Many chemical mutagens were proven to cause mutation and inactivation of the cancer suppressor genes such as P53, BRCA1 and BRCA2. One of the most influential chemical compounds that could cause a mutation in these genes are the mycotoxins (1). Mycotoxins are carcinogenic toxins that are produced by many Aspergillus and Penicillium species growing on food commodities (1). Among the different mycotoxins, aflatoxin B1 has been reported as the highest carcinogenic mycotoxin (2) and aflatoxin B1 can penetrate the cell membrane and attach to its DNA where it causes irreversible mutations (2). The chemical nature of aflatoxins makes it a highly liposoluble compound that can be absorbed from the site of exposure such as from the gastrointestinal and respiratory tract to the blood stream where it can move throughout the body (3). The exposure to these carcinogenic mycotoxins can be through the ingestion of the contaminated food that ends up in the stomach where it gets absorbed or by inhaling the dust particles of aflatoxins B1 from the food that is contaminated with these aflatoxins (3). Once the aflatoxins enter the cells, they are metabolized by the action of cytochrome P450, a microsomal enzyme to aflatoxin-8, 9-epoxide in the detoxification metabolic pathway for aflatoxins. It is highly reactive and unstable and requires the binding to a DNA or to the protein molecule in order to become more stable (3). Once the highly unstable aflatoxin-8, 9-epoxide binds to the DNA molecule with high affinity, it forms aflatoxin-N7-guanine that cause a guanine (G) to thymine (T) transversion mutations which will directly affect the cell cycle by affecting the P53 gene which carries the codes for tumor suppressor proteins, meant to inhibit the development of tumors and cancers (3).

The role of aflatoxin B1 in causing mutation in the humans genome was extensively studied (2), many other mycotoxins are yet to be investigated to understand their method of action once they are in contact with the humans genome. This is particularly crucial because many mycotoxins have a closely related chemical composition and similar functions inside the human body. The researchers decided on two research questions in this review that accurately describe the objectives of this research: What are the different types of mycotoxins that can cause cancer? What is the role of mycotoxins in causing cancer and what types of cancers can be caused by mycotoxins?

The reason for this review is due to the fact that there is an increase in mycotoxin contamination in the world and by understanding the role of different mycotoxins in the human body and their levels of toxicity and carcinogenicity, many new measures could be followed and many human lives and animals alike could be saved. In addition, there is a gap in cancer studies relating to mycotoxins as it has been only related to liver cancer (4). Although due to the similarity in nature and functions, mycotoxins can be related to many types of cancer. This review will concentrate on the previously published studies that answer both of our research questions and build on the arguments that support these questions.

In an experiment done by El-Banna et al (5) nearly 1400 Penicillium isolates were collected from several cultures, isolated directly from food and feed. Each isolate was identified using Pitt's classification to investigate their mycotoxins production, and 18 different mycotoxins were isolated. Each isolate was allowed to grow on malt extract agar medium and was incubated for the period between one to three weeks at 25°C. The mycotoxins were then extracted using chloroform and filtration, and the produced mycotoxins were concentrated. Finally, the mycotoxins were classified and characterized by mycotoxins analysis using TLC (6–8). This experiment resulted in the production and the identification of 18 different mycotoxins from one or more species of Penicillium. The toxins are as follows: Brevianamid A produced by 3 species, Citreoviridin produced by 2 species, Citrinin (Fig. 2) produced by 3 species, Cyclopiazonic acid produced by 8 species, Fumitremorgin B produced by 1 species, Griseofulvin produced by 6 species, luteoskyrin produced by 1 species, Ochratoxin A produced by 2 species, Patulin produced by 4 species, Penicillic acid produced by 2 species, Penitrem A produced by 1 species, PR-toxin produced by 1 species, Roquefortine produced by 2 species, rugulosin produced by 2 species, Verrucosidin produced by 1 species, Verruculogen produced by 1 species, Viridicarumtoxin produced by produced by 2 species and finally, Xanthomegnin produced by 2 species (5).

