Fatigue Due to Mold Exposure: Pathophysiology

Tolle Causam

Lauren Tessier, ND

Illness resulting from mold and mycotoxin exposure is gaining more traction and attention. As the paradigm shift occurs, mold and mycotoxin-induced illness (MMII) should be brought to the forefront of clinical education, both in school curriculum and continuing education. In the busy life of the clinician, soundbites and snippets of clinical management are considered gold. The difficulty therein is that MMII is multifaceted, and, as such, comes in different forms, including allergy, infection, colonization, mycotoxicosis, and Chronic Inflammatory Response Syndrome (CIRS) – potentially in addition to other less defined clinical pictures. As a result, management of MMII cannot be boiled down into isolated soundbites, lest we aim to overstate and under-deliver, thus failing case management. A perfect example of this is fatigue as a symptom of MMII.

The definition of fatigue, although simple at face value, can be difficult to truly pin down. It can be considered a standalone symptom, and the word itself is often used interchangeably with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Although CFS may include a constellation of symptoms beyond fatigue, this can still be the sole and major symptom. For the sake of this article, fatigue as a standalone symptom will be examined. However, there are some key pieces of research that demonstrate the remarkable interplay between fatigue and mold exposure which the reader should keep in mind. A recent article, published in 2019, reported that 39.4% of CFS patients sampled reported that their symptoms of post-exertional malaise were triggered by a mold exposure.1 Moreover, another study demonstrated that 93% of CFS patients were found to have at least 1 mycotoxin in their urine, while nearly 30% of CFS patients had more than 1 mycotoxin present in their urine.2

However, correlations between fatigue and mold exposure can occur in real-world cases where CFS/ME is not the topic of investigation. A human case study of 12 people exposed to Alternaria tenuis in in their workplace reported fatigue as a prominent symptom.3 Moreover, a study of school children in Malaysia demonstrated a correlation between total fungal DNA and tiredness in 22.1% of study participants. Further regression analysis revealed positive associations between symptoms of fatigue and the presence of Aspergillus versicolor and/or the mycotoxin verrucarol.4 While there are plenty of similar pieces of research in the literature, one will be hard-pressed to find an article that goes so far as to investigate the pathophysiology of the reported fatigue. This is where in-vitro and animal studies help to fill the knowledge gap.

In the clinical setting, fatigue is a common complaint of MMII clients; however, the pathophysiology is rarely sought and thus not properly addressed. This is understandable given that clinicians are overworked, pressed for time, and concerned about insurance coverage and the patient perception of cost and value. As result, MMII clients may undergo a litany of presumptive treatments aimed at addressing fatigue, but without resolution. The result is wasted time and money and, in some cases, exacerbation of illness and potentially damaged rapport.

Understanding the Mechanisms

In order to properly treat MMII-related fatigue, one must first attempt to understand its pathophysiology. Admittedly, there numerous ways that mold and mycotoxin exposure can cause fatigue; however, the length of this article will limit us to examining the implications of decreased oxygenation, decreased mitochondrial functioning, and neurotransmitter imbalance. Decreased oxygenation can result from reduced hemoglobin levels, poor hemoglobin functionality, and compromised blood delivery. Decreased mitochondrial functioning can occur through frank mitochondrial damage, lipid peroxidation and oxidative damage, altered mitochondrial metabolism, and nutrient deficiencies.

Decreased Oxygenation

Oxygenation that is dependent upon hemoglobin health is impacted by the nutrients iron, B12, and folate. Iron deficiency is often implicated in fatigue, and is often the first factor to be considered when fatigue is initially reported. Iron depletion occurs via 2 mechanisms in MMII. Research demonstrates that the mycotoxins ochratoxin A5 and citrinin6,7 can sequester Fe3+, thus possibly interfering with host availability. Further exacerbating hemoglobin dysfunction, fungal infections may also extract heme,8-13 from hemoglobin, thereby causing decreased functionality, damage, and potentially frank decreases in hemoglobin levels.

The interplay of iron with MMI becomes complicated with the introduction of “nutritional immunity,” which is the process by which, in the face of an infection, the host’s system will attempt to sequester nutrients in order to control the pathogenicity of an offending agent.14,15 In the case of fungal infections, the body will sequester iron, thereby removing it from circulation. As a result, it can no longer be of use to the infective agent, nor to the host. The patient may appear as iron “deficient” if total serum iron is the sole parameter examined. It is imperative that a full laboratory work-up is done in order to assess whether iron sequestration is occurring, as indicated by possible elevations in hepcidin, lactoferrin, ferritin, and haptoglobin in the face of a low serum iron.16 In these cases, it is important to identify and treat the infection before supplementing with iron, as supplementation can perpetuate fungal growth17-20 and mycotoxin production.20,21

Yet, mycotoxin effects on oxygenation via hemoglobin disruption do not stop with iron. Decreased hemoglobin may be associated with a B12- or folate-induced macrocytic anemia, arising from mycotoxin exposure. For instance, the mycotoxin deoxynivalenol (DON) interferes with absorption of 5-methylenetetrahydrofolate (5-MTHF),22 while the group of mycotoxins called “fumonisins” can hinder folate transport23 – accomplished in part by interfering with the transcription (and thus proper functioning) of folate receptors.24,25 Research also demonstrates that the ileum, which is the foci of B12 absorption in the gut, is damaged by aflatoxin,26 fumonisins,27,28 and DON.29-32 Fatigue due to macrocytic anemia is just one possible issue resulting from interruption of these nutrients; let us not forget the implications of disruption of the methylation pathway.

