staatsbl 193:42808–42912

    Google Scholar 

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

    CAS  Google Scholar 

  • Mariat D, Firmesse O, Levenez F et al (2009) The firmicutes/bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 9:123

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maul R, Warth B, Kant JS et al (2012) Investigation of the hepatic glucuronidation pattern of the Fusarium mycotoxin deoxynivalenol in various species. Chem Res Toxicol 25:2715–2717

    CAS  PubMed  Google Scholar 

  • Maul R, Warth B, Schebb NH et al (2015) In vitro glucuronidation kinetics of deoxynivalenol by human and animal microsomes and recombinant human UGT enzymes. Arch Toxicol 89:949–960

    CAS  PubMed  Google Scholar 

  • McCance RA (1974) The effect of age on the weight and lengths of pigs’ intestines. J Anat 117:475–479

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchell AD, Ramsay TG, Caperna TJ, Scholz AM (2017) Body composition of piglets exhibiting different growth rates. Arch Anim Breed 55:356–363

    Google Scholar 

  • Moeser AJ, Ryan KA, Nighot PK, Blikslager AT (2007) Gastrointestinal dysfunction induced by early weaning is attenuated by delayed weaning and mast cell blockade in pigs. Am J Physiol Liver Physiol 293:413–421

    Google Scholar 

  • Monbaliu S, Van Poucke C, Detavernier CTL et al (2010) Occurrence of mycotoxins in feed as analyzed by a multi-mycotoxin LC–MS/MS method. J Agric Food Chem 58:66–71. https://doi.org/10.1021/jf903859z

    Article  CAS  PubMed  Google Scholar 

  • Nagl V, Schwartz H, Krska R et al (2012) Metabolism of the masked mycotoxin deoxynivalenol-3-glucoside in rats. Toxicol Lett 213:367–373

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nagl V, Woechtl B, Schwartz-Zimmermann HE et al (2014) Metabolism of the masked mycotoxin deoxynivalenol-3-glucoside in pigs. Toxicol Lett 229:190–197

    CAS  PubMed  Google Scholar 

  • Paulick M, Winkler J, Kersten S et al (2015) Studies on the bioavailability of deoxynivalenol (DON) and DON sulfonate (DONS) 1, 2, and 3 in pigs fed with sodium sulfite-treated DON-contaminated maize. Toxins (Basel) 7:4622–4644

    CAS  Google Scholar 

  • Pestka JJ (2007) Deoxynivalenol: Toxicity, mechanisms and animal health risks. Anim Feed Sci Technol 137:283–298

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Pestka JJ, Clark ES, Schwartz-Zimmermann HE, Berthiller F (2017) Sex is a determinant for deoxynivalenol metabolism and elimination in the mouse. Toxins (Basel) 9:240. https://doi.org/10.3390/toxins9080240

    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. https://doi.org/10.1016/j.toxlet.2008.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pierron A, Mimoun S, Murate LS et al (2016) Intestinal toxicity of the masked mycotoxin deoxynivalenol-3-β-d-glucoside. Arch Toxicol. https://doi.org/10.1007/s00204-015-1592-8

    Article  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  • Poppenberger B, Berthiller F, Lucyshyn D et al (2003) Detoxification of the Fusarium mycotoxin deoxynivalenol by a UDP-glucosyltransferase from Arabidopsis thaliana. J Biol Chem 278:47905–47914

    CAS  PubMed  Google Scholar 

  • Prelusky DB, Hartin KE, Trenholm HL, Miller JD (1988) Pharmacokinetic fate ofc-labeled deoxynivalenol in swine. Toxicol Sci 10:276–286

    CAS  Google Scholar 

  • Raiola A, Tenore GC, Manyes L et al (2015) Risk analysis of main mycotoxins occurring in food for children: an overview. Food Chem Toxicol 84:169–180

    CAS  PubMed  Google Scholar 

  • Rohweder D, Kersten S, Valenta H et al (2013) Bioavailability of the Fusarium toxin deoxynivalenol (DON) from wheat straw and chaff in pigs. Arch Anim Nutr 67:37–47

    CAS  PubMed  Google Scholar 

  • Saint-Cyr MJ, Perrin-Guyomard A, Manceau J et al (2015) Risk assessment of deoxynivalenol by revisiting its bioavailability in pig and rat models to establish which is more suitable. Toxins (Basel) 7:5167–5181

    CAS  Google Scholar 

  • Schwartz-Zimmermann HE, Hametner C, Nagl V et al (2017) Glucuronidation of deoxynivalenol (DON) by different animal species: identification of iso-DON glucuronides and iso-deepoxy-DON glucuronides as novel DON metabolites in pigs, rats, mice, and cows. Arch Toxicol 91:3857–3872. https://doi.org/10.1007/s00204-017-2012-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sergent T, Parys M, Garsou S et al (2006) Deoxynivalenol transport across human intestinal Caco-2 cells and its effects on cellular metabolism at realistic intestinal concentrations. Toxicol Lett 164:167–176. https://doi.org/10.1016/j.toxlet.2005.12.006

    Article  CAS  PubMed  Google Scholar 

  • Snoeck V, Huyghebaert N, Cox E et al (2004) Gastrointestinal transit time of nondisintegrating radio-opaque pellets in suckling and recently weaned piglets. J Control Release 94:143–153

