Deoxynivalenol (DON)-contaminated feed represents a serious problem for pigs due to their high sensitivity to its toxicological effects. The aim of the present study was to evaluate the impact of intrauterine DON exposure on the immune system of piglets. Pure DON was intravenously administered to sows at the end of gestation (during the last 2-3 days of gestation, one dose of 300 µg per day). The plasma concentration of DON was analyzed using liquid chromatography combined with high-resolution Orbitrap-based mass spectrometry (LC-MS/MS (HR)) and selected immune parameters were monitored six times in piglets from birth to 18 weeks. DON was found in the plasma of 90% of newborn piglets at a mean concentration of 6.28 ng/mL and subsequently, at one, three, and seven weeks after birth with decreasing concentrations. Trace amounts were still present in the plasma 14 weeks after birth. Flow cytometry revealed a significant impact of DON on T lymphocyte subpopulations during the early postnatal period. Lower percentages of regulatory T cells, T helper lymphocytes, and their double positive CD4+CD8+ subset were followed by increased percentages of cytotoxic T lymphocytes and γδ T cells. The capacity to produce pro-inflammatory cytokines was also significantly lower after intrauterine DON exposure. In conclusion, this study revealed a long-term persistence of DON in the plasma of the piglets as a consequence of short-term intrauterine exposure, leading to altered immune parameters.

Veterinary Research Institute 62100 Brno Czech Republic

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European Commission COMMISSION RECOMMENDATION 2006/576/EC 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. Off. J. Eur. Union. 2006;229:7–9.

Pestka J.J., Smolinski A.T. Deoxynivalenol: Toxicology and potential effects on humans. J. Toxicol. Environ. Heal.-Part B Crit. Rev. 2005;8:39–69. doi: 10.1080/10937400590889458. PubMed DOI

Pestka J.J. Deoxynivalenol: Toxicity, mechanisms and animal health risks. Anim. Feed Sci. Technol. 2007;137:283–298. doi: 10.1016/j.anifeedsci.2007.06.006. DOI

Lauwers M., Croubels S., Letor B., Gougoulias C., Devreese M. Biomarkers for exposure as a tool for efficacy testing of a mycotoxin detoxifier in broiler chickens and pigs. Toxins. 2019;11:187. doi: 10.3390/toxins11040187. PubMed DOI PMC

Maul R., Warth B., Kant J.S., Schebb N.H., Krska R., Koch M., Sulyok M. Investigation of the hepatic glucuronidation pattern of the Fusarium mycotoxin deoxynivalenol in various species. Chem. Res. Toxicol. 2012;25:2715–2717. doi: 10.1021/tx300348x. PubMed DOI

Schwartz-Zimmermann H.E., Hametner C., Nagl V., Fiby I., Macheiner L., Winkler J., Dänicke S., Clark E., Pestka J.J., Berthiller F. 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. 2017;91:3857–3872. doi: 10.1007/s00204-017-2012-z. PubMed DOI PMC

Fuchs E., Binder E.M., Heidler D., Krska R. Structural characterization of metabolites after the microbial degradation of type A trichothecenes by the bacterial strain BBSH 797. Food Addit. Contam. 2002;19:379–386. doi: 10.1080/02652030110091154. PubMed DOI

Dänicke S., Brezina U. Kinetics and metabolism of the Fusarium toxin deoxynivalenol in farm animals: Consequences for diagnosis of exposure and intoxication and carry over. Food Chem. Toxicol. 2013;60:58–75. doi: 10.1016/j.fct.2013.07.017. PubMed DOI

Young L.G., McGirr L., Valli V.E., Lumsden J.H., Lun A. Vomitoxin in corn fed to young pigs. J. Anim. Sci. 1983;57:655–664. doi: 10.2527/jas1983.573655x. PubMed DOI

Rotter B.A., Prelusky D.B., Pestka J.J. Toxicology of deoxynivalenol (vomitoxin) J. Toxicol. Environ. Health. 1996;48:1–2. doi: 10.1080/009841096161447. PubMed 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

Maresca M. From the gut to the brain: Journey and pathophysiological effects of the food-associated trichothecene mycotoxin deoxynivalenol. Toxins. 2013;5:784–820. doi: 10.3390/toxins5040784. PubMed DOI PMC

Flannery B.M., Clark E.S., Pestka J.J. Anorexia induction by the trichothecene deoxynivalenol (vomitoxin) is mediated by the release of the gut satiety hormone peptide YY. Toxicol. Sci. 2012;130:289–297. doi: 10.1093/toxsci/kfs255. PubMed DOI PMC