Nutrient levels are not the only means by which hemoglobin can be impacted by mycotoxin exposure. In animal studies, frankly low hemoglobin levels have been correlated with exposure to secondary metabolites of Stachybotrys,33 as well as exposure to other mycotoxins,49 such as ochratoxin,34-38 fusarium-based mycotoxins,39-41 fumonisin B-1,42 T-2 toxin,43 aflatoxin,44,45 and also combinations of mycotoxins.46-48 In animals, the mycotoxin sporidesmin has been shown to promote the conversion of hemoglobin to non-functional methemoglobin and, in some instances, to cause irreversible oxidative damage, as indicated by the presence of Heinz bodies.50

Decreased oxygenation via depressed hemoglobin levels or depressed functionality of hemoglobin is just one etiology of the fatigue seen with MMI. Additionally of concern is decreased oxygenation as a result of decreased blood delivery. Mycotoxins are widely known to be cardiotoxic51-68; in the cardiomyocyte, they have been shown to reduce mitochondrial functioning59,66 and disrupt calcium balance,64,67 which may potentially correlate with the findings of reduced contractility55-57,68 and reduced cardiac output.51-53,56,60,61-63,69

Decreased Mitochondrial Functioning

Mitochondria are the powerhouses of the cells; their proper functionally is imperative to healthy energy levels. Mycotoxins are known disruptors of mitochondrial functioning, as mediated by oxidative stress70-72; this can result in disruptions of membrane potential, calcium homeostasis, and enzymes such as cytochrome oxidase and NADH dehydrogenase.73-77 Moreover, mycotoxins such as ochratoxin A/B/C, T-2, citrinin, DON (and analogues), stergimatocystin, zearalenone, the aflatoxin group, the fumonisin group, beauvericin, and others are known initiators of lipid peroxidation,5,71,77,109-128 which can also injure mitochondrial functionality.

Further exacerbating mitochondrial dysfunction, the interface between nutrient status and MMII, once again presents itself. Zinc is required for proper mitochondrial functioning, and numerous mycotoxins have been implicated in zinc issues. For example, the fusariotoxin toxin T-2 interferes with zinc absorption,78 ochratoxin A causes a reduction in intracellular zinc concentrations,79 and aflatoxin exposure has been correlated with zinc deficiencies.80 Once again, nutritional immunity should be considered in the face of what appears to be a zinc “deficiency” at first glance. When the host is faced with a fungal infection, extracellular zinc is sequestered by various means, including zinc transporters and zinc-binding proteins such as calprotectin. Keeping zinc sequestered in different intracellular compartments, such as lysosomes, zincosomes, and endosomes, translates into less bioavailable zinc for the mitochondria, thus potentially interfering with mitochondrial function. As adequate zinc levelsare required for both fungal survival81-101 and mycotoxin production,102 the correction of nutritional immunity-induced zinc “deficiencies” may wreak havoc if not properly ordered with respect to infection management.

Neurotransmitter Imbalance

Important to the etiology of fatigue is the relationship of mycotoxins to dopamine levels. Neurotransmitter imbalances are theorized to have an impact on fatigue, particularly an increased ratio of serotonin to dopamine.103 Studies have correlated fatigue to lower levels of dopamine precursors104 and decreased basal ganglia activation.105 Some mycotoxins, able to cross the blood-brain barrier, can interfere with proper neurotransmitter production and function. Animal research demonstrates a decreased level of dopamine with DON106 exposure. Meanwhile, ochratoxin A causes depletion of striatal dopamine107 and impairment of phenylalanine hydroxylase activity,108 which may also lead to a decrease in dopamine synthesis.

Summary

The goal of this article is to remind the physician that although a patient’s symptoms may look like a deficiency-induced fatigue at first glance, there may be a deeper cause than a simple nutritional deficit. Always test nutrient status before implementing an intervention, and in instances where mold exposure is of high clinical suspicion, consider ordering urine mycotoxin testing, fungal serology, or antigen detection to assess underlying cause. For iron assessment, consider running a CBC (with MCV and hemoglobin), total iron, TIBC, transferrin, ferritin, and haptoglobin. For B12 and folate assessment, consider a CBC (with MCV and hemoglobin), homocysteine, and methylmalonic acid, at a minimum; to further assess cellular utilization, RBC folate, serum folate, and serum cobalamin may also be useful. For zinc assessment, consider zinc (serum or plasma) and alkaline phosphatase; further assessment may involve measurements of copper (serum) and ceruloplasmin.

