Mycotoxins-induced immunotoxicity is the term applied when the adverse effects of these toxins alter both the local and systemic immune system. In animal production, mycotoxins can cause suppression or stimulation of the immune system. However, the mechanisms of action are not fully clarified. Among mycotoxins, there are six that are mostly investigated and controlled under the legislation of the European Food Safety Authority (EFSA), which are: aflatoxin B1 (AFB1), deoxynivalenol (DON), ochratoxin A (OTA), toxin T-2, fumonisin B1 (FB1) and zearalenone (ZEN) (Sun et.al, 2022).
Aflatoxin B1 is a metabolite derived from Aspergillus flavus, whose target organs are the liver and kidneys. Its action in the animals is nephrotoxic, hepatotoxic and immunotoxic (Dhakal, Hashmi, & Sbar , 2020). Deoxynivalenol and T-2 toxin, on the other hand, are derived from the Fusarium genus.
DON has a primary toxic action in the intestine and also affects the immune system. The T-2 toxin damages the heart muscle, nerves and the immune system (Sun, Huang, Long, Yang, & Zhang, 2022). As for ochratoxin A, it is derived from the genus Aspergillus and Penicillium, and its target organ is the kidney. This toxin causes damage at the immune, liver, and kidney levels of the animals (Tao, et al., 2018). In contrast, fumonisin B1 is a carcinogenic, neurotoxic, and nephrotoxic metabolite from fungi of the Fusarium genus. Finally, zearalenone is a Fusarium-derived estrogenic toxin, which affects the reproductive and immune systems (Sun et.al, 2022). In summary, these six toxins damage the integrity of the immune system. Given the immunological complexity of each organism, there is no single parameter that determines mycotoxins-induced immunotoxicity.
Mycotoxins can suppress or stimulate the immune system depending on multiple factors, such as: dose and time of exposure to the toxin, route of administration, and presence or absence of immunological stimulants (Sun et.al, 2022). Depending on the dose of mycotoxins, low levels of exposure can induce the inflammatory response of the animal. On the contrary, a high dose causes immunosuppression (Abbès et.al, 2016). In the same way, it is observed that long periods of exposure to the toxin can cause immunosuppression unlike short periods of time. Additionally, the presence or absence of the immunological stimulants (lipopolysaccharides, phytohemagglutinin, concanavalin A, others) changes the action of mycotoxins in the immune system. They are immunosuppressive when stimulant agents are present, and they are immunostimulatory when the stimulant agents are absent. (Sun et.al, 2022).
Other factors, although no less important, includes species, sex and age. According to the species, the pig is the most susceptible to mycotoxins, followed by humans, poultry, rodents, marine organisms and finally ruminants. According to the sex, it has been described that female animals have greater susceptibility to mycotoxins such as DON or FB1 than in male. On the other hand, the age of the animals is also a relevant factor, since young animals are more sensitive to mycotoxins than the old ones. All these previously mentioned circumstances, are associated with the variables of each individual. Therefore, the immunotoxicity induced by mycotoxins does not completely depend on the dose of exposure, time or appearance of immunological stimulants (Sun et.al, 2022).
Mycotoxins-induced immunosuppression
The toxicity of mycotoxins on the immune system is subject to mechanisms such as oxidative stress, apoptosis, autophagy of immune cells (macrophages, lymphocytes, neutrophils and T cells), immune signaling pathways and other routes of cell communication (Sun et.al , 2022). The following are the mechanisms of immunosuppression used by different mycotoxins:
Aflatoxin B1 has an immunosuppressive mechanism that involves oxidative stress, apoptosis, and interference with immune system-related signals. To induce oxidative stress, AFB1 increases reactive oxygen species (ROS) and biomolecule oxidation (Mary et.al, 2012). Apoptosis or programmed cell death is linked to oxidative stress. Apoptosis requires a large group of molecular machinery to be carried out, and it is known that AFB1 can stimulate ROS-dependent caspase, mediating cell apoptosis (Kumar & Chul, 2020). In the cell signaling pathway, AFB1 can inhibit lymphocyte proliferation and IL-2 production. Additionally, it promotes the secretion of IL-10, allowing the phenotypic change of alveolar macrophages from its M1 (immunostimulatory) to M2 (immunosuppressive) form. Although the mechanism of immunosuppression of aflatoxin B1 is understood, other routes of suppression of the immune system remain to be studied (Sun et.al, 2022).
In the case of deoxynivalenol, it is an immunosuppressive agent that exerts its action through various pathways. It has been shown to depress the immune system through the mitochondrial pathway mediated by ROS, and it can even activate the apoptosis of T lymphocytes, impairing their immune function. DON also has mechanisms that activate autophagy and can directly inhibit inflammatory mediators, interfering with the immune response (Sun et al., 2022).
