Aflatoxin B₁: An Immunomodulator and Cancer Agent

Abstract

The type I interferon signaling pathway of the innate immune system plays a key role in the first line of defense in eliminating pathogens and other chemical agents that are introduced into the body and is also known to exhibit the anticancer properties. Therefore, any agent being chemical or components of microorganisms that tend to inhibit or suppress the type I interferon response pathway will weaken the innate immune system and predispose individuals to infectious agents and cancers. Aflatoxin B1 has been reported to modulate the immune system by suppressing inflammatory cytokines, monocytes, lymphocytes and the type I interferon signaling response pathway. Aflatoxin B1 contamination of food is very high in most sub-Saharan African countries. Aflatoxin B1 contamination of diet coupled with subsequent prolonged heavy exposure is one of the major risk factors for the development of hepatocellular carcinoma. Aflatoxin B1 is known to cause hepatocellular carcinoma by inducing mutation in the tumor suppressor gene TP53. We present in this review the mechanism by which aflatoxin B1 inhibits the type I interferon signaling pathway thus pre-disposing exposed individuals to cancers and other infections.

1. Introduction

Aflatoxins (AFBs) are mycotoxins that were discovered in the 1960s when 120,000 turkeys and poultry birds fed with poultry feed imported from South America died of Turkey X disease in England [1]. Aspergillus parasiticus and Aspergillus flavus are the two most common species of the genus Aspergillus that are known to biosynthesize aflatoxins. Chemically, aflatoxins are secondary metabolites that is they are substances that are made by living agents which do not need them for their survival. In relation to their chemical structure, AFBs consist of bifuran ring that is fused to a coumarins ring. Twenty (20) different metabolites of AFBs have been currently discovered. The most important AFBs out of the 20 currently discovered ones are aflatoxin B₁ (AFB₁), aflatoxin B₂ (AFB₂), aflatoxin G₁ (AFG₁) and aflatoxin G₂ (AFG₂).

Out of the different varieties of AFBs discovered, AFB₁ is reported to be the commonest contaminant of food stuffs such as groundnut and maize that are heavily consumed by many Africans and is considered the most lethal carcinogen in humans [2, 3]. The International Agency for Research on Cancer (IARC) has classified AFB₁as group 1 human carcinogen [4]. It is estimated that about 4.5 billion people worldwide are persistently exposed to food stuffs contaminated with aflatoxins. In many developing countries including Ghana, most people rely heavily on maize, groundnut and other types of cereals as their staple food which are invariably contaminated with AFB₁. In countries like Ghana, Benin and Togo which are located in West Africa, it has been reported that some food stuffs meant for human consumption contain high levels of AFBs [5, 6, 7]. The reasons for the high level of AFB₁ in these foods are due to poor storage conditions, high humidity in the West African sub region as well as sub-optimal farming practices. Weanimix, a local food made from maize and groundnut in Ghana has been reported to contain high level of AFBs above the national acceptable level of 15ppb [8]. Prolonged heavy consumption of diet contaminated with AFB₁ is a significant risk factor that can cause hepatocellular carcinoma (HCC) [9, 10]. In addition to prolonged AFB₁ exposure, chronic infections with hepatitis B and C viruses (HBV; HCV), iron overload and excessive alcohol consumption have been identified as other factors of the environment that can cause HCC [11]. It has been reported that every year approximately 550,000 to 600,000 new HCC cases are recorded globally and that 25,200 to 155,000 are induced by AFBs exposure with majority of AFBs induced HCC cases occurring China, Southeastern part of Asia and West Africa [12].

Even though AFB₁ has serious negative effects in the human system, the type I interferon signaling response pathway of the innate immune system continually work in protecting individuals against disease causing agents and the harmful effects of AFBs. The type I interferon signaling response pathway plays a key role in eliminating disease causing microorganisms such as viruses as well as cancer cells. A study conducted to determine the capability of interferon to change back the phenotypic characteristics of tumor cells to normal phenotype reported that interferon was able to partially reverse phenotype of the tumorigenic cells in human osteosarcoma cells [13].