Another group of mycotoxins is produced by Aspergillus species, and these mycotoxins are called Aflatoxins (12). They were found to be extremely toxic and highly cariogenic. Aflatoxins are chemical compounds that are released by the fungi Asergillus Flavus and Aspergillus Parasiticus as secondary metabolites, and the different laboratory investigations confirmed the high carcinogenicity of these chemical compounds and how they are associated with many cancers such as liver and kidney (9–12). The different types of aflatoxins include aflatoxin B1 and B2, produced by Aspergillus Flavus and Aspergillus parasiticus, Aflatoxin G1 and G2, produced by Aspergillus parasiticus (13–16). Among these toxins, it was found the B1 and G1 are the most toxic with the highest carcinogenic effect on animal cells (9). Food products that can be contaminated with aflatoxins include cereal (maize, sorghum, pearl millet, rice, and wheat), oil seeds (groundnut, soybean, sunflower, and cotton), spices (chilies, black pepper, coriander, turmeric, and ginger), tree nuts (almonds, pistachio, walnuts, and coconut) and milk (17–22). Moreover, aflatoxins are found in the contaminated tobacco leaves (23). Aflatoxins can also be present in the dry soil, which can move through underground water with rain and be ingested by humans and animals through drinking water (24).

Another group of mycotoxins that is produced by Aspergillus, Penicillium and Fusarium were classified and characterized based on the frequency of their accordance with nature and their severity of the diseases they cause. These mycotoxins are Deoxynivalenol (Fig. 8), Fumonisins (Fig. 4), Zearalenone (Fig. 10), T-2 toxin (Fig. 7), and finally certain types of ergot alkaloids. Found mainly on grain crops (29–31), they were known to develop a set of diseases called Mycotoxicoses, and these diseases include blood toxicity, food poisoning and sometimes cancer (25–27).

Another group of mycotoxins is produced by the Fusarium species and when culturing the Fusarium moniliforme cultures on corn, a mycotoxin called Fumonisins was found to be produced (28). When analyzing fumonisins using liquid chromatography, three types of fumonisins were found namely B1 (FB1), B2 (FB2), and B3 (FB3) and all three types are isolated when allowing the fusarium to grow on corn and the concentrations of fumonisins will range from 800–12800 ng total fumonisins/g (29).

In addition to the aflatoxins, another group of mycotoxins were found to have a similar action on humans and animals, grouped as the Ochratoxins (30–32). The Ochratoxins are mycotoxins produced by some Aspergillus species such as A. Ochraceus and A. Niger, whereas some Penicillium species such as P. Verrucosum and P. Carbonarius are also found to produce Ochratoxins (32). Among all the types mentioned, Ochratoxin A is the most common and it has the highest degree of toxicity (33–35). The Ochratoxins can be found in cereals, coffee, dried fruit, and red wine. It can be accumulated in the meat of animals and thus, meat and meat products can be contaminated with this toxin (36–39).

As previous literature indicates, fungal strains can be found in many terrestrial habitats which make the availability of different mycotoxins a very common phenomenon. Since many different fungal strains such as Penicillium, Aspergillus and Fusarium species grow very well on commodities such as crops, grains and stored animal feed, the chances of mycotoxins entering the humans or animal biological system are very high, mostly accompanied with many health concerns and medical complications (40).

Researched confirmed that the most important mycotoxins are Citrine, Aflatoxin B1, Ergot, fumonisins akaloids, Patulin, Trichothecene, Zearalenone and Ochratoxin A and the reason behind their importance is the fact that they are involved in many human and animal diseases which sometimes leads to death (41).

The most dangerous mycotoxins are the aflatoxin B1 (Fig. 1) and Ochratoxin A (Fig. 5) for their lethal effect on humans and animal. Aflatoxin B1 has the highest carcinogenicity among all mycotoxins and it is capable of penetrating the cell membrane and attach to its DNA where it makes changes to the genome in order to become more stable (2,82,83). Aflatoxin B1 is considered a liposoluble compound which can be absorbed from the site of exposure and move into the blood stream throughout the body (84). As soon as the aflatoxins enter the cells, they get metabolized by cytochrome P450, to aflatoxin-8, 9-epoxide which is highly reactive and unstable and requires the binding to a DNA or to the protein molecule in order to become more stable (85,86). Once the highly unstable aflatoxin-8, 9-epoxide binds to the DNA molecule with high affinity, it forms aflatoxin-N7-guanine that causes GC to TA transversion mutations. This will directly affect the cell cycle by affecting the P53 gene which encodes tumor suppressor protein that inhibits the development of tumors and cancers (87,88).