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

Pierron A., Alassane-Kpembi I., Oswald I.P. Impact of mycotoxin on immune response and consequences for pig health. Anim. Nutr. 2016;2:63–68. doi: 10.1016/j.aninu.2016.03.001. PubMed DOI PMC

Alizadeh A., Braber S., Akbari P., Garssen J., Fink-Gremmels J. Deoxynivalenol Impairs Weight Gain and Affects Markers of Gut Health after Low-Dose, Short-Term Exposure of Growing Pigs. Toxins. 2015;7:2071–2095. doi: 10.3390/toxins7062071. PubMed DOI PMC

Luongo D., De Luna R., Russo R., Severino L. Effects of four Fusarium toxins (fumonisin B1, α-zearalenol, nivalenol and deoxynivalenol) on porcine whole-blood cellular proliferation. Toxicon. 2008;52:156–162. doi: 10.1016/j.toxicon.2008.04.162. PubMed DOI

Zhou H.-R., Islam Z., Pestka J.J. Rapid, sequential activation of mitogen-activated protein kinases and transcription factors precedes proinflammatory cytokine mRNA expression in spleens of mice exposed to the trichothecene vomitoxin. Toxicol. Sci. 2003;72:130–142. doi: 10.1093/toxsci/kfg006. PubMed DOI

Tiemann U., Dänicke S. In vivo and in vitro effects of the mycotoxins zearalenone and deoxynivalenol on different non-reproductive and reproductive organs in female pigs: A review. Food Addit. Contam. 2007;24:306–314. doi: 10.1080/02652030601053626. PubMed DOI

Jakovac-Strajn B., Vengust A., Pestevsek U. Effects of a deoxynivalenol-contaminated diet on the reproductive performance and immunoglobulin concentrations in pigs. Vet. Rec. 2009;165:713–718. doi: 10.1136/vr.165.24.713. PubMed DOI

Yang M., Wu X., Zhang W., Ye P., Wang Y., Zhu W., Tao Q., Xu Y., Shang J., Zhao D., et al. Transcriptional analysis of deoxynivalenol-induced apoptosis of sow ovarian granulosa cell. Reprod. Domest. Anim. 2020;55:217–228. doi: 10.1111/rda.13610. PubMed DOI

Goyarts T., Dänicke S., Brüssow K.-P., Valenta H., Ueberschär K.-H., Tiemann U. On the transfer of the Fusarium toxins deoxynivalenol (DON) and zearalenone (ZON) from sows to their fetuses during days 35–70 of gestation. Toxicol. Lett. 2007;171:38–49. doi: 10.1016/j.toxlet.2007.04.003. PubMed DOI

Dänicke S., Brüssow K.P., Goyarts T., Valenta H., Ueberschär K.H., Tiemann U. On the transfer of the Fusarium toxins deoxynivalenol (DON) and zearalenone (ZON) from the sow to the full-term piglet during the last third of gestation. Food Chem. Toxicol. 2007;45:1565–1574. doi: 10.1016/j.fct.2007.02.016. PubMed DOI

Wippermann W., Heckmann A., Jäger K., Dänicke S., Schoon H.-A. Exposure of pregnant sows to deoxynivalenol during 35–70 days of gestation does not affect pathomorphological and immunohistochemical properties of fetal organs. Mycotoxin Res. 2018;34:99–106. doi: 10.1007/s12550-017-0304-z. PubMed DOI

Pasternak J.A., Aiyer V.I.A., Hamonic G., Beaulieu A.D., Columbus D.A., Wilson H.L. Molecular and physiological effects on the small intestine of weaner pigs following feeding with deoxynivalenol-contaminated feed. Toxins. 2018;10:40. doi: 10.3390/toxins10010040. PubMed DOI PMC

Accensi F., Pinton P., Callu P., Abella-Bourges N., Guelfi J.-F., Grosjean F., Oswald I.P. Ingestion of low doses of deoxynivalenol does not affect hematological, biochemical, or immune responses of piglets. J. Anim. Sci. 2006;84:1935. doi: 10.2527/jas.2005-355. PubMed DOI

Sayyari A., Framstad T., Krogenæs A.K., Sivertsen T. Effects of feeding naturally contaminated deoxynivalenol diets to sows during late gestation and lactation in a high-yield specific pathogen-free herd. Porc. Heal. Manag. 2018;4:26. doi: 10.1186/s40813-018-0102-9. PubMed DOI PMC