In 1986, Food and Drug Administration (FDA) of United States of America (USA) sanctioned the use of interferon-alpha 2a and 2b to treat Kaposi sarcoma in AIDS patients, cancer of the bone marrow (hairy cell leukemia) and other cancers [14]. Interferon treatment has been reported to activate p53, an anti-oncogene that plays a significant role in programmed cancer cell death [14]. Additionally, interferon-alpha has been reported to exhibit a significant protective effect against hepatic carcinogenesis as well as fibrogenesis [15]. Aziz et al. [15] treated liver cells of rat with carcinogenic compounds carbon tetrachloride and AFB₁ and revealed that cirrhotic and fibrotic processes in cells that were able to express ectopic IFN-α were minimized. Even though the experiment conducted by Aziz et al. [15] has not been replicated in the liver cells of human to evaluate the ability of viruses to induce the production of IFN in cases where individuals have been exposed to AFB₁, it demonstrated that interferon-alpha is a major protective agent against liver cancer. In this review, we present the mechanisms by which AFB₁ suppresses the type I interferon signaling response pathway thus pre-disposing individuals exposed to AFB₁ to cancers and other infections.

2. Distribution of fungi that produce aflatoxins

Aflatoxins are synthesized in food crops by two main fungal agents namely Aspergillus parasiticus and Aspergillus flavus. Even though the geographical locations of both Aspergillus parasiticus and Aspergillus flavus are similar, Aspergillus parasiticus is uncommon in Southeastern region of Asia. However, Aspergillus flavus is found everywhere predominantly in cereals that are grown in environment with low water condition and high temperature. Aspergillus parasiticus and Aspergillus flavus are mostly found in food crops like groundnuts, maize, peanuts, spices, oilseeds, walnuts, millet, almonds, corn, cottonseed, corn, and others. Aspergillus flavus and Aspergillus parasiticus predominantly produce AFB₁ and AFB₂ during growth periods, when crops are being harvested, threshed, dried, stored and transported [16]. Aspergillus parasiticus predominantly produce AFG₁ and AFG₂ [16]. Aspergillus nomius, Aspergillus australis, Aspergillus fumigatus and Aspergillus niger are other species of Aspergillus which produce AFBs. Aspergillus species mainly colonize the soil, decaying organic matter, grains and hay that are deteriorating microbiologically. Aspergillus species grow and produce AFBs in an environment that is moist and hot [17].

3. Types of aflatoxins, structure and properties of AFB₁

To date twenty (20) different types of AFBs have been discovered. Of these 20 currently known AFBs, the major ones include AFB₁, AFB₂, AFG₁, AFG₂, aflatoxin M₁ (AFM₁) and aflatoxin M₂ (AFM₂). The AFB₁, AFB₂, AFG₁ and AFG₂ are made by fungi while AFM₁ and AFM₂ are made as intermediate products when AFB₁ and AFB₂ respectively are metabolized. The B and G descriptions of AFBs refer to the type of color generated when AFBs are placed under short-wave UV (ultraviolet) illumination during thin layer chromatography. The B description of AFB₁ and AFB₂ refers to the blue light generated under UV illumination while the G description refers to the green light generated under UV illumination on thin layer chromatographic plates. The AFM₁ and AFM₂ were initially detected in raw milk of livestock that had ingested feed contaminated with AFBs thus the description M. The subscript numbers 1 and 2 indicate the major and minor compounds respectively [18, 19, 20].

Structurally, AFB₁ like all other AFBs consist of bifuran ring that is fused to a coumarins ring. AFB molecules differ from AFG molecules in that AFB molecules have cyclopentenone ring while the AFG molecules have lactone ring. There are double bonds at loci 8 and 9 on the terminal furan ring of the AFB₁ structure and these double bonds confer the unique carcinogenic characteristics to AFB₁ (Figure 1) [21].