Ochratoxin (Fig. 5) is another mycotoxin which is given a similar importance as Aflatoxin B1 because of how it targets the kidney (89). Ochratoxin A is considered a nephrotoxin to animals and humans and is a very strong liver toxin, potent teratogen, carcinogenic and immune suppressant (90,91). Ochratoxin A will mainly disturb cellular physiology in several ways, but the primary effects of it are usually associated with the enzymes that are involved in phenylalanine metabolism which inhibits the enzyme involved in the synthesis of the phenylalanine-tRNA complex (92,93). Moreover, Ochratoxin A is capable of inhibiting mitochondrial ATP production and is considered a strong stimulant for lipid peroxidation (35,94).

Trichothecene mycotoxins are proven to have multiple inhibition effects on eukaryote cells where they inhibit protein, DNA and RNA synthesis, mitochondrial function and effects both cell division and cell membrane of the eukaryotic cells (95). Trichothecenes are capable of inducing a programmed cell death response within infected cells, causing a reduction in downstream gene products, starting a ribotoxic stress response and activating a mitogen-activated protein kinase (96). Deoxynivalenol mycotoxin (Fig. 8) usually mediates an inflammatory response by controlling the binding activities of some transcription factors which will results in inducing cytokine gene expression (97). In animal cells, Trichothecenes are capable of inhibiting protein synthesis, inhibiting RNA and DNA synthesis; altering cellular membrane structure, interfere with mitochondria functions, initiating apoptosis, activation of MAPK and finally, activation of the cytokine (98–104).

Citrinin (Fig. 2) is considered as one of the strongest nephrotoxins to animals, and the levels of toxicity differ between species (56). Citrinin can act together with Ochratoxin A, interfere with RNA synthesis and suppress it in rodent kidneys (105). Citrinin is known to inhibit cytokine expression and reduce the interleukin-4 in T-helper type 1 which would result in increasing the risk of allergies in humans (106). It is considered genotoxic at high concentrations to cultured human lymphocytes (107). Finally, Citrinin is considered a nephrotoxin which causes nephropathy and impose oxidative stress, or increase the permeability of mitochondrial membranes (108). Ergot Alkaloids mycotoxins are a type of Citrinin, and they are known to induce humans ergotism, low nerve fever in humans and have a strong influence on fertility (109–111). Although certain cleaning processes for grains has overcome the problem of ergotism, it is still considered a significant animal problem which causes symptoms such as abortion, suppression of lactation, hypersensitivity, ataxia and gangrene (112,113) and smooth muscle contractions (114). Despite its toxicity, Ergot Alkaloids mycotoxins and its derivatives are used widely in abortifacient and as a drug to accelerate uterine contractions during labor (114). They are also used for the treatment of migraine headaches, prolactin inhibitors for the treatment of Parkinsonism and for the treatment of cerebrovascular insufficiency (59). Unfortunately, the use of ergot alkaloids may result in the development of human ergotism (115).

Fumonisin B1 (Fig. 4) is an important Fumonisins mycotoxin which was reported to be a hepatotoxic and carcinogenic toxin (28,116,117). In addition, fumonisin B1 was reported to cause apoptosis in the liver of rats (118) and there is a possibility that it can be linked to esophageal cancer (119). FB1's main action is to disrupt sphingolipid metabolism which induces lipid peroxidation that will end up altering the cell membrane, causing cell death through apoptosis. It also has the potential of inhibiting protein synthesis and in higher concentration to inhibit DNA synthesis (120). It was proven to have some carcinogenic activity by stimulating ³H thymidine incorporation (121). Fumonisin mycotoxins are involved in the neural tube defects in animals, and it was hypothesized that it can have the same effect on humans. A cluster of anencephaly and spina bifida cases in Texas in the USA is related to fumonisins mycotoxins infection in corn products (122,123) and it was evaluated by the International Agency for Research that fumonisins have a cancer risk to humans. Its carcinogenicity is classified as group 2B which means probably carcinogenic (124). Another mycotoxin that affects humans on a cellular level is Patulin (Fig. 6) which is just as toxic at high concentration in but there is not enough evidence for natural poisoning, and its recorded poisonous effects are inconclusive (125).