Kollarczik B., Gareis M., Hanelt M. In vitro transformation of theFusarium mycotoxins deoxynivalenol and zearalenone by the normal gut microflora of pigs. Nat. Toxins. 1994;2:105–110. doi: 10.1002/nt.2620020303. PubMed DOI

Stastny K., Stepanova H., Hlavova K., Faldyna M. Identification and determination of deoxynivalenol (DON) and deepoxy-deoxynivalenol (DOM-1) in pig colostrum and serum using liquid chromatography in combination with high resolution mass spectrometry (LC-MS/MS (HR)) J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 2019;1126–1127:121735. doi: 10.1016/j.jchromb.2019.121735. PubMed DOI

Dänicke S., Beyer M., Breves G., Valenta H., Humpf H.U. Effects of oral exposure of pigs to deoxynivalenol (DON) sulfonate (DONS) as the non-toxic derivative of DON on tissue residues of DON and de-epoxy-DON and on DONS blood levels. Food Addit. Contam.-Part A Chem. Anal. Control. Expo. Risk Assess. 2010;27:1558–1565. doi: 10.1080/19440049.2010.501036. PubMed DOI

Prelusky D.B., Hartin K.E., Trenholm H.L., Miller J.D. Pharmacokinetic Fate of 14 C-Labeled Deoxynivalenol in Swine. Toxicol. Sci. 1988;10:276–286. doi: 10.1093/toxsci/10.2.276. PubMed DOI

Paulick M., Winkler J., Kersten S., Schatzmayr D., Schwartz-Zimmermann H.E., Dänicke S. 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. 2015;7:4622–4644. doi: 10.3390/toxins7114622. PubMed DOI PMC

Warth B., Sulyok M., Berthiller F., Schuhmacher R., Krska R. New insights into the human metabolism of the Fusarium mycotoxins deoxynivalenol and zearalenone. Toxicol. Lett. 2013;220:88–94. doi: 10.1016/j.toxlet.2013.04.012. PubMed DOI

Weaver A.C., Todd See M., Hansen J.A., Kim Y.B., De Souza A.L.P., Middleton T.F., Kim S.W. The use of feed additives to reduce the effects of aflatoxin and deoxynivalenol on pig growth, organ health and immune status during chronic exposure. Toxins. 2013;5:1261–1281. doi: 10.3390/toxins5071261. PubMed DOI PMC

Wu Q., Dohnal V., Huang L., Kuča K., Yuan Z. Metabolic pathways of trichothecenes. Drug Metab. Rev. 2010;42:250–267. doi: 10.3109/03602530903125807. PubMed DOI

Maul R., Warth B., Schebb N.H., Krska R., Koch M., Sulyok M. In vitro glucuronidation kinetics of deoxynivalenol by human and animal microsomes and recombinant human UGT enzymes. Arch. Toxicol. 2015;89:949–960. doi: 10.1007/s00204-014-1286-7. PubMed DOI

Gail McCarver D., Hines R.N. The ontogeny of human drug-metabolizing enzymes: Phase II conjugation enzymes and regulatory mechanisms. J. Pharmacol. Exp. Ther. 2002;300:361–366. doi: 10.1124/jpet.300.2.361. PubMed DOI

Pretheeban M., Hammond G., Bandiera S., Riggs W., Rurak D. Ontogenesis of UDP-glucuronosyltransferase enzymes in sheep. Comp. Biochem. Physiol. Part A Mol. Integr. Physiol. 2011;159:159–166. doi: 10.1016/j.cbpa.2011.02.014. PubMed DOI

Hu S.X. Age-related change of hepatic uridine diphosphate glucuronosyltransferase and sulfotransferase activities in male chickens and pigs. J. Vet. Pharmacol. Ther. 2017;40:270–278. doi: 10.1111/jvp.12355. PubMed DOI

Oswald I.P., Marin D.E., Bouhet S., Pinton P., Taranu I., Accensi F. Immunotoxicological risk of mycotoxins for domestic animals. Food Addit. Contam. 2005;22:354–360. doi: 10.1080/02652030500058320. PubMed DOI

Goyarts T., Dänicke S., Tiemann U., Rothkötter H.J. Effect of the Fusarium toxin deoxynivalenol (DON) on IgA, IgM and IgG concentrations and proliferation of porcine blood lymphocytes. Toxicol. Vitr. 2006;20:858–867. doi: 10.1016/j.tiv.2005.12.006. PubMed DOI