Figure 1.

Chemical structure of AFB₁.

Generally, AFBs occur as crystals which appear as uncolored or lemon-yellow at 25 to 28°C [22]. AFBs are partially soluble in water and hydrocarbons but cannot be dissolved in hydrophobic solvents. AFBs are completely dissolvable in polar solvent like alcohol (e.g. methanol), acetone and chloroform. To degrade AFBs, they can be placed in light and air. AFBs can also be degraded by exposing them to UV light, strong acid solution, strong basic solution and oxidizing agents. AFBs can be broken down by exposing them to very high temperature conditions ranging between 237 to 299°C. Complete destruction of AFBs can be achieved when they are autoclaved with ammonia or when they are treated with bleach containing sodium hypochlorite. Normal cooking temperatures cannot degrade AFBs.

4. Biotransformation of aflatoxins

Metabolism of AFB₁ largely occurs in the liver by a group of enzymes called cytochrome P450 (CYP 450). When AFB₁ is ingested, it is transported to the liver where the CYP 450 enzymes convert AFB₁into different compounds which include AFM₁, aflatoxicol, aflatoxin P₁ (AFP₁) and aflatoxin Q₁ (AFQ₁). Additionally, the CYP450 enzymes especially CYP1A2 and CYP3A4 convert AFB₁ into reactive oxygen species (ROS) AB₁–8, 9-epoxide which exists in two (2) forms; endo-AFB₁–8, 9-epoxide and exo-AB₁–8, 9-epoxide. Whereas the CYP3A4 produces exo-AB₁–8, 9-epoxide and a small quantity of AFQ₁, the CYP1A2 produces both endo and exo-AFB₁–8, 9-epoxides as well as AFM₁ [23]. Of the two epoxide species, exo-AFB₁–8, 9-epoxide is considered to be the toxic species that confers genotoxic characteristics on AFB₁ [2, 3, 24]. The AFB₁–8, 9 epoxide metabolites formed can form conjugates with glutathione leading to the formation of a stable, harmless, soluble product which is excreted in the bile. The conjugation process is catalyzed by the enzyme glutathione-S-transferase (GST). The conjugation and the subsequent excretion of the soluble product formed is the mechanism by which AFB₁ is detoxified as a hepatocarcinogen. The AFB₁–8, 9 epoxide-glutathione complex formed is also broken down in the liver and kidney is excreted in the urine as mercapturic acid [25]. On the other hand, when individuals are exposed to high levels of AFB₁ beyond the capability of GST enzymes to break down the epoxides into harmless forms, or when the activity of GST enzymes is reduced through mutations of the GST gene, the AFB₁–8, 9 epoxides can bind to liver proteins and cause their failure which can result in acute hepatotoxicity or aflatoxicosis.

Conversely, the 8, 9 epoxides can cause mutations of DNA in the liver cells and as a results pro-mutagenic lesions may be formed. When the pro-mutagenic lesions are formed, proto-oncogenes are activated and this may cause the tumor suppressor genes to become inactivated. The AFB₁–8, 9 epoxide has affinity for the N⁷ atom of guanine and so bind with it which leads to the production of a pro-mutagenic DNA adduct (AFB₁-N⁷-Gua adduct). The AFB₁-N⁷-Gua adduct is not stable and so goes through depurination process which results in the adduct being excreted in the urine. Animals such as mice that are more immune to the carcinogenic effects of AFB₁ have much greater GST action compared to animals such as rats which more susceptible to the carcinogenic effects of AFB₁. In humans, the action of GST enzymes is much lower when compared with rats and mice. This suggests that the ability of humans to detoxify AFB₁–8, 9 epoxides is lower [26] and therefore humans stand a greater chance of suffering from the carcinogenic effects of AFB₁ when compared with rats and mice. Figure 2 below shows the schematic flow chart on how metabolism of AFB₁ occurs in the liver.