Assessment of nutrient status, in conjunction with MMII assessment, is especially important in instances of nutritional immunity associated with fungal infection. Proper ordering of treatment is of utmost importance, as correcting a presumed “deficiency” prior to identifying and clearing an infection may worsen the patient. The difficulty, therein, is that serology and antigen detection testing for fungal infections are flawed. However, if these tests do return positive results, it is important that measures be taken to eradicate infection (potentially colonization) before correcting the “deficiency.” It is in such scenarios that it is reasonable to use antifungal interventions, which is in juxtaposition with many current practices of providing an antifungal for a positive urine mycotoxin test. The latter increases the risk of antifungal resistance and also increases the risk of mortality for millions of people worldwide each year, including immunocompetent and immunocompromised people alike. If nutrient screening does not reveal any actionable deficiencies, but there is a high suspicion or known mold exposure or elevated urine mycotoxins, consider testing for oxidative damage. Lipid peroxide testing can be accomplished via malondialdehyde, commonly referred to as a TBARS assay or lipid peroxide testing. Additional oxidative stress assessments can include 8-OH-deoxyguanosine and GGT levels.

References:

  1. Holtzman CS, Bhatia S, Cotler J, Jason LA. Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey. Diagnostics (Basel). 2019; 9(1). pii: E26. doi: 10.3390/diagnostics9010026.
  2. Brewer JH, Thrasher JD, Straus DC, et al. Detection of mycotoxins in patients with chronic fatigue syndrome. Toxins. 2013;5(4):605-617.
  3. Anyanwu EC, Kanu I, Nwachukwu NC, Saleh MA. Chronic environmental exposure to Alternaria tenuis may manifest symptoms of neuropsychological illnesses: a study of 12 cases. Environm Manage. 2005;9(3):45-51.
  4. Norbäck D, Hashim JH, Cai GH, et al. Rhinitis, Ocular, Throat and Dermal Symptoms, Headache and Tiredness among Students in Schools from Johor Bahru, Malaysia: Associations with Fungal DNA and Mycotoxins in Classroom Dust. PLoS One. 2016;11(2):e0147996.
  5. Omar RF, Hasinoff BB, Mejilla F, Rahimtula AD. Mechanism of ochratoxin a stimulated lipid peroxidation. Biochem Pharmacol. 1990;40(6):1183-1191.
  6. Da Lozzo EJ, Mangrich AS, Rocha MEM, et al. Effects of citrinin on iron-redox cycle. Cell Biochem Funct. 2002;20(1):19-29.
  7. Ribeiro SM, Campello AP, Chagas GM, Klüppel ML. Mechanism of citrinin-induced dysfunction of mitochondria. VI. Effect on iron-induced lipid peroxidation of rat liver mitochondria and microsomes. Cell Biochem Funct. 1998;16(1):15-20.
  8. Kuznets G, Vigonsky E, Weissman Z, et al. A relay network of extracellular heme-binding proteins drives C. albicans iron acquisition from hemoglobin. PLoS Pathog. 2014;10(10):e1004407.
  9. Bailão EF, Parente JA, Pigosso LL, et al. Hemoglobin uptake by Paracoccidioides spp. is receptor-mediated. PLoS Negl Trop Dis. 2014;8(5):e2856.
  10. Manns JM, Mosser DM, Buckley HR. Production of a hemolytic factor by Candida albicans. Infect Immun. 1994;62(11):5154-5156.
  11. Nasser L, Weissman Z, Pinsky M, et al. Structural basis of haem-iron acquisition by fungal pathogens. Nat Microbiol. 2016;1(11):16156.
  12. Bairwa G, Hee Jung W, Kronstad JW. Iron acquisition in fungal pathogens of humans. Metallomics. 2017;9(3):215-227.
  13. Malavia D, Crawford A, Wilson D. Nutritional Immunity and Fungal Pathogenesis: The Struggle for Micronutrients at the Host-Pathogen Interface. Adv Microb Physiol. 2017;70:85-103.
  14. Hennigar SR, McClung JP. Nutritional Immunity: Starving Pathogens of Trace Minerals. Am J Lifestyle Med. 2016;10(3):170-173.
  15. Gerwien F, Skrahina V, Kasper L, et al. Metals in fungal virulence. FEMS Microbiol Rev. 2018;42(1). doi: 10.1093/femsre/fux050.
  16. Northrop-Clewes CA. Interpreting indicators of iron status during an acute phase response–lessons from malaria and human immunodeficiency virus. Ann Clin Biochem. 2008;45(Pt 1):18-32.