The immunosuppressive action of other mycotoxins is also a topic of equal relevance. For example, ochratoxin A is closely related to autophagy, as it inhibits the regulation pathway of this cellular mechanism (Hwan, Kim, Kim, & Moon, 2015). The T-2 toxin, on the other hand, is similar to DON. T-2 is capable of stimulating the apoptosis of splenic cells and reducing the number of CD4+ and CD8+ T cells. Additionally, T-2 toxin decreases the level of inflammatory cytokines (IL-6, IL-10, and IL-1β) by causing stress on the endoplasmic reticulum and, in turn, decreasing the production of inflammatory mediators such as IL-1β, TNF-α, and NO (Sun et al., 2022). Finally, the immunotoxic mechanism of fumonisin B1 is based on oxidative stress, while there are few studies on zearalenone. However, it is considered to be capable of stimulating the apoptosis pathway of T lymphocytes (Marin et al., 2011).
In animal production, all these described immunosuppressive mechanisms lead to a weak immune response of the organism against pathogens. Therefore, the animal remains exposed to different diseases that, on many occasions, are not evident with clinical signs but with the deterioration of production parameters.
The stimulation of the immune system by mycotoxins encompasses the use of immune signaling and cellular communication pathways. Aflatoxin B1, ochratoxin A, deoxynivalenol and T-2 toxin are the mycotoxins reported with immune stimulation mechanisms (Sun et.al, 2022).
Aflatoxin B1 stimulates the inflammatory response and liver damage, activating the NF-κB regulatory pathway. It is a toxin capable of increasing the number of pro-inflammatory cytokines, including IL-6 and tumor necrosis factor α, which are mediated by the activation of the NF-κB pathway. Similarly, aflatoxin B1 uses the oxidative stress mechanism to cause an inflammatory response (Sun et.al, 2022).
Similarly to AFB1, ochratoxin A increases the pro-inflammatory cytokines through the activation of the NF-κB pathway (Hou et al., 2018). It also induces intestinal inflammation and activates T-cell response. On the other hand, deoxynivalenol has a greater effect on immune cells than on other cell types. Some of the immune actions of DON include activating T-cell response (by increasing intracellular calcium), promoting pro-inflammatory genes (IL-6, IL-1β, and TNF-α), and enhancing COX-2 expression and other inflammation pathways (Sun et al., 2022).
Finally, the immune stimulation mechanism of T-2 toxin is the activation of pathways that lead to apoptosis and enhance inflammatory signals. Like several other mycotoxins, T-2 toxin can induce inflammation and damage through oxidative stress, which increases pro-inflammatory cytokines and enhances the inflammatory process (Wu et al., 2017).
Having described the stimulating effect of mycotoxins on the immune system, it is important to emphasize that this is a complex process where inflammatory mediators and molecular signaling pathways converge, allowing the activation and proliferation of immune cells that carry out the immune response. However, several factors determine or intervene in its development, acting differently in each animal organism.
The effect of mycotoxins on the immune system of animals will be described below.
Swine
In swine, susceptibility to mycotoxins is reflected in pathological findings and low productivity. The effect of mycotoxins on the immune system of pigs varies according to the toxin and the conditions present at the time of exposure.
In swine, it has been observed that aflatoxins are capable of deregulating antigen presentation mediated by dendritic cells when exposed to low concentrations. Additionally, these toxins can compromise the synthesis of pro-inflammatory cytokines. In growing piglets, there is a high susceptibility to aflatoxin B1, as it reduces the overall lymphoproliferative response. Studies have shown that when sows are exposed to this type of mycotoxin, the macrophages and neutrophils of piglets also lose certain functional capabilities (Pierron, Alassane, & Oswald, 2016).
Trichothecenes such as DON and T-2 toxin can both up- and down-regulate immune functions (Pierron, Alassane, & Oswald, 2016). The literature asserts that deoxynivalenol suppresses the immune system when found at high concentrations and, conversely, stimulates the immune system at low concentrations (Muratori & Woo, 2021). According to this, a study conducted in pigs showed that chronic consumption of DON in contaminated diets increases the expression of inflammatory cytokines and generates a greater amount of IgA and IgG antibodies (Pestka et al., 2004). Regarding the T-2 toxin, it can cause leukopenia and a decrease in the number of lymphoid organ cells in pigs. At the same time, prolonged exposure to low doses of T-2 toxin influences memory T lymphocytes, generating an adverse effect on humoral response mediated by B lymphocytes and causing a deficient secondary immune response (Adhikari et al., 2017).
Other toxins with great influence on the immune system are fumonisins and, to a lesser extent, ochratoxin A. In swine, fumonisin B1 modifies the balance of Th1 and Th2 cytokines, altering the humoral response. Additionally, exposure to FB1 significantly reduces the number of viable cells through the process of apoptosis or cell death (Zhu & Wang, 2022). Several studies report that fumonisin B1 alters the maturation of antigen-presenting cells by reducing the expression of IL-12 p40 at the intestinal level and decreasing positive expression of the major histocompatibility complex class II, which reduces T-cell stimulation (Pierron, Alassane, & Oswald, 2016). Ochratoxin A in pigs has an impact on cytokine expression rather than on the total and specific immunoglobulin concentrations (Pierron, Alassane, & Oswald, 2016).
Regarding zearalenone, it is better known for its toxic effect on fertility than on immunity, and information is scarce (Zakil et al., 2012). However, a study confirmed that the pig immune response is inadequate when exposed to zearalenone and its derivatives, highlighting that the toxin decreases immune cell viability, antibody formation, and cytokine production (Marín et al., 2011).
