Hello again,
We are going to continue with our current series: “Common Questions with Dr. Matt.” Today’s common question is “Does mold and mycotoxins exposure contribute to cancer?” The short answer is yes, however, we are going to go through the different types of mycotoxins can lead to cancer formation, how it promotes cancer growth, and in what tissues/organs this is most likely to happen. The four mycotoxins that have been found to be carcinogenic (meaning that it can cause cancer) are Aflatoxin, Ochratoxin A, Zearalenone, and Citrinin.
All of these chemicals are products of different mold species, such as Aspergillus and Penicillium. The exposure to these chemicals can come through the ingestion of contaminated foods, however, more likely is from mold contamination in homes. A discussion about the debate of on weather mycotoxin exposure come from food or building exposure can be seen here (LINK). With most of the samples I have seen exposure most likely has come from inhalation or absorption through the skin.
Aflatoxin is mainly produced by the Aspergillus genus of mold. It first became known during several feed outbreaks in the 1960s (1). Because many of these foods were first studied because of food contamination, and because mycotoxicosis is still a problem in developing countries it is still widely believed that mycotoxin exposure only comes through food. However, no matter it’s route of entry, once it is inside the body it is regarded carcinogenic. The International Agency for Research on Cancer evaluated aflatoxin as a group 1 carcinogen(2). This indicates that Aflatoxin is extremely likely to cause cancer in those exposed over an extended period of time. However, Aflatoxin can cause other problems besides causing cancer. As depicted in Figure 1 from a paper by Noreddine Benkerroum (3),there are three main sources of damage. The first is the genotoxicity (or cancer formation), second is acute toxicity (which is caused by cellular damage), and third is the dysregulation of the immune response (which leads to secondary inflections such as Clostridia.
Aflatoxin’s mechanism to damaging DNA is through binding (epoxidation) to the DNA itself. The AFB1 form of Aflatoxin forms an adduct to the DNA base guanine(4). These adducts lead to breaks in the DNA, which then leads to mutations. These mutations are most likely random, however there is a report that the mutations are somewhat selective for the p53 tumor suppressor gene(5). However, mutations to growth inducers or suppressors could lead to cancerous cells and lead to tumors. In addition to DNA break formation, aflatoxin can cause DNA damage through the creation of oxidative stress. AFB1 creates reactive oxygen species (ROS),which then activates mitochondrial ROS-dependent signal pathways(6).
Aflatoxin has been linked to multiple types of cancers. One of the most common is liver cancer. Because AFB1. AFB1 has contributed to the formation of about 4.6-28.2% of the hepatocellular carcinoma cases worldwide (7). The second type of cancer is gastrointestinal cancer. After AFB1 passes through the liver (which is the most common location of cancer caused by AFB1), it will be deposited into the intestine. In most instances AFB1 is more carcinogenic thanAFM1, a metabolite, however in the intestine it has been shown that AFM1 may have higher carcinogenicity because of its retention due in the digestive tract due to its higher polarity (8). The third type of cancer caused by Aflatoxin is lung cancer. Studies have shown that individuals exposed to AFB1 in the air can develop lung cancer (9). AFB1 is bioactivated by the cytochrome P450enzymes (CYP450) in the lungs, which causes the AFB1 to become more carcinogenic. Polycyclic aromatic hydrocarbons (PAHs) cause more CYPs to be produce, which can increase the harmful exposure of AFB1 (10).
Ochratoxin A (OTA) is one of the most common mycotoxins we see in buildings. It is produced by multiple species of mold. There are many different types of Aspergillus that produce OTA and a few different species of Penicillium (11, 12). As of 1993 OTA has been grouped as 2B by the IARC, which means that it is possibly carcinogenic to humans. As seen in Figure 2 from Malir et al, OTA produces ROS molecules in cells. These ROS elements lead to DNA breaks, which then can lead to cancer formation.
The third mycotoxin that has links to cancer is zearalenone(ZEN). It is produced by Fusarium species of fungus (13). ZEN shares structural similarity with the hormone 17β-estradiol, which allows it to activate the estrogen receptors. ZEN and its metabolites have different estrogenic potencies, which leads to different affects of fertility and cancer formation(14). In humans ZEN has been shown to play a role in reproductive organ cancer in humans(15). These affects can be seen in figure 3 from Kowalska et al. Their paper shows that ZEN increase ROS, DNA damage, G2/M cell cycle arrest, and NRF2 expression; which all can lead to cancer cell formation (16).