  17. Reed C, Ibrahim A, Edwards JE, et al. Deferasirox, an iron-chelating agent, as salvage therapy for rhinocerebral mucormycosis. Antimicrob Agents Chemother. 2006;50(11):3968-3969.
  18. Ibrahim AS, Edwards JE, Fu Y, Spellberg B. Deferiprone iron chelation as a novel therapy for experimental mucormycosis. J Antimicrob Chemother. 2006;58(5):1070-1073.
  19. Leal SM, Roy S, Vareechon C, et al. Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum. PLoS Pathog. 2013;9(7):e1003436.
  20. Cuero R, Ouellet T. Metal ions modulate gene expression and accumulation of the mycotoxins aflatoxin and zearalenone. J Appl Microbiol. 2005;98(3):598-605.
  21. Weinberg ED. Roles of trace metals in transcriptional control of microbial secondary metabolism. Biol Met. 1990;2(4):191-196.
  22. Hunder G, Schümann K, Strugala G, et al. Influence of subchronic exposure to low dietary deoxynivalenol, a trichothecene mycotoxin, on intestinal absorption of nutrients in mice. Food Chem Toxicol. 1991;29(12):809-814.
  23. Marasas WF, Riley RT, Hendricks KA, et al. Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize. J Nutr. 2004;134(4):711-716.
  24. Pellanda H, Forges T, Bressenot A, et al. Fumonisin FB1 treatment acts synergistically with methyl donor deficiency during rat pregnancy to produce alterations of H3- and H4-histone methylation patterns in fetuses. Mol Nutr Food Res. 2012;56(6):976-985.
  25. Stevens VL, Tang J. Fumonisin B1-induced Sphingolipid Depletion Inhibits Vitamin Uptake via the Glycosylphosphatidylinositol-anchored Folate Receptor. J Biol Chem. 1997;272(29):18020-18025.
  26. Akinrinmade FJ, Akinrinde AS, Amid A. Changes in serum cytokine levels, hepatic and intestinal morphology in aflatoxin B1-induced injury: modulatory roles of melatonin and flavonoid-rich fractions from Chromolena odorata. Mycotoxin Res. 2016;32(2):53-60.
  27. Grenier B, Schwartz-Zimmermann HE, Caha S, et al. Dose-dependent effects on sphingoid bases and cytokines in chickens fed diets prepared with fusarium verticillioides culture material containing fumonisins. Toxins (Basel). 2015;7(4):1253-1272.
  28. Antonissen G, Croubels S, Pasmans F, et al. Fumonisins affect the intestinal microbial homeostasis in broiler chickens, predisposing to necrotic enteritis. Vet Res. 2015;46:98.
  29. Waśkiewicz A, Beszterda M, Kostecki M, et al. Deoxynivalenol in the gastrointestinal tract of immature gilts under per os toxin application. Toxins (Basel). 2014;6(3):973-987.
  30. Wu L, Liao P, He L, et al. Dietary L-arginine supplementation protects weanling pigs from deoxynivalenol-induced toxicity. Toxins (Basel). 2015;7(4):1341-1354.
  31. Lessard M, Savard C, Deschene K, et al. Impact of deoxynivalenol (DON) contaminated feed on intestinal integrity and immune response in swine. Food Chem Toxicol. 2015;80:7-16.
  32. Zielonka Ł, Wiśniewska M, Gajecka M, et al. Influence of low doses of deoxynivalenol on histopathology of selected organs of pigs. Pol J Vet Sci. 2009;12(1):89-95.
  33. Piecková E, Hurbánková M, Cerná S, et al. Inflammatory and haematotoxic potential of indoor Stachybotrys chartarum (Ehrenb.) Hughes metabolites. Arh Hig Rada Toksikol. 2009;60(4):401-409.
  34. Huff WE, Chang CF, Warren MF, Hamilton PB. Ochratoxin A-induced iron deficiency anemia. Appl Environ Microbiol. 1979;37(3):601-604.
  35. Borzecki A, Borzecka H, Sobieszek-Dziuba U, et al. Vitamin E influence on selected parameters in rats after ochratoxin A intoxication. Ann Univ Mariae Curie Sklodowska Med. 2001;56:231-235.
  36. Agawane SB, Lonkar PS. Effect of probiotic containing Saccharomyces boulardii on experimental ochratoxicosis in broilers: hematobiochemical studies. J Vet Sci. 2004;5(4):359-367.
  37. Kibugu JK, Ngeranwa JJ, Makumi JN, et al. Aggravation of pathogenesis mediated by ochratoxin A in mice infected with Trypanosoma brucei rhodesiense. Parasitology. 2009;136(3):273-281.
  38. Huff WE, Kubena LF, Harvey RB. Progression of ochratoxicosis in broiler chickens. Poult Sci. 1988;67(8):1139-1146.