Trichothecene mycotoxins were proven to be extremely potent inhibitors of eukaryotic protein synthesis, and were found to interfere with initiation, elongation, and termination stages of protein synthesis. They are the first mycotoxin from the trichothecene group known to inhibit peptidyl transferase activity during protein synthesis (126,127). The way trichothecenes inhibit peptidyl transferase is by binding to the same ribosome-binding site, leading to correlation with different functional groups and subsequently affecting the protein synthesis process (128). Among all Trichothecene mycotoxins, Deoxynivalenol is the most commonly found mycotoxin in different grains and once they are ingested, are reported to cause nausea, vomiting, and diarrhea with refusal for food and weight loss in animals (129). Deoxynivalenol was found to have a mitogen-activated protein kinase-mediated IL-8 expression in cloned human monocytes and peripheral blood mononuclear cells where the concentration of deoxynivalenol is from 250 to 1000 ng/ml. This will induce both IL-8 mRNA and IL-8 heteronuclear RNA which is an indicator of IL-8 transcription in human U937 monocytic cell line in a concentration-dependent manner (130).

Other Trichothecene mycotoxins that were found to have a great toxic effect on humans and animals are T-2 (Fig. 7) and diacetoxyscirpenol. Both were proven to be immunosuppressive in which they reduce resistance towards different infections and microbes (129,131). T-2 mycotoxin was proven to induce apoptosis at 10 ng/ml concentration (132) and was reported to inhibit the platelet aggregation and the release of dense bodies with a change in the membrane permeability (133). On the other hand, diacetoxyscirpenol is capable of inhibiting protein synthesis, has high immunomodulatory effects (134) and was reported to cause alimentary intoxication, food poisoning and induce hematological symptoms (135). Moreover, it was proven that T-2 and diacetoxyscirpenol are capable of causing several dermatological, gastrointestinal, and neurologic symptoms in humans and animals (136). Finally, T-2 and diacetoxyscirpenol are hypothesized to be associated with a humans disease called alimentary toxic aleukia in which the infected person will have skin inflammation, continuous vomiting, and damage to hematopoietic tissues that gives rise to blood cells and in advanced stages, cause central nervous system disorders, oral cavity, and severe bleeding from the nose, mouth, and vagina (111).

Zearalenone mycotoxins (F-2) (Fig. 10) are a unique mycotoxin that is biologically potent but is hardly toxic and resembles 17β-estradiol, which is an ovary hormone which humans produce to help the ovaries bind to estrogen receptors in the target cells. Therefore, it can be classified as a non-steroidal estrogen or mycoestroge (137) and used to reduce the postmenopausal symptoms in women (138). The major effects of Zearalenone are on the reproduction in females, where it affects reproductive organs and their function, eventually leading to a medical condition called hyperestrogenism (137). Zearalenone in its reduced form, zearalenol, is known to increase estrogenic activity (139) but it was proven to cause disrupted conception, abortion, and other problems in female pigs (140) and that can be hypothesized for humans as well.

The effects of mycotoxins on humans and animals will vary based on the nature of the toxins. While several are considered to be mutagenic; it was proven that Aflatoxin B1, Ochratoxin A and Sterigmatocystin are strong carcinogens (17). In a study made to identify the DNA-attacking ability of carcinogenic mycotoxins, six Penicillium toxins that include patulin, Citrinin, penicillic acid negative-luteoskyrin, positive-rugulosin, and PR-toxin, 5 aspergillus toxins including O-acetylsterigmatocystin, sterigmatocystin, O-acetyldihydrosterigmatocystin aflatoxin B1 and aflatoxin G1, and two fusarium toxins that include zearalenol-b and zearalenone, all these mycotoxins were found to have destructive ability towards genomic DNA (141). Although these 13 mycotoxins have the ability to attack the genomic DNA, 8 of them were found to be highly carcinogenic, including penicillic acid, citrinin, patulin, negative-luteoskyrin, positive-rugulosin, sterigmatocystin, aflatoxins B1, and G1 (141).