Figure 2.

Schematic flow chart on metabolism of AFB₁.

5. Effects of aflatoxins on human health

AFBs are very genotoxic agents that can still cause ailment in human beings when individuals are exposed to small quantities [27]. Even though AFBs can cause disease in many parts of the human system, they are largely known to cause acute and or chronic disease in the liver as well as liver cancer. There are so many ways by which AFBs manifest their toxic side effects when ingested into the body. AFBs can modify the integrity of the intestines [28] and regulate the expression of cytokines. These negative effects of AFBs can lead to impaired growth and weakening of the immune system in children [29]. The quantity or amount of AFBs consumed or ingested coupled with how long the individual has been exposed largely determine the negative impact of AFBs in humans and other animals. Acute exposure of humans to AFBs occur when large amount of AFBs are consumed within shortest possible time. Chronic exposure occurs when humans consume minute quantities of AFBs over a prolonged period of time.

When humans are exposed to large quantities of AFBs over a relatively short time period, it can results in vomiting, stomach aches, mental retardation, improper digestion of food, liver disease, coma and hepatotoxicity or aflatoxicosis. About 25% of individuals who experience acute AFBs exposure die from AFBs-related diseases [30]. There are environmental factors which predispose humans to acute aflatoxicosis. These factors are scarcity of food, high temperatures and humid environment which promotes the growth of the fungi that produce AFBs and inadequate systems to regulate and monitor food stuffs for the presence AFBs. Globally acute aflatoxicosis has become a recurrent public health problem [31, 32].

Research indicates that prolong exposure of individuals to small quantities of AFBs can cause impairment of the immune system, reduction in absorption of nutrients from the small intestines which may ultimately result in stunted growth especially in children and young infants [33, 34]. Reports from research conducted within Togo as well as Benin, countries located in the West African sub-region indicate that there is a correlation between levels of AFB-protein (albumin) adduct and growth impairment [35, 36]. In 2005 Jiang et al. [37] undertook a study in Ghana and reported that individuals who had higher levels of AFB₁-albumin adducts had reduced levels of certain leukocytes types. Similarly, Turner et al. [38] undertook a study in Gambia and reported that infants who had high levels of aflatoxin-albumin adducts had lower quantities of IgA antibodies in their saliva.

6. Immunomodulatory effects of AFB₁ in humans

Data or information on how AFBs and the related compounds regulate the immune system is scanty. Reports indicate that AFBs and other mycotoxins can suppress the immune system through the inhibition of DNA replication, transcription and translation of genes that are required to switch on the innate and acquired immune system response by using myriad of mechanisms [39]. Studies have indicated that the AFB₁–8, 9-exo-epoxide that is formed when AFB₁ is metabolized reacts with DNA found in the mitochondria rather than with DNA found in the nucleus of the cell and this hinders the synthesis of ATP [40, 41]. The binding of the AFB₁–8, 9-exo-epoxide to DNA of the mitochondria results in the formation AFB₁-mitochondrial DNA adduct which leads to mutations in the membranes causing ballooning of the cell as well as disrupting the production of ATP [40, 42].

Studies have reported that AFB₁ and its intermediate products inhibit translation when they bind to important enzymes that are needed in the translation of mRNAs into proteins. AFB₁ and its intermediate products also suppress translation by blocking the activities of translocase in ribosomes and this suppress translation [43]. Additionally, it has been reported that aflatoxins negatively affect protein synthesis by interfering with substrates and enzymes that are needed for initiation, transcription and translation [44].