    CAS  PubMed  Google Scholar 

  • Suenderhauf C, Parrott N (2013) A physiologically based pharmacokinetic model of the minipig: data compilation and model implementation. Pharm Res 30:1–15

    CAS  PubMed  Google Scholar 

  • Sulaiman S, Marciani L (2019) MRI of the colon in the pharmaceutical field: the future before us. Pharmaceutics 11:146

    CAS  PubMed Central  Google Scholar 

  • Sundstøl Eriksen G, Pettersson H, Lundh T (2004) Comparative cytotoxicity of deoxynivalenol, nivalenol, their acetylated derivatives and de-epoxy metabolites. Food Chem Toxicol 42:619–624

    PubMed  Google Scholar 

  • Svendsen O (2006) The minipig in toxicology. Exp Toxicol Pathol 57:335–339

    PubMed  Google Scholar 

  • ’t Jong G (2014) Pediatric development: physiology enzymes, drug metabolism, pharmacokinetics and pharmacodynamics., pp 9–24

    Google Scholar 

  • Turner PC, Hopton RP, White KLM et al (2011) Assessment of deoxynivalenol metabolite profiles in UK adults. Food Chem Toxicol 49:132–135. https://doi.org/10.1016/j.fct.2010.10.007

    Article  CAS  PubMed  Google Scholar 

  • Uhlig S, Ivanova L, Fæste CK (2013) Enzyme-assisted synthesis and structural characterization of the 3-, 8-, and 15-glucuronides of deoxynivalenol. J Agric Food Chem. https://doi.org/10.1021/jf304655d

    Article  PubMed  Google Scholar 

  • Van Elburg RM, Uil JJ, De Monchy JGR, Heymans HSA (1992) Intestinal permeability in pediatric gastroenterology. Scand J Gastroenterol 194:19–24

    Google Scholar 

  • Veršilovskis A, Geys J, Huybrechts B et al (2012) Simultaneous determination of masked forms of deoxynivalenol and zearalenone after oral dosing in rats by LC–MS/MS. World Mycotoxin J 5:303–318

    Google Scholar 

  • VICH Steering Committee (1998) Validation of analytical procedures: definition and terminology. CVMP/VICH/590/98

  • Vidal A, Claeys L, Mengelers M et al (2018) Humans significantly metabolize and excrete the mycotoxin deoxynivalenol and its modified form deoxynivalenol-3-glucoside within 24 hours. Sci Rep 8:5255

    PubMed  PubMed Central  Google Scholar 

  • Warth B, Sulyok M, Berthiller F et al (2013) New insights into the human metabolism of the Fusarium mycotoxins deoxynivalenol and zearalenone. Toxicol Lett 220:88–94

    CAS  PubMed  Google Scholar 

  • Warth B, Sulyok M, Fruhmann P et al (2012) Assessment of human deoxynivalenol exposure using an LC–MS/MS based biomarker method. Toxicol Lett 211:85–90

    CAS  PubMed  Google Scholar 

  • Winter ME (1988) Basic clinical pharmacokinetics. 7–93

  • Wu QH, Wang X, Yang W et al (2014) Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update. Arch Toxicol 88:1309–1326

    CAS  PubMed  Google Scholar 

  • Wu X, Murphy P, Cunnick J, Hendrich S (2007) Synthesis and characterization of deoxynivalenol glucuronide: its comparative immunotoxicity with deoxynivalenol. Food Chem Toxicol 45:1846–1855

    CAS  PubMed  Google Scholar 

  • Yatsunenko T, Rey FE, Manary MJ et al (2012) Human gut microbiome viewed across age and geography. Nature 486:222–227

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao W, Wang Y, Liu S et al (2015) The dynamic distribution of porcine microbiota across different ages and gastrointestinal tract segments. PLoS ONE 10:1–13

    Google Scholar 

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Acknowledgements

The authors are grateful towards Prof. Adams (Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna) for the synthesis of the DON3G standard, used for animal and analytical experiments. The financial support from the European Union’s Horizon 2020 research and innovation programme under grant agreement H2020-MYCOKEY-GA 678781 is gratefully acknowledged.

Funding

This work was supported by Horizon 2020 (H2020-MYCOKEY-GA 678781).

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Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium

    Amelie Catteuw, Mathias Devreese, Siegrid De Baere, Gunther Antonissen & Siska Croubels

  2. Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium

    Gunther Antonissen

  3. Toxinology Research Group, Norwegian Veterinary Institute, Ullevålsveien 68, 0454, Oslo, Norway

    Lada Ivanova & Silvio Uhlig

  4. Department of Surgery and Anaesthesiology of Domestic Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium

    Ann Martens

  5. Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000, Ghent, Belgium

    Sarah De Saeger & Marthe De Boevre

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  1. Amelie Catteuw
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Catteuw, A., Devreese, M., De Baere, S. et al. Investigation of age-related differences in toxicokinetic processes of deoxynivalenol and deoxynivalenol-3-glucoside in weaned piglets. Arch Toxicol 94, 417–425 (2020). https://doi.org/10.1007/s00204-019-02644-x

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