Mycotoxin Fumonisin B 1 Alters the Cytokine Profile and Decreases the Vaccinal Antibody Titer in Pigs Ionelia Taranu,* , † Daniela E. Marin,* , † Sandrine Bouhet,* Florentina Pascale,‡ Jean-Denis Bailly,§ J. David Miller, ¶ Philippe Pinton,* and Isabelle P. Oswald* ,1 *Pharmacology and Toxicology Laboratory, UR 66, National Institute of Agronomic Research INRA, Toulouse, France; †IBNA, Institute of Biology and Animal Nutrition, Balotesti, Romania; ‡Pasteur Institute, Bucarest, Romania; §Department of Mycotoxicology, Veterinary School of Toulouse, Toulouse, France; ¶ Ottawa-Carleton Institute of Chemistry, Carleton University, Ottawa, Canada Received October 19, 2004; accepted January 4, 2005 Fumonisin B 1 (FB 1 ), a mycotoxin produced by Fusarium verticillioides, may contaminate feed and food. In the present study, we investigated the effect of FB 1 on the modulation of the cytokine profile and on the establishment of a vaccinal antibody response. In vitro investigations on pig peripheral blood mono- nuclear cells (PBMC) indicate that FB 1 decreased interleukin-4 (IL-4) and increased interferon-gamma (IFN-g) synthesis at both the protein and mRNA levels. A short in vivo exposure (7 days) of weanling piglets to 1.5 mg/kg body weight of purified FB 1 altered the cytokine balance in mesenteric lymph nodes and spleen similarly to the in vitro PBMC results. We also investigated the effect of FB 1 on the antibody response during a vaccination process. A prolonged in vivo exposure (28 days) of weanling piglets to feed contaminated with 8 mg FB 1 /kg significantly decreased the expression of IL-4 mRNA by porcine whole blood cells and diminished the specific antibody titer after vaccination against Mycoplasma agalactiae. By contrast, ingestion of the contaminated feed had no effect on the serum concentration of the immunoglobulin subset (IgG, IgA, and IgM). Taken together, our data suggest that FB 1 alters the cytokine profile and decreases the specific antibody response built during a vaccination protocol. These results may have implications for humans or animals eating contaminated food or feed. Key Words: fumonisin B 1 ; PBMC; swine; cytokine; Th1/Th2; specific antibody; immunoglobulin. INTRODUCTION Mycotoxins are secondary metabolites of fungi, which may contaminate animal and human feeds. Because of their toxicological effects, their global occurrence is considered an important risk factor for human and animal health (Mannon and Johnson, 1985). Fumonisins are a family of cytotoxic and carcinogenic mycotoxins produced by Fusarium verticillioides and F. proliferatum, fungi that commonly contaminate maize. Recent surveys on fumonisins in food and feed throughout the world, including the United States and most European countries, have raised concerns about the extent of FB 1 contamination of maize and its implications for food safety (IPCS, 2000; Murphy et al., 1993). The mechanism(s) of FB 1 toxicity is complex and may involve several molecular sites (Riley et al., 1998). The primary biochemical effect of fumonisins is the inhibition of the ceramide synthase leading to the accumulation of sphingoid bases and sphingoid base metabolites, and the depletion of more complex sphingolipids (Merrill et al., 2001; Riley et al., 1998). At high concentrations, FB 1 causes a variety of species- specific acute toxicological effects in domestic and laboratory animals. It induces leukoencephalomalacia in horses, pulmo- nary edema in pigs, and nephrotoxicity in rats, rabbits, and lambs. It also causes hepatotoxicity in all species thus far examined (Bolger et al., 2001; Haschek et al., 2001). This toxin has also been reported to be a carcinogen in rodents, and there is evidence that it is a contributing factor in human esophageal cancers (IPCS, 2000). The effects of ingestion of low doses of FB 1 are less completely documented, but recent studies have shown that it does not have a major effect on clinical signs in mice or in swine (Bondy et al., 2000; Rotter et al., 1996; Zomborszky-Kovacs et al., 2002). However, ingestion of low doses of FB 1 revealed pathological alterations of the lungs and an increase of intestinal colonization by opportunistic patho- genic bacteria in piglets (Halloy et al., submitted; Oswald et al. 2003). Cellular immune responses generated after antigen stimula- tion of lymphocyte populations can be characterized by the distinct cytokines that are produced (Abbas et al., 1996). CD4 þ T cell clones are broadly divided into two subsets, based on the cytokines they secrete: the Th1-producing forms (interleukin-2 [IL-2], interferon-gamma [IFN-c], and tumor necrosis factor [TNF]) or Th2-producing forms (IL-4, IL-5, IL-6, IL-10, and IL-13) (Abbas et al., 1996; Asnagli and Murphy, 2001). The 1 To whom correspondence should be addressed at Laboratoire de Pharma- cologie Toxicologie, INRA, 180 Chemin de Tournefeuille, 31931 Toulouse Cedex 9, France. Tel: 33 (0) 561285480. Fax: 33 (0) 561285310. E-mail: ioswald@toulouse.inra.fr. Toxicological Sciences vol. 84 no. 2 Ó The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org TOXICOLOGICAL SCIENCES 84, 301–307 (2005) doi:10.1093/toxsci/kfi086 Advance Access publication January 19, 2005 Downloaded from https://academic.oup.com/toxsci/article/84/2/301/1692308 by guest on 04 June 2022