Furthermore, several research works have looked at how AFB₁ inhibit the immune system in humans. In 2015, Jiang et al. conducted a study to evaluate how the regulation of some pro-inflammatory cytokines such as IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ and TNF-α in the bowels of broiler birds could be affected by AFB₁. They reported that the transcript levels of the studied pro-inflammatory cytokines in broiler birds treated with AFB₁ were much lower than the levels in broiler birds that were not treated with AFB₁. Furthermore, Jiang et al. indicated that broiler birds that were treated with AFB₁ exhibited reduced amount of T-cells in the intestines in comparison with broiler birds that were not treated. Several studies have also reported the suppression or inhibition of transcription and translation of IL-4, IL-6 and IL-10 genes respectively by AFB₁in the peritoneal macrophages, splenic lymphocytes and macrophage cell lines [45, 46, 47].

On the contrarily, a study conducted by Li et al. [48] indicated that broiler birds that were fed with livestock feed containing 0.074 mg/kg showed an increase in the levels of IL-6, IFN-γ and TNF-α mRNA and protein expression in the spleen and serum. In 2014, Qian et al. [49] undertook a study to determine the impact of AFB₁ on the splenic lymphocyte phenotypes and the inflammatory cytokine production in male F344 rats. They indicated that rats that were exposed to AFB₁ showed a dose-dependent reduction in the level of IL-4 produced by CD4⁺ T cells. Also Bruneau et al. [50] reported that AFB₁ induced the suppression or inhibition of IFN-γ and TNF-α expression by CD4⁺T cells and CD3⁻CD8a NK cells respectively. Bruneau et al. [45] in addition indicated that murine macrophages that were exposed to AFB₁in vitro showed a reduction in the level of anti-inflammatory cytokine IL-10 but rather increased the level of pro-inflammatory cytokine IL-6. Taken together these studies suggest aflatoxins are immunosuppressive agents.

A study was conducted by Forouharmehr, Harkinezhad [50] to determine the impact of AFB₁ on how the expression of STAT5A can be affected by treating bovine mammary epithelial cells with AFB₁ and quantifying the mRNA levels of STAT5A using RT-qPCR. They indicated that cells that were treated with AFB₁ showed a great decline in the mRNA levels of STAT5A in a dose-dependent manner. They further reported that the suppression of the mRNA levels of STAT5A minimized the proliferation and differentiation of mammary epithelial cells, thus affecting the amount and the quality of milk protein that is produced.

In 1999, Rossano et al. [51] treated human monocytes that have been activated with lipopolysaccharide of bacteria with 0.01–1.0 pg/mL of AFB₁ in order to determine how AFB₁ could affect the expression and release of IL-1α, IL-6α, TNF-α. They reported that at 0.05 pg/mL of AFB₁, the levels of IL-1α, IL-6α, and TNF-α were greatly reduced and that AFB₁ totally shut off the transcription of their mRNAs. Rossano et al. further reported that transcript levels of β-actin remained unchanged by AFB_1. These findings made the researchers to make a conclusion that AFB₁ exerts it effects on the expression of cytokines likely by suppressing the transcription of certain mRNAs without affecting translation.

The type I interferon signaling response pathway of the innate immune system plays a significant part in eliminating disease causing microorganisms and cancer cells in the human system. The type I interferons exhibit antiviral as well as anti-cancer properties. The anti-cancer activities of type I interferon led to their use to treat cancers such as Kaposi sarcoma in AIDS patients, cancer of the bone marrow (hairy cell leukemia) and other forms of cancers [14]. In 1979, Hahon et al. [52] conducted a study to determine how AFB₁ could affect the induction of interferon production in monkey kidney cells (LLC-MK) that had been infected with influenza virus. They reported that AFB₁ inhibited influenza viral induction of interferon dose-dependently.