  39. Chattopadhyay P, Upadhyay A, Agnihotri A, et al. Comparative Hematoxicity of Fusarium Mycotoxin in Experimental Sprague-Dawley Rats. Toxicol Int. 2013;20(1):25-29.
  40. Chowdhury SR, Smith TK, Boermans HJ, et al. Effects of feeding blends of grains naturally contaminated with Fusarium mycotoxins on performance, metabolism, hematology, and immunocompetence of ducklings. Poult Sci. 2005;84(8):1179-1185.
  41. Dänicke S, Winkler J, Meyer U, et al. Haematological, clinical-chemical and immunological consequences of feeding Fusarium toxin contaminated diets to early lactating dairy cows. Mycotoxin Res. 2017;33(1):1-13.
  42. Deepthi BV, Somashekaraiah R, Poornachandra Rao K, et al. Lactobacillus plantarum MYS6 Ameliorates Fumonisin B1-Induced Hepatorenal Damage in Broilers. Front Microbiol. 2017;8:2317.
  43. Rafai P, Tuboly S, Bata A, et al. Effect of various levels of T-2 toxin in the immune system of growing pigs. Vet Rec. 1995;136(20):511-514.
  44. Dönmez N, Dönmez HH, Keskin E, Kısadere İ. Effects of aflatoxin on some haematological parameters and protective effectiveness of esterified glucomannan in Merino rams. ScientificWorldJournal. 2012;2012:342468.
  45. Tung HT, Cook FW, Wyatt RD, Hamilton PB. The anemia caused by aflatoxin. Poult Sci. 1975;54(6):1962-1969.
  46. Huang S, Zheng N, Fan C, et al. Effects of aflatoxin B1 combined with ochratoxin A and/or zearalenone on metabolism, immune function, and antioxidant status in lactating dairy goats. Asian-Australas J Anim Sci. 2018;31(4):505-513.
  47. Sobrane Filho ST, Junqueira OM, de Laurentiz AC, et al. Effects of mycotoxin adsorbents in aflatoxin B 1 – and fumonisin B 1 -contaminated broiler diet on performance and blood metabolite. Revista Brasileira de Zootecnia. 2016;45(5):250-256.
  48. Harvey RB, Kubena LF, Elissalde MH, et al. Administration of ochratoxin A and T-2 toxin to growing swine. Am J Vet Res. 1994;55(12):1757-1761.
  49. Andretta I, Kipper M, Lehnen CR, Lovatto PA. Meta-analysis of the relationship of mycotoxins with biochemical and hematological parameters in broilers. Poult Sci. 2012;91(2):376-382.
  50. Munday R. Studies on the mechanism of toxicity of the mycotoxin sporidesmin. 2—evidence for intracellular generation of superoxide radical from sporidesmin. J Appl Toxicol. 1984;4(4):176-181.
  51. Smith GW, Constable PD, Foreman JH, et al. Cardiovascular changes associated with intravenous administration of fumonisin B1 in horses. Am J Vet Res. 2002;63(4):538-545.
  52. Smith GW, Constable PD, Haschek WM. Cardiovascular responses to short-term fumonisin exposure in swine. Fundam Appl Toxicol. 1996;33(1):140-148.
  53. Smith GW, Constable PD, Eppley RM, et al. Purified fumonisin B(1) decreases cardiovascular function but does not alter pulmonary capillary permeability in swine. Toxicol Sci. 2000;56(1):240-249.
  54. Yilmaz S, Kaya E, Karaca A, Karatas O. Aflatoxin B1 induced renal and cardiac damage in rats: Protective effect of lycopene. Res Vet Sci. 2018;119:268-275.
  55. Magnuson BA, Schiefer HB, Hancock DS, Bhatti AR. Cardiovascular effects of mycotoxin T-2 after topical application in rats. Can J Physiol Pharmacol. 1987;65(5):799-802.
  56. Constable PD, Smith GW, Rottinghaus GE, Haschek WM. Ingestion of fumonisin B1-containing culture material decreases cardiac contractility and mechanical efficiency in swine. Toxicol Appl Pharmacol. 2000;162(3):151-160.
  57. Kamyar MR, Kouri K, Rawnduzi P, et al. Effects of moniliformin in presence of cyclohexadepsipeptides on isolated mammalian tissue and cells. Toxicol In Vitro. 2006;20(8):1284-1291.
  58. Kibugu JK, Ngeranwa JJN, Makumi JN, et al. Aggravation of pathogenesis mediated by ochratoxin A in mice infected with Trypanosoma brucei rhodesiense. Parasitology. 2009;136(3):273-281.
  59. Wang YM, Liu JB, Peng SQ. Effects of Fusarium mycotoxin butenolide on myocardial mitochondria in vitro. Toxicol Mech Methods. 2009;19(2):79-85.
  60. Feuerstein G, Goldstein DS, Ramwell PW, et al. Cardiorespiratory, sympathetic and biochemical responses to T-2 toxin in the guinea pig and rat. J Pharmacol Exp Ther. 1985;232(3):786-794.