In another experiment conducted on mice, the effect of luteoskyrin and cyclochlorotine mycotoxins was investigated, and it was found that both toxins have hepatotoxic and hepatocarcinogenic activities on rats (142) with a hypothetical possibility to affect humans in a similar fashion. Fumonisin mycotoxins were found to be carcinogenic in rats due to their action in inhibiting ceramide synthase in vitro which in turn would enhance the production of tumor necrosis factor α (TNFα). This leads to the initiation of cells apoptosis (143). In addition, an experiment was conducted using 28 mycotoxins to investigate their action against hepatocytes of rats and mice. The results of the experiment showed that unknown carcinogenic mycotoxins such as 5,6-dimethoxysterigmatocystin, versicolorins A and B, averufin, xanthomegnin, luteosporin, and chrysazin, known carcinogenic mycotoxins such as aflatoxin B1 (Fig. 1), sterigmatocystin, luteoskyrin, Ochratoxin A (Fig. 5), azaserine, mitomycin C, and actinomycin D have the tendency to elicit DNA repair synthesis, which suggest the possibility of these mycotoxins to be genotoxic carcinogens (144). On the other hand, some carcinogenic mycotoxins such as penicillic acid, patulin, griseofulvin, and rugulosin were not found to elicit DNA repair synthesis and suggest the possibility of these mycotoxins being nongenotoxic carcinogens (144).

Many studies were conducted on the effect of mycotoxins on the biological system and their carcinogenicity-toxicity as mentioned before in this study but unfortunately, many of these studies were done on animal models and the action of mycotoxins in human biological systems were simply hypothesized and no solid data were generated for many mycotoxins. As mentioned earlier, food products that can be contaminated with mycotoxins include cereal (maize, sorghum, pearl millet, rice, and wheat), oil seeds (ground nut, soybean, sunflower, cotton), spices (chilies, black pepper, coriander, turmeric, and ginger), tree nuts (almonds, pistachio, walnuts, and coconut) and finally milk (27,229–232). In addition, aflatoxins are found in the contaminated tobacco leaves (233). Finally, aflatoxins can be present in dry soil, which can move to the underground water with rain and be ingested by humans and animals through the drinking water (234). All these food sources and food products are the basic food items for people around the world which make their contamination with mycotoxin considered as a major health concern for their high carcinogenic-toxic nature and potential in both animals and humans biological system (40).

It is well known that the availability of safe and edible food is essential for sustaining humans and animal life and the fact that food shortage was the reason behind provoking many wars, people started to store and preserve food on large scale for longer time to avoid any shortage that aid in storing and transporting food items in different forms of packages and containers. That happened right before the Second World War and continues to grow exponentially after that (235). As the food industry became bigger after the Second World War (236), packaging and distribution importance grew exponentially, and both processes became more susceptible to different weather conditions and the exposure to different microorganisms that may lead to food spoilage and contamination with different microorganisms including fungi and the mycotoxins they produce (237,238). An increase in the rates of testicular cancer incidences across Europe was observed post Second World War (239) and the reasons for it was not clear. It can hypothesized that the reasons for it can be linked to the increase in the stored food contamination with mycotoxins that can lead to testicular cancer (173,174).

During and after the 2nd World War, there was an increase in the incidents of lung cancer in Coastal Georgia specifically between males working in the shipyards in a warm and humid conditions (240). Due to the high humidity, tobacco leaves were contaminated with Aspergillus Flavus that produces aflatoxin B1 (23) which is a highly carcinogenic substance that was associated with different cancer types including lung cancer (161). No solid data were generated to support the induction of human lung cancer by aflatoxin B1 but it can be hypothesized that their involvement induce lung cancer since aflatoxin B1 inactivates GSTM1-1 that is responsible for the production of cytosolic Glutathione S-transferases that helps in detoxifying several carcinogenic electrophiles that cause lung cancer, hence additional lab experiments need to be conducted to confirm this involvement. Moreover, aflatoxin B1 was suggested to cause primary lung cancer also through the activation of GSTM1-1 (161) and this mycotoxin can be inhaled and cause a direct effect on the lung cells (157) and that can indicate the effect of mycotoxin in causing lung cancer, but very limited data were collected in this area and further studies need to be conducted.