Ferrari L., Cantoni A.M., Borghetti P., De Angelis E., Corradi A. Cellular immune response and immunotoxicity induced by DON (deoxynivalenol) in piglets. Vet. Res. Commun. 2009;33:133–135. doi: 10.1007/s11259-009-9265-9. PubMed DOI

Reddy K.E., Song J., Lee H.J., Kim M., Kim D.W., Jung H.J., Kim B., Lee Y., Yu D., Kim D.W., et al. Effects of high levels of deoxynivalenol and zearalenone on growth performance, and hematological and immunological parameters in pigs. Toxins. 2018;10:114. doi: 10.3390/toxins10030114. PubMed DOI PMC

Pestka J.J., Dong W., Warner R.L., Rasooly L., Bondy G.S., Brooks K.H. Elevated membrane IgA+ and CD4+ (T helper) populations in murine peyer’s patch and splenic lymphocytes during dietary administration of the trichothecene vomitoxin (deoxynivalenol) Food Chem. Toxicol. 1990;28:409–420. doi: 10.1016/0278-6915(90)90087-4. PubMed DOI

Rasooly L., Pestka J.J. Vomitoxin-induced dysregulation of serum IgA, IgM and IgG reactive with gut bacterial and self antigens. Food Chem. Toxicol. 1992;30:499–504. doi: 10.1016/0278-6915(92)90101-P. PubMed DOI

Islam M.R., Roh Y.S., Kim J., Lim C.W., Kim B. Differential immune modulation by deoxynivalenol (vomitoxin) in mice. Toxicol. Lett. 2013;221:152–163. doi: 10.1016/j.toxlet.2013.05.656. PubMed DOI

Pestka J.J. Mechanisms of deoxynivalenol-induced gene expression and apoptosis. Food Addit. Contam.-Part A Chem. Anal. Control. Expo. Risk Assess. 2008;25:1128–1140. doi: 10.1080/02652030802056626. PubMed DOI PMC

Wada K., Hashiba Y., Ohtsuka H., Kohiruimaki M., Masui M., Kawamura S., Endo H., Ogata Y. Effects of mycotoxins on mitogen-stimulated proliferation of bovine peripheral blood mononuclear cells. J. Vet. Med. Sci. 2008;70:193–196. doi: 10.1292/jvms.70.193. PubMed DOI

Novak B., Vatzia E., Springler A., Pierron A., Gerner W., Reisinger N., Hessenberger S., Schatzmayr G., Mayer E. Bovine peripheral blood mononuclear cells are more sensitive to deoxynivalenol than those derived from poultry and swine. Toxins. 2018;10:152. doi: 10.3390/toxins10040152. PubMed DOI PMC

Dąbrowski M., Obremski K., Gajęcka M., Gajęcki M., Zielonka Ł. Changes in the Subpopulations of Porcine Peripheral Blood Lymphocytes Induced by Exposure to Low Doses of Zearalenone (ZEN) and Deoxynivalenol (DON) Molecules. 2016;21:557. doi: 10.3390/molecules21050557. PubMed DOI PMC

Dąbrowski M., Jakimiuk E., Baranowski M., Gajȩcka M., Zielonka Ł., Gajȩcki M.T. The effect of deoxynivalenol on selected populations of immunocompetent cells in porcine blood-a preliminary study. Molecules. 2017;22:691. doi: 10.3390/molecules22050691. PubMed DOI PMC

Hlavová K., Štěpánová H., Šťastný K., Levá L., Hodkovicová N., Vícenová M., Matiašovic J., Faldyna M., Št’astný K., Levá L., et al. Minimal concentrations of deoxynivalenol reduce cytokine production in individual lymphocyte populations in pigs. Toxins. 2020;12:190. doi: 10.3390/toxins12030190. PubMed DOI PMC

Swamy H.V.L.N., Smith T.K., MacDonald E.J., Karrow N.A., Woodward B., Boermans H.J. Effects of feeding a blend of grains naturally contaminated with Fusarium mycotoxins on growth and immunological measurements of starter pigs, and the efficacy of a polymeric glucomannan mycotoxin adsorbent1. J. Anim. Sci. 2003;81:2792–2803. doi: 10.2527/2003.81112792x. PubMed DOI

Stepanova H., Samankova P., Leva L., Sinkora J., Faldyna M. Early postnatal development of the immune system in piglets: The redistribution of T lymphocyte subsets. Cell. Immunol. 2007;249:73–79. doi: 10.1016/j.cellimm.2007.11.007. PubMed DOI