In other to understand the mechanism of AFB₁ inhibition of the interferon signaling response pathway, Narkwa et al., demonstrated in a study that AFB₁ suppressed IFN-α induced ISRE (interferon stimulated response element) signaling in a dose dependent manner using luciferase reporter gene assay (Figure 3), [53]. Further using RT-qPCR Narkwa et al. [53] showed that AFB₁ inhibits transcript expression levels of key signaling elements such as STAT1, JAK1 and OAS3 genes of the JAK–STAT-ISRE arm of the type 1 IFN response pathway. Some studies have reported that post-transcriptional processes may be involved in the translation of mRNA into protein [54]. This suggests that low mRNA expression may not directly results in lower expression of protein and oppositely. Consequently, after demonstrating that AFB₁ suppresses the transcript expression levels of STAT1, JAK1 and OAS3, Western blot assay was used to determine whether the suppression of transcript expression level of STAT1 by AFB₁ would ultimately affect its translation into protein. The authors observed that AFB₁ suppressed the translation of STAT1 mRNA into protein. The type I IFN signaling has been reported to exert its anti-cancer and antiviral response through the activation of the JAK–STAT-ISRE arm of the pathway (Figure 4) [53]. One component of the JAK–STAT-ISRE signaling pathway considered to have tumor suppressor function is STAT1 [55]. When activated, STAT1 suppresses tumor development by inducing programmed cell death [56] and also inhibit tumor maturation or growth [57]. Therefore the suppression/inhibition of STAT1 by AFB₁ as demonstrated by Narkwa et al., would definitely weaken the capacity of STAT1 to coordinate the expression of multitude of genes necessary to stimulate programmed cell death, prohibit multiplication and maturation of cells in response to AFB₁. Therefore, the above stated studies provide overwhelming evidence that aflatoxins in general and AFB₁ in particular suppress the immune system and predispose individuals to diseases including cancers.

Figure 3.

AFB₁ suppresses the antiviral and anticancer type I interferon response signaling in a dose dependent manner. Source: [34].

Figure 4.

Key antiviral and anticancer elements of the innate immune type I interferon signaling response pathway suppressed by AFB₁. Source: [34].

7. AFB₁ as a cancer agent

As stated above, humans get exposed to AFB₁ when they consume food contaminated with aflatoxins or when they inhale dust particles containing aflatoxins and this could lead to acute or chronic aflatoxicosis. The signs and symptoms of aflatoxicosis include stomach ache, regurgitation, pulmonary congestion, multifocal hepatic necrosis and non-alcoholic fatty pancreatic disease. Again, AFB₁ is the major potent lethal human hepatocarcinogen and is classified as group 1 human carcinogen by the IARC [4] Data from Global Cancer Observatory Report (GLOBOCAN 2020) indicate that the global incidence of cancers in 2020 was roughly 19.3 million with 10 million cancer deaths. Cancer is reported as the leading cause of premature deaths globally [58]. The global rise of the cancers as leading cause of mortality resulted in the decline of both communicable and non-communicable diseases among humans.

HCC is the sixth commonest diagnosed cancer and the third leading cause of cancer mortality globally according to global cancer statistics 2020 report. HCC is more prevalent in resource limited countries. The most important factors that put individuals at risk of developing HCC comprise persistent HBV and HCV infections, AFB₁ exposure, excessive intake of alcohol and iron overload [11]. Aflatoxins particularly AFB₁ are established risk factors of HCC in humans and animals. In a case–control study to determine the association between aflatoxins and HCC, the authors reported that the average aflatoxin exposure per day in cases of HCC was 4.5 times higher than in the control groups [59]. A similar study in Mozambique directly correlated high dietary intake of aflatoxins to incidence of HCC [60]. Importantly, in the context of AFB₁ and HBV infection co-existing, the risk of developing HCC is increased by more than 30 times [61] compared to either HBV or aflatoxin exposure alone.

8. Mechanism of carcinogenesis of AFB₁

AFB₁ is a known genotoxic hepatocarcinogen that causes genetic damage such as formation of DNA adducts, albumin adduct, gene mutations, micronucleus formation, sister chromatid exchange and mitotic recombination which result in genetic changes in the target cells, which then cause DNA damage and ultimately cancer [26].

