Immunotoxicity of other mycotoxins

Several other mycotoxins, beside aflatoxin, are present in the food crops consumed by people chronically exposed to aflatoxin (Cardwell, 200i). Fusarium mycotoxins, including fumonisins produced primarily by F. verticillioides, and deoxynivalenol (DON, sometimes termed vomitoxin) produced primarily by F. graminearum, are contaminants of food in areas of the world where people are exposed to aflatoxin. These mycotoxins occur worldwide on maize, wheat and other cereal grains (Bullerman, 1996). Aspergillus and Fusarium are two of the most abundant fungi found in grains (Hill et al., 1984). Fumonisin B1 is a major contaminant of maize and maize products worldwide (Nelson et al., 1992). There have been several reports on the co-occurrence of aflatoxin and fumonisins and aflatoxin and other mycotoxins such as trichothecenes and ochratoxin in maize and other food products (Chamberlain et al., 1993; Chu and Li, 1994; Kpodo et al., 2000; Park et al., 2002).

Fumonisin B1 stimulates T-cell proliferation and induces nitric oxide production by rat spleenic macrophages (Dombrink-Kurtzman et al., 2000). Also, macrophages from mice treated with fumonisin B1 showed increased TNF-a production (Dugyala et al., 1998). The phagocytic activity of swine alveolar macrophages was suppressed to 55% and 36% of control levels by fumonisin B1 (50 ng/ml fumonisin B1) and aflatoxin B1 (100 ng/ml aflatoxin B1) respectively. Fumonisin B1 was toxic at lower concentrations than aflatoxin B1 (Liu et al., 2002). A dramatic decrease in mRNA levels of IL-10 and TNF-a was observed in alveolar macrophages incubated with 2 and 10 ^g/ml fumonisin B1 for 24 hours, while aflatoxin B1 did not alter IL-10 and TNF-a mRNA expression (Liu et al., 2002). Humoral immune responses in mice or rats were not affected by fumonisin B1 (Martinova and Merrill, 1995; Tryphonas et al., 1997).

In 2005, Taranu et al. (2005) reported that fumonisin B1 altered the cytokine profile (IL-4, IFN-y) and decreased antibody titer to a vaccine in pigs. In pig PBMC in vitro, they found that fumonisin B1 decreased IL-4 and increased IFN-y synthesis at both the mRNA and protein levels. In a brief in vivo study, they found that fumonisin B1 altered cytokine balance in mesenteric lymph nodes and spleen of weanling piglets exposed to 1.5 mg fumonisin B1/kg body weight for 7 days in a manner similar to that observed in the in vitro results. In vivo exposure of weanling piglets for a prolonged period (28 days) to 8 mg fumonisin B1/kg in feed resulted in a significant decrease in the expression of IL-4 mRNA by porcine whole blood cells. Specific antibody titer after vaccination against Mycoplasma agalactiae was diminished but there was no effect of fumonisin Bi on serum concentrations of IgG, IgA and IgM.

Fumonisin Bi is structurally analogous with sphingosine and sphinganine and interferes with sphingolipid metabolism causing accumulation of free sphingoid bases (Merrill et al., 2001). These free sphingoid bases inhibit lymphocyte growth, and Th2 lymphocytes are more sensitive to their action than Thi lymphocytes (Tokura et al., 1996). Thus, Tokura et al. (1996) hypothesize that fumonisin B1 may selectively act on Th2 cells decreasing the synthesis of IL-4. Fumonisin B1 also modulates glycolipid synthesis (Merrill et al., 2001) but how modulation of glycolipid synthesis by fumonisin B1 affects lymphocyte function has not been determined. Since Th2 cytokines function in the development of immune responses that lead to antibody production, the authors postulate that decrease of IL-4 by fumonisin B1 resulted in decrease of the specific antibody response to the M. agalactiae vaccine.

Data from Martinova and Merrill (1995) suggest that fumonisin-induced immunomodulation may result from changes in the expression of certain cell surface receptors involved in immune communication in mice such as CD3 and sphingomyelin. However, the immunomodulation also may result from changes in cytokine secretion such as TNF-a (Du-gyala et al., 1998). Further study of the role of fumonisin B1 on sphingolipids in immune cell signaling is needed to provide information on the immunomodulatory effects of fumonisin B1.

The trichothecenes (produced by Fusarium spp. and other species of fungi) present in cereal grains also are immunotoxins (Bondy and Pestka, 2000). Trichothecenes at high doses can cause leukocyte apoptosis since they target actively dividing cells in the bone marrow, lymph node, spleen and thymus. Low dose trichothecenes seem to promote expression of a diverse array of cytokines that can either up-regulate or down-regulate immune functions (Bondy and Pestka, 2000). Immunosuppression by trichothecenes may be explained by their ability to bind ribosomes and inhibit protein synthesis (Bamburg, 1983).

Ochratoxin A is another immunotoxic mycotoxin that has multiple effects on immune cells (Richard, 1991; Bondy and Pestka, 2000). Harvey et al. (1992) showed that ochratoxin A suppressed cell-mediated and phagocytic cell responses in pigs. Lea et al. (1989) reported that ochratoxin A abrogated the ability of purified human lymphocytes to respond to activating stimuli in vitro. They found that expression of both IL-2 and IL-2 receptors was severely affected in cells exposed to ochratoxin A. Antibody production also was inhibited in purified B lymphocytes. This effect was not due only to the blocking of T helper cell function but also to the inability to respond to polyclonal activation after treatment with ochratoxin A. Therefore, the authors concluded that ochratoxin A interferes with essential processes in cell metabolism regardless of the subpopulation of lymphocytes.

Berek et al. (2001) tested the effects of eight important fusarium mycotoxins (deoxyniva-lenol, 3-acetyldeoxynivalenol, fusarenon-X, T-2 toxin, zearalenone, a-zearalenol, P-zearalenol, and nivalenol) on T and B cell proliferation, antibody-dependent cellular cytotox-icity (ADCC) and NK cell activity in healthy monocyte-free human PBMCs. Concentrations of mycotoxins similar to those found in normal human peripheral blood (0.2-1800 ng/ml) were used. T-2 toxin, fusarenon-X, nivalenol and 3-acetyldeoxynivalenol had the highest immunosuppressive effects and depressed T and B lymphocyte proliferation in a dose-dependent manner. The other five mycotoxins had significantly less or no effect. Deoxyni-valenol, T-2 toxin and nivalenol each significantly inhibited the ADCC reaction with the effect of T-2 toxin being dose-dependent. These three mycotoxins also inhibited NK cell activity in a dose-dependent manner with significant inhibition at higher concentrations.

The combined effect of several mycotoxins as immunotoxins, each with a potentially different mechanism of toxicity, is unknown. However, a mixture of mycotoxins should have at least additive, if not synergistic, effects (Miller and Wilson, 1994).

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