  61. Lorenzana RM, Beasley VR, Buck WB, et al. Experimental T-2 toxicosis in swine. I. Changes in cardiac output, aortic mean pressure, catecholamines, 6-keto-PGF1 alpha, thromboxane B2, and acid-base parameters. Fundam Appl Toxicol. 1985;5(5):879-892.
  62. Smith GW, Constable PD, Tumbleson ME, et al. Sequence of cardiovascular changes leading to pulmonary edema in swine fed culture material containing fumonisin. Am J Vet Res. 1999;60(10):1292-1300.
  63. Smith GW, Constable PD, Bacon CW, et al. Cardiovascular effects of fumonisins in swine. Fundam Appl Toxicol. 1996;31(2):169-172.
  64. Haschek WM, Gumprecht LA, Smith G, et al. Fumonisin toxicosis in swine: an overview of porcine pulmonary edema and current perspectives. Environ Health Perspect. 2001;109 Suppl 2:251-257.
  65. Yarom R, Hasin Y, Raz S, et al. T-2 toxin effect on cultured myocardial cells. Toxicol Lett. 1986;31(1):1-8.
  66. Ngampongsa S, Hanafusa M, Ando K, et al. Toxic effects of T-2 toxin and deoxynivalenol on the mitochondrial electron transport system of cardiomyocytes in rats. J Toxicol Sci. 2013;38(3):495-502.
  67. Lemmens-Gruber R, Rachoy B, Steininger E, et al. The effect of the Fusarium metabolite beauvericin on electromechanical and -physiological properties in isolated smooth and heart muscle preparations of guinea pigs. Mycopathologia. 2000;149(1):5-12.
  68. Fan LL, Li J, Sun LH. Effect of moniliformin on myocardial contractility in rats. Biomed Environ Sci. 1991;4(3):290-294.
  69. Smith GW, Constable PD, Eppley RM, et al. Purified fumonisin B(1) decreases cardiovascular function but does not alter pulmonary capillary permeability in swine. Toxicol Sci. 2000;56(1):240-249.
  70. Barhoumi R, Burghardt RC. Kinetic analysis of the chronology of patulin- and gossypol-induced cytotoxicity in vitro. Fundam Appl Toxicol. 1996;30(2):290-297.
  71. Luhe A, Hildebrand H, Bach U, et al. A new approach to studying ochratoxin A (OTA)-induced nephrotoxicity: expression profiling in vivo and in vitro employing cDNA microarrays. Toxicol Sci. 2003;73(2):315-328.
  72. Liu BH, Wu TS, Yu FY, Su CC. Induction of Oxidative Stress Response by the Mycotoxin Patulin in Mammalian Cells. Toxicol Sci. 2007;95(2):340-347.
  73. Domijan AM, Abramov AY. Fumonisin B1 inhibits mitochondrial respiration and deregulates calcium homeostasis–implication to mechanism of cell toxicity. Int J Biochem Cell Biol. 2011;43(6):897-904.
  74. Doi K, Uetsuka K. Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. Int J Mol Sci. 2011;12(8):5213-5237.
  75. Morris G, Berk M, Walder K, Maes M. The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability. Mol Neurobiol. 2016;53(4):2550-2571.
  76. Bin-Umer MA, McLaughlin JE, Basu D, et al. Trichothecene Mycotoxins Inhibit Mitochondrial Translation—Implication for the Mechanism of Toxicity. Toxins. 2011;3(12):1484-1501.
  77. Prosperini A, Juan-García A, Font G, Ruiz MJ. Beauvericin-induced cytotoxicity via ROS production and mitochondrial damage in Caco-2 cells. Toxicol Lett. 2013;222(2):204-211.
  78. Chanin BE, Hamilton DL, Hancock DS, Schiefer HB. Biointeraction of dietary T-2 toxin and zinc in mice. Can J Physiol Pharmacol. 1984;62(10):1320-1326.
  79. Zheng J, Zhang Y, Xu W, et al. Zinc protects HepG2 cells against the oxidative damage and DNA damage induced by ochratoxin A. Toxicol Appl Pharmacol. 2013;268(2):123-131.
  80. Watson S, Chen G, Sylla A, et al. Dietary exposure to aflatoxin and micronutrient status among young children from Guinea. Mol Nutr Food Res. 2016;60(3):511-518.
  81. Gerwien F, Skrahina V, Kasper L, et al. Metals in fungal virulence. FEMS Microbiol Rev. 2018;42(1). doi: 10.1093/femsre/fux050.
  82. Ramirez-Ortiz ZG, Lee CK, Wang JP, et al. A nonredundant role for plasmacytoid dendritic cells in host defense against the human fungal pathogen Aspergillus fumigatus. Cell Host Microbe. 2011;9(5):415-424.
  83. Citiulo F, Jacobsen ID, Miramón P, et al. Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion. PLoS Pathog. 2012;8(6):e1002777.
  84. Lulloff SJ, Hahn BL, Sohnle PG. Fungal susceptibility to zinc deprivation. J Lab Clin Med. 2004;144(4):208-214.