As seen above, the swine immune system changes its response to toxicity depending on the type of mycotoxin, toxin dose, and other related factors. Therefore, the variety of results differs between the stimulating or immunosuppressive effect of the mycotoxin. It can be deduced that, for both immunity results, the immune cells, cell signaling pathways, and inflammatory mediators are always altered (Cimbalo et al., 2020).
Poultry
Despite being studied for more than 50 years, the mechanisms of immunosuppression caused by aflatoxicosis are still not well understood. It is known that in the starter stages of exposure to this toxin, the humoral immune response of birds increases noticeably. However, humoral immunity decreases as the exposure period lengthens. It is presumed that aflatoxins, especially B1, deplete the number of lymphoid cells present in the thymus, spleen, and bursa of Fabricius. This inhibits the synthesis of antibodies by lymphocytes, leading to the aforementioned immune suppression (Yunus, Razzazi, & Bohm, 2011).
DON is characterized by inhibiting the biosynthesis of proteins, RNA, and DNA, not to mention its effect on altering cell membranes. Tissues with high protein turnover are the most affected by the exposure to DON, and the immune system is one of these tissues. Information on immunotoxicity by DON in poultry is still quite limited. In chickens, DON along with other trichothecenes can stimulate or impair humoral immunity (Awad, Ghareeb, Bohm, & Zentek, 2013). The use of serum antibody titers against common viral vaccines is often useful in understanding the effect of DON on humoral immunity. It has been identified that DON suppresses the post-vaccination response to viruses such as infectious bronchitis virus (IBV) or Newcastle disease virus (NDV) (Ghareeb, Awad, & Bohm, 2012). Recent studies suggest that DON may have an effect on the reduction of IgA and spleen weight. Other studies conducted in chickens concluded that exposure to DON results in an increase in antibody response, although the immune response changes depending on the concentration of mycotoxins and the manifestation of other variables (Hwan, Kim, Kim, & Moon, 2015). Additionally, in laying hens, DON has been found to reduce the total number of white blood cells and lymphocytes (Awad, Ghareeb, Bohm, & Zentek, 2013).
Regarding the T-2 toxin, it causes a lower immune response in birds because it reduces the number of lymphoid cells located in bone marrow, thymus, and spleen, allowing pathogens to become more resistant during infections. With cellular decline, various lymphoid organs lose their original size, including the bursa of Fabricius in birds (Filazi et.al, 2017).
Finally, other mycotoxins have a certain impact on the avian immune system, although at a lower level. For example, ochratoxin A is capable of reducing the size of immune organs such as the thymus and bursa of Fabricius. Meanwhile, fumonisin B1 alters the morphology and functionality of macrophages, making chickens more susceptible to bacterial infections. Deficiencies in antibody titers are also observed (Hwan, Kim, Kim, & Moon, 2015).
Ruminants
In ruminants, mycotoxins interfere with the immune function in different ways. On the one hand, they can alter cell-mediated immunity (reducing phagocytosis) and, on the other hand, impair humoral immunity. With immune dysfunction, the risk of disease increases, especially during stressful periods such as calving or weaning. It should be noted that transition cows and calves are most susceptible to the immunosuppressive effects of mycotoxins, rather than mature cows (Gott & Schwandt, 2021).
Due to the toxin degradation capacity present in the rumen, a large part of mycotoxins do not have the same effect observed in monogastric animals. However, aflatoxins are partially degraded into a metabolite known as Aflatoxicol. The toxic effect of the metabolite acts based on different mechanisms in the livestock immune system, which includes inhibiting lymphocyte blastogenesis and suppressing lymphocyte proliferation (mainly mediated by AFB1). Finally, it is emphasized that chronic exposure to mycotoxins in ruminants interferes with the immunity provided by vaccines (Bola, 2017).
Pets
In companion animals, both dogs and cats suffer from the immunosuppressive effect of mycotoxins. There is little information about mycotoxin contamination in dog and cat food formulations, and the effect of these toxins remains an unexplored field. Currently, it is understood that prolonged consumption of contaminated food has consequences for the health of dogs and cats, and their immune system is left in suboptimal conditions (Grandi et al., 2019). In dogs, the most reported and problematic group of mycotoxins are aflatoxins, as they are quite susceptible, as are pigs (Barth et al., 2013). Another described mycotoxin is ochratoxin, which has had repercussions on low resistance to infections, leaving the animal’s overall health exposed (Koerich & Scussel, 2012).
In conclusion, the immune system is a complex set of signals and specialized cells that work to mitigate infectious threats, exerting nonspecific and immediate responses (innate immunity) or specific long-term responses (adaptive immunity). Due to the great diversity of how this system is organized, often the actions or responses differ between etiological agents. Mycotoxins, as immunotoxic agents, can alter the properties of the immune system, and depending on the toxin and its concentration, the severity and action in the immune system changes. There are several reports of the immunotoxic effect of mycotoxins on the animal immune system, but it is still a field of research that needs further exploration.
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