I hope this entry has been helpful for you. Obviously, I tried to simplify a very complex situation. However, the take home is that multiple mycotoxins can increase your risk for cancer and if you are exposed to a high concentration, you should seek a practitioner to help you detoxify as well as a mold remediation company to help to remedy your living situation.
Resource Materials
1. A.G. Oettle, The aetiology of primary carcinoma of the liver in Africa: acritical appraisal of previous ideas with an outline of the mycotoxin hypothesis. S Afr Med J 39, 817-825 (1965).
2. H. Vainio, E. Heseltine, J. Wilbourn, Report on an IARC working group meeting on some naturally occurring substances. Int J Cancer 53, 535-537 (1993).
3. N. Benkerroum, Retrospective and Prospective Look at Aflatoxin Research and Development from a Practical Standpoint. Int J Environ Res Public Health 16(2019).
4. J.D. Groopman et al., Molecular epidemiology of aflatoxin exposures: validation of aflatoxin-N7-guanine levels in urine as a biomarker in experimental rat models and humans. Environ Health Perspect 99, 107-113 (1993).
5. K. Mace et al., Aflatoxin B1-induced DNA adduct formation and p53 mutations in CYP450-expressing human liver cell lines. Carcinogenesis 18, 1291-1297 (1997).
6. Y. Liu, W. Wang, Aflatoxin B1 impairs mitochondrial functions, activates ROS generation, induces apoptosis and involves Nrf2 signal pathway in primary broiler hepatocytes. Anim Sci J 87, 1490-1500 (2016).
7. B. Kucukcakan, Z. Hayrulai-Musliu, Challenging Role of Dietary Aflatoxin B1Exposure and Hepatitis B Infection on Risk of Hepatocellular Carcinoma. Open Access Maced J Med Sci 3, 363-369 (2015).
8. J.M. Cullen, B. H. Ruebner, L. S. Hsieh, D. M. Hyde, D. P. Hsieh, Carcinogenicityof dietary aflatoxin M1 in male Fischer rats compared to aflatoxin B1. Cancer Res 47, 1913-1917 (1987).
9. R.B. Hayes, J. P. van Nieuwenhuize, J. W. Raatgever, F. J. ten Kate, Aflatoxinexposures in the industrial setting: an epidemiological study of mortality. Food Chem Toxicol 22, 39-43 (1984).
10. T.R. Van Vleet, P. J. Klein, R. A. Coulombe, Jr., Metabolism of aflatoxin B1 by normal human bronchial epithelial cells. J Toxicol Environ Health A 63,525-540 (2001).
11. A. Ciegler, D. I. Fennell, G. A. Sansing, R. W. Detroy, G. A. Bennett, Mycotoxin-producing strains of Penicillium viridicatum: classification into subgroups. Appl Microbiol 26, 271-278 (1973).
12. T.O. Larsen et al., Production of mycotoxins by Aspergillus lentulus and other medically important and closely related species in section Fumigati. MedMycol 45, 225-232 (2007).
13. C. Frizzell et al., Endocrine disrupting effects of zearalenone, alpha- and beta-zearalenol at the level of nuclear receptor binding and steroidogenesis. Toxicol Lett 206, 210-217 (2011).
14. E.P. o. C. i. t. F. Chain et al., Appropriateness to set a group health based guidance value for nivalenol and its modified forms. EFSA J 15, e04751 (2017).
15. M.A. Ahmed Adam, Y. M. Tabana, K. B. Musa, D. A. Sandai, Effects of different mycotoxins on humans, cell genome and their involvement in cancer (Review). Oncol Rep 37, 1321-1336 (2017).
16. K. Kowalska, D. E. Habrowska-Gorczynska, K. Dominska, K. A. Urbanek, A. W. Piastowska-Ciesielska, ERbeta and NFkappaB-Modulators of Zearalenone-Induced Oxidative Stress in Human Prostate Cancer Cells. Toxins (Basel) 12 (2020).