  85. Haase H. An element of life: competition for zinc in host-pathogen interaction. Immunity. 2013;39(4):623-624.
  86. Subramanian Vignesh K, Landero Figueroa JA, Porollo A, et al. Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival. Immunity. 2013;39(4):697-710.
  87. Winters MS, Chan Q, Caruso JA, Deepe GS. Metallomic analysis of macrophages infected with Histoplasma capsulatum reveals a fundamental role for zinc in host defenses. J Infect Dis. 2010;202(7):1136-1145.
  88. Subramanian Vignesh K, Landero Figueroa JA, Porollo A, et al. Zinc sequestration: arming phagocyte defense against fungal attack. PLoS Pathog. 2013;9(12):e1003815.
  89. Wilson D. An evolutionary perspective on zinc uptake by human fungal pathogens. Metallomics. 2015;7(6):979-985.
  90. Schneider RO, Diehl C, Dos Santos FM, et al. Effects of zinc transporters on Cryptococcus gattii virulence. Sci Rep. 2015;5:10104.
  91. Garfoot AL, Rappleye CA. Histoplasma capsulatum surmounts obstacles to intracellular pathogenesis. FEBS J. 2016;283(4):619-633.
  92. Crawford A, Wilson D. Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens. FEMS Yeast Res. 2015;15(7). pii: fov071. doi: 10.1093/femsyr/fov071. 
  93. Clark HL, Jhingran A, Sun Y, et al. Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection. J Immunol. 2016;196(1):336-344.
  94. Ballou ER, Wilson D. The roles of zinc and copper sensing in fungal pathogenesis. Curr Opin Microbiol. 2016;32:128-134.
  95. Shen Q, Rappleye CA. Differentiation of the fungus Histoplasma capsulatum into a pathogen of phagocytes. Curr Opin Microbiol. 2017;40:1-7.
  96. Blatzer M, Latgé JP. Metal-homeostasis in the pathobiology of the opportunistic human fungal pathogen Aspergillus fumigatus. Curr Opin Microbiol. 2017;40:152-159.
  97. Cohrt KAO, Marín L, Kjellerup L, et al. Novel Zinc-Attenuating Compounds as Potent Broad-Spectrum Antifungal Agents with In Vitro and In Vivo Efficacy. Antimicrob Agents Chemother. 2018;62(5). pii: e02024-17. doi: 10.1128/AAC.02024-17. 
  98. Garcia Silva-Bailão M, Lobato Potenciano da Silva K, Raniere Borges Dos Anjos L, et al. Mechanisms of copper and zinc homeostasis in pathogenic black fungi. Fungal Biol. 2018;122(6):526-537.
  99. Walencik PK, Watly J, Rowinska-Zyrek M. Fungal Zinc Homeostasis – A Tug of War Between the Pathogen and Host. Curr Med Chem. 2016;23(32):3717-3729.
  100. Staats CC, Kmetzsch L, Schrank A, Vainstein MH. Fungal zinc metabolism and its connections to virulence. Front Cell Infect Microbiol. 2013;3:65.
  101. Cuero R, Ouellet T. Metal ions modulate gene expression and accumulation of the mycotoxins aflatoxin and zearalenone. J Appl Microbiol. 2005;98(3):598-605.
  102. Weinberg ED. Roles of trace metals in transcriptional control of microbial secondary metabolism. Biol Met. 1990;2(4):191-196.
  103. Meeusen R, Watson P, Hasegawa H, et al. Central fatigue: the serotonin hypothesis and beyond. Sports Med. 2006;36(10):881-909.
  104. Georgiades E, Behan WM, Kilduff LP, et al. Chronic fatigue syndrome: new evidence for a central fatigue disorder. Clin Sci (Lond). 2003;105(2):213-218.
  105. Miller AH, Jones JF, Drake DF, et al. Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue. PLoS One. 2014;9(5):e98156.
  106. Wang X, Tang J, Geng F, et al. Effects of deoxynivalenol exposure on cerebral lipid peroxidation, neurotransmitter and calcium homeostasis of chicks in vivo. Toxicon. 2018;150:60-65.
  107. Doi K, Uetsuka K. Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. Int J Mol Sci. 2011;12(8):5213-5237.
  108. Creppy EE, Chakor K, Fisher MJ, Dirheimer G. The myocotoxin ochratoxin A is a substrate for phenylalanine hydroxylase in isolated rat hepatocytes and in vivo. Arch Toxicol. 1990;64(4):279-284.
  109. Sava V, Reunova O, Velasquez A, Sanchez-Ramos J. Can low level exposure to ochratoxin-A cause parkinsonism? J Neurol Sci. 2006;249(1):68-75.
  110. Sava V, Reunova O, Velasquez A, et al. Acute neurotoxic effects of the fungal metabolite ochratoxin-A. Neurotoxicology. 2006;27(1):82-92.