Another study was conducted in Norway where it was found that the rates of breast cancer increased greatly during and after World War II and the reasons were not conclusive, and they linked the increase in the breast cancer rate to the change in the people's lifestyle (241). The fact that eating habits and food storage and transportation changed greatly during and after World War II, the possibility of food contamination increased greatly and fungal contamination started to become a common phenomenon in stored food and mycotoxin contamination could spread widely. Mycotoxins such as Aflatoxin B1 (Fig. 1) and Ochratoxin A (Fig. 5) were confirmed to suppress tumor suppressor genes BRCA1, BRCA2 and P52 (2,172). A hypothesis can be made to conclude the involvement of mycotoxin in inducing breast cancer around the world, but there is a huge gap in this area and additional laboratory work need to be established to confirm it. In addition, HER-1, HER-2 and the c-myc oncogenes were found to be overexpressed in many breast cancer cases (242–244) and that can also be related to the involvement of mycotoxins since they have the ability to impose different changes in the human genome but further studies need to be conducted.

Patulin (Fig. 6) causes an inactivation of the active site of protein tyrosine phosphatase (PTP) and this protein is a key regulator of intestinal epithelial barrier function and the active site of PTP contains a cysteine residue (Cys215). This is important and required for phosphatase activity and sulfhydryl-reacting compounds such as acetaldehyde decrease the transepithelial resistance (TER) through a covalent modification of cysteine residue Cys215 of the protein tyrosine phosphatase. This toxicity can lead to damage in the intestinal cells that eventually may lead to intestinal and stomach cancer.

Some mycotoxins such as Fumonisins can cause neurodegenerative disease (187,188). Their mode of action can be further studied to detect if they are involved in causing brain cancer and tumors by studying their effect on different genes in the brain. Fumonisins were also found to be involved in the development of neural tube defects among Mexican-American woman in south Texas which is characterized by defects in the brain, spine, or spinal cord of fetus in the first month of pregnancy (190) this involvement can also be used to hypothesize the involvement of Fumonisins in causing brain cancer in humans and further studies need to be conducted to support and confirm this hypothesis.

Zearalenone mycotoxin (F-2) major effects will be on the reproduction ability in females where they effects the reproductive organs, and their functions which will eventually lead to a medical condition called hyperestrogenism (137) and this phenomenon can be studied further to uncover if F-2 can be involved in developing ovary cancer. Finally, Fumonisin B1 was found to cause inhibition in the production of ceramide synthase which will lead to enhancing tumor necrosis factor α, production leading to apoptosis (143) and the ability of this mycotoxin to induce apoptosis can be used to detect the involvement of this mycotoxin in causing skin cancer.

Many mycotoxins have the ability of causing major changes to the human genome which may result in the development of cancer, and many other mycotoxins are capable of causing highly toxic effects on the biological systems they enter. The different mycotoxins that can cause cancer are Aflatoxin B1, Citrinin, Fumonisins, Patulin, Trichothecene and Zearalenone. The role of mycotoxins in causing cancer will vary with the type of mycotoxin and it will depend on the mode of action within the biological system.

Aflatoxin B1 (Fig. 1) can penetrate the cell membrane and attach to its DNA where it causes irreversible mutations. As soon as aflatoxin B1 enters the cells, they are metabolized by cytochrome P450, to aflatoxin-8, 9-epoxide which is highly reactive and unstable and requires the binding to a DNA or to the protein molecule in order to become more stable and it will form aflatoxin-N7-guanine that cause GC to TA transversion mutations which will directly affect the cell cycle by affecting the P53 gene which encodes for tumor suppressor protein that inhibits the development of cancer.

