Table 4.

Mechanisms of carcinogenicity caused by mycotoxins.

Mechanism/Toxin	Description
DNA Damage and Mutagenicity	Aflatoxins, particularly aflatoxin B1 (AFB1), are potent carcinogens that exert their effects by directly damaging DNA. Once ingested, AFB1 is metabolized in the liver by cytochrome P450 enzymes into a reactive intermediate, aflatoxin B1-8,9-epoxide. This metabolite can bind covalently to DNA, forming DNA adducts, particularly at the guanine base, leading to mutations. One of the most common mutations caused by AFB1 is the G-to-T transversion in the TP53 tumor suppressor gene, which is crucial in regulating cell growth and apoptosis. Mutations in TP53 result in uncontrolled cell proliferation and are strongly associated with hepatocellular carcinoma (liver cancer). Aflatoxin-induced DNA damage is thus a key mechanism driving the initiation of cancer [57].
Oxidative Stress	Mycotoxins can also induce oxidative stress, a condition where there is an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify them. Aflatoxins and other mycotoxins, such as fumonisins and ochratoxins, can generate ROS during their metabolism, leading to oxidative damage to cellular components like DNA, proteins, and lipids. This oxidative damage can cause mutations, promote inflammation, and contribute to the initiation and progression of cancer. In addition, chronic oxidative stress can disrupt cellular signaling pathways that control cell growth and apoptosis, further promoting carcinogenesis [58].
Cell Cycle Disruption and Apoptosis Inhibition	Mycotoxins can interfere with normal cell cycle regulation, contributing to the development of cancer. For instance, fumonisin B1, commonly found in maize, disrupts sphingolipid metabolism by inhibiting ceramide synthase. Sphingolipids are essential in regulating cell growth, differentiation, and apoptosis. The disruption of sphingolipid pathways can impair apoptosis (programmed cell death), allowing damaged cells to survive and proliferate uncontrollably, a hallmark of cancer development. Additionally, by blocking apoptosis, mycotoxins facilitate the survival of cells with DNA damage, increasing the likelihood of malignant transformation [59].
Immune Suppression	Chronic exposure to certain mycotoxins can lead to immune suppression, which further increases cancer risk. Aflatoxins, for example, are known to impair the immune system by reducing the production and function of immune cells like T-cells and macrophages. This weakened immune response hampers the body’s ability to recognize and eliminate cancerous or pre-cancerous cells. Furthermore, immune suppression can promote the persistence of viral infections, such as hepatitis B virus (HBV), which is a significant cofactor in aflatoxin-induced liver cancer. Individuals who are exposed to both aflatoxins and HBV are at a much higher risk of developing liver cancer due to the combined effects of viral infection and toxin-induced DNA damage [60].
Epigenetic Modifications	In addition to directly damaging DNA, mycotoxins can cause epigenetic changes that alter gene expression without affecting the underlying DNA sequence. For instance, mycotoxins like ochratoxin A have been shown to induce changes in DNA methylation and histone modifications, which can silence tumor suppressor genes or activate oncogenes. These epigenetic alterations can promote carcinogenesis by disrupting normal cellular functions and facilitating uncontrolled cell growth [61].
Zearalenone (ZEA)	Zearalenone is a nonsteroidal estrogenic mycotoxin primarily produced by Fusarium species, commonly found in cereals and grains. The carcinogenicity of ZEA is primarily linked to its estrogenic properties, as it mimics the action of natural estrogens by binding to estrogen receptors (ERs) in target tissues. This interaction leads to hormonal disruption, which promotes the proliferation of estrogen-sensitive cells, particularly in reproductive tissues. Over time, the hyperproliferation of these cells increases the risk of hormone-dependent cancers, such as breast, ovarian, and endometrial cancers. ZEA’s ability to activate ER signaling can also induce DNA damage and oxidative stress, further contributing to its carcinogenic potential. Oxidative stress generates reactive oxygen species (ROS), which can cause mutations, impair DNA repair mechanisms, and lead to genomic instability. Additionally, ZEA may disrupt normal cell cycle regulation, promoting abnormal cell division and enhancing the risk of cancer development [62].
Patulin	Patulin, produced by Penicillium and Aspergillus species, is a mycotoxin primarily found in apples and apple products. Its carcinogenicity is associated with its ability to induce oxidative stress and DNA damage. Patulin promotes the generation of ROS, which can damage cellular components, including lipids, proteins, and nucleic acids. This oxidative damage leads to mutations and chromosomal aberrations, increasing the risk of malignant transformations. Furthermore, patulin interferes with key cellular pathways involved in apoptosis (programmed cell death) and cell cycle regulation. By inhibiting apoptosis, patulin allows damaged cells to survive and proliferate, which may contribute to cancer initiation and progression. Patulin also impairs the function of tumor suppressor proteins, such as p53, which generally help to maintain genomic integrity by halting the cell cycle in response to DNA damage. When p53 function is disrupted, cells with damaged DNA can continue to divide uncontrollably, further contributing to the carcinogenic process [63].