  111. Chaudhary M, Rao PV. Brain oxidative stress after dermal and subcutaneous exposure of T-2 toxin in mice. Food Chem Toxicol. 2010;48(12):3436-3442.
  112. Sundstøl Eriksen G, Pettersson H, Lundh T. Comparative cytotoxicity of deoxynivalenol, nivalenol, their acetylated derivatives and de-epoxy metabolites. Food Chem Toxicol. 2004;42(4):619-624.
  113. Mézes M, Barta M, Nagy G. Comparative investigation on the effect of T-2 mycotoxin on lipid peroxidation and antioxidant status in different poultry species. Res Vet Sci. 1999;66(1):19-23.
  114. Mobio TA, Tavan E, Baudrimont I, et al. Comparative study of the toxic effects of fumonisin B1 in rat C6 glioma cells and p53-null mouse embryo fibroblasts. Toxicology. 2003;183(1-3):65-75.
  115. Abado-Becognee K, Mobio TA, Ennamany R, et al. Cytotoxicity of fumonisin B1: implication of lipid peroxidation  and inhibition of protein and DNA syntheses. Arch Toxicol. 1998;72(4):233-236.
  116. Leal M, Shimada A, Ruı́z F, González de Mejı́a E. Effect of lycopene on lipid peroxidation and glutathione-dependent enzymes induced by T-2 toxin in vivo. Toxicol Lett. 1999;109(1):1-10.
  117. Stockmann-Juvala H, Mikkola J, Naarala J, et al. Fumonisin B1-induced toxicity and oxidative damage in U-118MG glioblastoma cells. Toxicology. 2004;202(3):173-183.
  118. Rahimtula AD, Béréziat J-C, Bussacchini-Griot V, Bartsch H. Lipid peroxidation as a possible cause of ochratoxin a toxicity. Biochem Pharmacol. 1988;37(23):4469-4477.
  119. Rastogi R, Srivastava AK, Rastogi AK. Long term effect of aflatoxin B1 on lipid peroxidation in rat liver and kidney: effect of picroliv and silymarin. Phytother Res. 2001;15(4):307-310.
  120. Doi K, Uetsuka K. Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. Int J Mol Sci. 2011;12(8):5213-5237.
  121. Ahmed N, Ram GC. Nuclear lipid peroxidation induced in rat liver by T-2 mycotoxin. Toxicon. 1986;24(9):947-949.
  122. Stockmann-Juvala H, Mikkola J, Naarala J, et al. Oxidative stress induced by fumonisin B1 in continuous human and rodent neural cell cultures. Free Radic Res. 2004;38(9):933-942.
  123. Kumar M, Dwivedi P, Sharma AK, et al. Apoptosis and lipid peroxidation in ochratoxin A- and citrinin-induced nephrotoxicity in rabbits. Toxicol Ind Health. 2014;30(1):90-98.
  124. Juan-García A, Juan C, Tolosa J, Ruiz MJ. Effects of deoxynivalenol, 3-acetyl-deoxynivalenol and 15-acetyl-deoxynivalenol on parameters associated with oxidative stress in HepG2 cells. Mycotoxin Res. 2019;35(2):197-205.
  125. da Silva EO, Gerez JR, Hohmann MSN, et al. Phytic Acid Decreases Oxidative Stress and Intestinal Lesions Induced by Fumonisin B₁ and Deoxynivalenol in Intestinal Explants of Pigs. Toxins (Basel). 2019;11(1). pii: E18. doi: 10.3390/toxins11010018.
  126. Xiao Y, Xu S, Zhao S, et al. Protective effects of selenium against zearalenone-induced apoptosis in chicken spleen lymphocyte via an endoplasmic reticulum stress signaling pathway. Cell Stress Chaperones. 2019;24(1):77-89.
  127.  Müller LKF, Paiano D, Bottari NB, et al. Spray-dried porcine plasma added to diets contaminated with aflatoxins and fumonisins shows beneficial effects to piglet health. An Acad Bras Cienc. 2018;90(3):3115-3128.
  128. Mallebrera B, Maietti A, Tedeschi P, et al. Antioxidant capacity of trans-resveratrol dietary supplements alone or combined with the mycotoxin beauvericin. Food Chem Toxicol. 2017;105:315-318.

Lauren Tessier, ND, is a licensed naturopathic physician specializing in mold-related illness. She is a nationally known speaker and is the vice president of the International Society for Environmentally Acquired Illness (ISEAI) – a non-profit dedicated to educating physicians about the diagnosis and treatment of environmentally acquired illness. Dr Tessier’s practice, “Life After Mold,” in Waterbury, VT, draws clients from all around the world who suffer from chronic complex illness as a result of environmental exposure and chronic infections. Dr Tessier’s e-booklet, Mold Prevention: 101, has been widely circulated and its suggestions implemented by many worldwide.

Related Posts

Upcoming Events

Scroll to Top