Šinkora M., Butler J.E. The ontogeny of the porcine immune system. Dev. Comp. Immunol. 2009;33:273–283. doi: 10.1016/j.dci.2008.07.011. PubMed DOI PMC

Saalmüller A., Werner T., Fachinger V. T-helper cells from naive to committed. Vet. Immunol. Immunopathol. 2002;87:137–145. doi: 10.1016/S0165-2427(02)00045-4. PubMed DOI

Vatzia E., Pierron A., Saalmüller A., Mayer E., Gerner W. Deoxynivalenol affects proliferation and expression of activation-related molecules in major porcine T-cell subsets. Toxins. 2019;11:644. doi: 10.3390/toxins11110644. PubMed DOI PMC

Bloom B.R., Salgame P., Diamond B. Revisiting and revising suppressor T cells. Immunol. Today. 1992;13:131–136. doi: 10.1016/0167-5699(92)90110-S. PubMed DOI

Käser T., Gerner W., Mair K., Hammer S.E., Patzl M., Saalmüller A. Current knowledge on porcine regulatory T cells. Vet. Immunol. Immunopathol. 2012;148:136–138. doi: 10.1016/j.vetimm.2011.05.035. PubMed DOI

Savard C., Pinilla V., Provost C., Gagnon C.A., Chorfi Y. In vivo effect of deoxynivalenol (DON) naturally contaminated feed on porcine reproductive and respiratory syndrome virus (PRRSV) infection. Vet. Microbiol. 2014;174:419–426. doi: 10.1016/j.vetmic.2014.10.019. PubMed DOI

Vandenbroucke V., Croubels S., Martel A., Verbrugghe E., Goossens J., Van Deun K., Boyen F., Thompson A., Shearer N., De Backer P., et al. The mycotoxin deoxynivalenol potentiates intestinal inflammation by Salmonella typhimurium in porcine ileal loops. PLoS ONE. 2011;6 doi: 10.1371/journal.pone.0023871. PubMed DOI PMC

Pinton P., Accensi F., Beauchamp E., Cossalter A.-M.M., Callu P., Grosjean F., Oswald I.P. Ingestion of deoxynivalenol (DON) contaminated feed alters the pig vaccinal immune responses. Toxicol. Lett. 2008;177:215–222. doi: 10.1016/j.toxlet.2008.01.015. PubMed DOI

Savard C., Gagnon C.A., Chorfi Y. Deoxynivalenol (DON) naturally contaminated feed impairs the immune response induced by porcine reproductive and respiratory syndrome virus (PRRSV) live attenuated vaccine. Vaccine. 2015;33:3881–3886. doi: 10.1016/j.vaccine.2015.06.069. PubMed DOI PMC

Bartkiene E., Zavistanaviciute P., Lele V., Ruzauskas M., Bartkevics V., Bernatoniene J., Gallo P., Tenore G.C., Santini A. Lactobacillus plantarum LUHS135 and paracasei LUHS244 as functional starter cultures for the food fermentation industry: Characterisation, mycotoxin-reducing properties, optimisation of biomass growth and sustainable encapsulation by using dairy by-products. LWT. 2018;93:649–658. doi: 10.1016/j.lwt.2018.04.017. DOI

McEwan A.D., Fisher E.W., Selman I.E., Penhale W.J. A turbidity test for the estimation of immune globulin levels in neonatal calf serum. Clin. Chim. Acta. 1970;27:155–163. doi: 10.1016/0009-8981(70)90390-6. PubMed DOI

Stepanova H., Mensikova M., Chlebova K., Faldyna M. CD4+ and γδTCR+ T lymphocytes are sources of interleukin-17 in swine. Cytokine. 2012;58:152–157. doi: 10.1016/j.cyto.2012.01.004. PubMed DOI

Volf J., Boyen F., Faldyna M., Pavlova B., Navratilova J., Rychlik I. Cytokine response of porcine cell lines to Salmonella enterica serovar Typhimurium and its hilA and ssrA mutants. Zoonoses Public Health. 2007;54:286–293. doi: 10.1111/j.1863-2378.2007.01064.x. PubMed DOI

Stepanova H., Pavlova B., Stromerova N., Matiasovic J., Kaevska M., Pavlik I., Faldyna M. Cell-mediated immune response in swine infected with Mycobacterium avium subsp. avium. Vet. Immunol. Immunopathol. 2011;142:107–112. doi: 10.1016/j.vetimm.2011.04.005. PubMed DOI