When AFB₁ is ingested by humans and other susceptible animals, it is transported to the liver where the CYP 450 enzymes convert AFB₁ into ROS endo-AFB₁–8, 9-epoxide and exo-AB₁–8, 9-epoxide the latter being more toxic than former, thus this confers genotoxic characteristics on AFB₁ [62]. The exo-AFB₁–8, 9 epoxide has affinity for the N⁷ atom of guanine and so bind with it leading to the formation of primary DNA adduct (AFB₁-N⁷-Gua adduct) [63]. The AFB₁-N⁷-Gua adduct is transformed into two minor compounds namely an apurinic (AP) site and a stable ring-opened AFB₁-Formamidopyrimidine (AFB₁-FAPY) adduct the latter being more mutagenic than the former [21]. The AP and AFB₁-FAPY adduct are mended by nucleotide excision repair (NER) or base excision repair (BER) [64, 65].

Conversely, when the mending process is improperly done, it results in AGG to AGT transversion mutations with these mutations taking place at codon 249 in the tumor suppressor gene TP53. When these mutations occur, the amino acid arginine in the tumor suppressor protein p53 become replaced with serine (R249S) [66, 67]. When the mutated R249S p53 is expressed, apoptosis is inhibited, p53 mediated transcription is also inhibited and liver cells are stimulated to grow uncontrollably resulting in HCC [68]. Studies have reported that the R249S mutation is mostly found in more than 50% of HCC cases especially in China and Africa where the incidence of HCC is high [66, 69]. On the other hand, the R249S mutation is rare in the regions of the world where aflatoxins exist at extremely low levels in the diet and in cancers other than HCC [70]. The TP53 directs the synthesis of p53 protein. When the conditions within the cells are normal, the p53 is kept at low levels through it binding to ubiquitin-ligases such as Mdm2 (also referred to as Hdm2 in humans) and then degraded by proteasome enzymes [71]. On the other hand, in the presence of some stress factors, the p53 goes through certain processes such as phosphorylation on serine 15 (Pser15-p53) and become activated after it has been produced. The activated p53 binds specific DNA response elements resulting in trans-activation of genes that play key roles in programmed cell death, the arrest of cell cycle, repair of DNA repair or aging [72]. These responses lead to repair of damage that have been caused to DNA which help to maintain the genetic integrity of the cells. The response may also stimulate apoptosis of damaged cells resulting in their elimination from the system.

Some studies reported that AFB₁ impair miRNA biogenesis; the authors also reported that AFB₁ suppress Wnt/β-catenin signaling pathway by inducing over-expression of miR-34a and thus causing liver cancer [73]. Other studies showed that AFB₁ promote HCC cell multiplication through an IGF-2-dependent signal axis [74]. AFB-mediated DNA damage results in the deregulation of the cell cycle and cause HCC through the up-regulation of pro-apoptotic pathways including p53, NF-kB, BCl2, c-Myc, CDK, Ras, protein kinase C, Cyclins and CKI’s [75, 76]. All these mechanisms of actions take place in the liver.

9. Conclusions

In this review, we summarize the distribution of fungi that produce aflatoxins, general properties of aflatoxins, metabolism of AFB₁ as well as the immunomodulatory effects and the mechanisms of carcinogenesis of AFB₁. All these information or data are already reported in literature.

We report from our previous study that AFB₁ inhibit the type I interferon signaling response pathway by suppressing transcript expression levels of JAK1, STAT1 and OAS3. We also report that AFB₁ suppresses the translation of STAT1 mRNA into protein. STAT1 which is a key component of the JAK–STAT-ISRE arm of the type I interferon signaling response pathway is known to exhibit its tumor suppressing function by inducing apoptosis and inhibiting angiogenesis. Therefore, by demonstrating in our study that AFB₁ inhibit translation of STAT1 mRNA into protein suggest that AFB₁ can suppress the immune system of individuals exposed to it thereby predisposing them to cancers and other diseases.