Ochratoxin A (Fig. 5) can cause an alteration of gene expression that results in affecting calcium homeostasis which will disrupt the different pathways regulated by the HNF4α and Nrf2 in the kidney, influence the expression of genes that are involved in DNA synthesis and repair, in response to DNA damage and it has a very small influence on the genes that are responsible for apoptosis. Ochratoxin A can cause genotoxicity by forming a DNA adduct and single cell death. Furthermore, Ochratoxin A can increase phosphorylation of a typical-PKC which in turn will lead to a downstream activation of ERK1 and ERK 2 and their substrate ELK1, ELK2 and p90RSK where PKC and the MEK-ERK MAP-kinase pathways activated by Ochratoxin A are involved in cell proliferation, cell survival, anti-apoptotic activity and most importantly renal cancer development. Ochratoxin A is suggested to have a renal carcinogenesis effect. Its mode of action is by means of direct genotoxicity through covalent DNA adduct formation. The effects of aflatoxin B1 and Ochratoxin A in causing breast cancer and lung cancer are demonstrated in only a few studies and additional studies need to be conducted in order to confirm the course of action which will help in controlling and reducing the rates of these cancers which are considered as the most common cancers in the world.

Citrinin produced micronuclei and DNA migration and it has the potential of inducing micronuclei. Citrinin would cause DNA damage which would increase the risk of cancer in humans. Citrinin can induce chromosomal aberrations in both human and rat livers and it can cause complex translocations within the cellular DNA at a high frequency and it is capable of inducing defects in chromosomal coiling which may lead to the formation of DNA adducts. Apart from this, it can cause DNA fragmentation and apoptosis and finally, it can cause a mitotic arrest and CREST-positive micronuclei where it will induce the formation of micronuclei containing a whole chromosome or chromatids and will eventually lead to cancer development.

Fumonisins (Fig. 4) are capable of inhibiting the biosynthesis of sphingosine and the complex sphingolipids by inhibiting the enzyme ceramide synthase. That, in turn, will lead to the increase in free sphinganine and the free sphingoid bases which are toxic in cells, and that will inhibit the growth, increase cell death, and initiate involvement in mitogenicity that would lead to the development of cancer.

Patulin (Fig. 6) will cause an inactivation of the active site of protein tyrosine phosphatase (PTP) and this protein is a key regulator of intestinal epithelial barrier function. The active site of PTP contains a cysteine residue (Cys215) which is important and required for phosphatase activity and sulfhydryl-reacting compounds such as acetaldehyde. Acetaldehyde decreases the transepithelial resistance (TER) through a covalent modification of cysteine residue Cys215 of the protein tyrosine phosphatase and this toxicity can lead to damage in the intestinal cells that may eventually lead to intestinal and stomach cancer.

T-2, a trichothecene mycotoxin is capable of inducing breaks in the DNA of lymphocytes when administered in vivo and in vitro once the fibroblast cells are treated with this mycotoxin combined with ³H thymidine. In addition, Nivalenol, a trichothecene mycotoxin is also involved in causing chromatid exchange in cells and it can cause DNA damage and that makes it a potential genotoxic agent. Finally, trichothecene mycotoxin can inhibit the proliferation and Ig production in the mitogen-stimulated human lymphocytes and it can induce apoptosis, the migration of sister chromatids as well as cause protein synthesis inhibition. The action of T-2 and Nivalenol on a cellular level can be responsible for the development of tumors and cancer.

Zearalenone (Fig. 10) shows hormonal activity in many animal species which makes it genotoxic, carcinogenic or both at the same time, and it can impose changes in the reproductive organs and systems of many laboratory animals such as mice and rats and different domestic animals such as horses. Thus, Zearalenone is capable of causing reproductive organ cancer in both man and animal.

The cancers that can be caused by mycotoxins include liver cancer, kidney cancer, esophageal cancer, lung cancer, renal cancer, breast cancer, testicular cancer, stomach cancer and reproductive organ cancer. Considering the danger caused by mycotoxins, additional investigations need to be conducted to confirm the ability of each mycotoxin in inducing cancer, as stated above.