Why is exposure to toxic mold becoming a major health concern for many individuals? Compared to sanitary conditions hundreds or perhaps thousands of years ago, modern hygiene, advanced technology in food processing, storage, and handling should offer a higher degree of protection against contamination and exposure to natural toxins. Yet effects of mold toxicity are widespread and many individuals suffer from various health problems that may involve the immune, pulmonary, intestinal, cardiovascular, hematological, lymphatic, nephropathic, and neurological systems.
It is reasonable to assume that humans have always been challenged by mold toxicity; so why has it only become a problem in the past several decades?
What are Mycotoxins?
Mycotoxins are small molecules produced by fungi or molds that contaminate agriculture products. Mycotoxins are commonly found in cereals, nuts, and seed oils, as well as in foods of animal origin, such as milk and milk derivatives, eggs and meat, when the source animals are fed contaminated fodder [1]. Mycotoxins such as aflatoxins, gliotoxin, ochratoxin A, and deoxynivalenol can contaminate food and exert detrimental effects on human health.
Super Toxic T-2 Trichothecenes is a Known Bioweapon
There is a type of extremely toxic mycotoxin called trichothecene produced by a variety of fungi, one being the S chartarum, which is an extremely common black mold that can grow on natural and artificial substrates including common building materials typically found indoors in residential and commercial buildings [19]. Trichothecenes are extremely toxic because they are potent inhibitors of protein synthesis in eukaryotes, including humans. This class of toxins can easily penetrate cell membranes and target rapidly dividing cells in bone marrow and gastrointestinal tracts [2].
Type A trichothecenes class T-2 mycotoxins produced by various fungi exert toxicity at such high levels that this toxin is the only known mycotoxin produced by fungi used as a bioweapon [3].
T-2 Multiple Cytotoxic Effects
T-2 toxin is able to modulate the immune system by either inhibiting or superinducing both interleukin and mRNA levels in CD4+ T cells [4]. Trichothecenes also disrupt hematopoietic systems and organs such as bone marrow and spleen [5, 6].
T-2 and Mycotoxins are Toxic to Heme
In animal studies that tested mycotoxin effects, T-2 trichothecene toxin was found to significantly suppress hematological functions. RBC and WBC reductions were observed in all groups exposed to mycotoxins. T-2 treated groups showed the most severe toxicity compared to other mycotoxin treated groups. In the presence of mycotoxins, granulocytes, lymphocytes, B cells, and platelets all showed significant reductions to different degrees [7].
Mycotoxins Bind to AChE, CYP450 and DNA to Cause Cytotoxicity
Human acetylcholinesterase (AChE) is an enzyme that is essential for neurological transmission. Mycotoxins like aflatoxin and T-2 trichothecenes can bind to AChE to cause neurological dysfunctions [8, 9]. Cytochrome p450 is a heme-thiolate protein responsible for the metabolism of drugs, xenobiotics, and endogenous substrates including melatonin [11].
T-2 and other mycotoxins, through binding to acetylcholinesterase (AChE) and cytochrome P450 receptors can significantly alter their functions, leading to carcinogenesis, teratogenesis, hepatotoxicity, nephrotoxicity, immunotoxicity and neurotoxicity. Studies now find associations between mycotoxins and neurodevelopmental disorders such as autism spectrum disorder [12]
DNA is the known target of mycotoxins after they are metabolized in the liver by cytochrome p450 enzymes. Binding to DNA creates a covalent adduct that leads to a carcinogenic lesion [13]. The cytotoxic effects of mycotoxins were first reported over 30 years ago when Thompson and Wannemacher demonstrated the in vivo inhibition of protein and DNA synthesis in rodents [14]. DNA damage from mycotoxin is an early event associated with the generation of reactive oxygen species (ROS) and lipid peroxidation.
Mycotoxins Can Cause Cancer by Suppressing p53
A systematic literature review of epidemiological studies was able to find associations between mycotoxins and cancer development in humans; the cancers studied included liver, breast, and cervical cancer [15]. The mechanisms used by mycotoxins to activate tumourigenesis may be the modulation of gene expression and transcription via epigenetic processes such as methylation. A recent in vitro study demonstrated that the mycotoxin fusaric acid was able to inhibit expression of the important p53 tumor suppressor protein by inducing hypermethylation of its promoter [16].
T-2 Elevates Oxidative Stress in Mitochondria
Trichothecenes are known to cause oxidative stress in mitochondria in a dose-dependent manner [17]. T-2 causes depolarization of mitochondria membranes resulting in mitochondrial membrane fragmentation in yeast models. This decrease in membrane potential results in a corresponding increase in reactive oxygen species [18]. Yeast with high sensitivity to trichothecenes exhibited higher levels of oxidative stress with increased ROS in mitochondria [18]. Yeast can increase their tolerance to trichothecene toxicity by enhancing degradation pathways known as mitophagy. By activating mitophagy, cells can efficiently eliminate mitochondria damaged by mycotoxins and reduce mitochondria oxidative stress levels [17].
Mycotoxins Can Cause Cell Death
The S. chartarum mold that thrives in damp buildings produces another trichothecene mycotoxin called satratoxin, in addition to T-2. Exposure to satratoxin has been found to cause apoptosis of olfactory sensory neurons (OSNs) in the olfactory epithelium [20]. Satratoxin mold can trigger programmed cell death by activating apoptotic signaling pathways including caspase-3 [21, 22]; p38 MAPK [23, 24], and ERK [25, 26]
Potential Long-term Effects from Lipid Peroxidation from T-2 Poisoning
As early as 1989, evidence showed that T-2 poisoning even in extremely small concentrations could induce significant lipid peroxidation [27]. Prolonged exposure to these mycotoxins even at minute subtoxic levels could potentially result in long-term health consequences as a result of systemic lipid peroxidation in plasma membranes. Low-level lipid peroxidation can cause membrane permeability that allows solutes and other molecules to permeate across lipid bilayers in plasma membranes [28]. The translocation of small nanoparticles is also enhanced when there is lipid peroxidation in membranes [29].
In the normal physiological or pathological environments, lipid peroxidation levels are usually quite low due to the presence of endogenous antioxidants like melatonin, as well as saturated fatty acids that are not susceptible to peroxidation [30]. However, consistent exposures to mycotoxins can induce systemic low-level lipid peroxidation that alters the structural formation of plasma membranes, making them more permeable to solutes [28].
Membrane integrity is essential for cell survival. Structural damages to membranes from lipid peroxidation can cause membrane-related diseases including diabetes and obesity [31], red blood cell abnormalities [32], multiple sclerosis [33], muscular dystrophy [34], Crohn's Disease [35], and even rheumatoid arthritis to name a few [36].
T-2 Toxin is a Radiomimetic Compound
Radiomimetics are drugs that elicit effects similar to radiation exposure. These pharmaceuticals are often used in chemotherapies to treat cancer. Animals exposed to T-2 trichothecenes would show 'radiomimetic' shock-like effects that may include diarrhea, vomiting, leukocytosis and hemorrhage. Higher doses would often result in the death of these lab animals [37, 38]. Chronic exposure to trichothecenes can exacerbate the effects of ionizing radiation. In addition, electromagnetic radiation ubiquitously present in our environment may enhance the toxicity of mycotoxins such as T-2 trichothecene.
Electromagnetic Radiation
Compelling evidence supports the theory that electromagnetic field (EMF) exposure can affect health by modulating redox-related processes in mitochondria to cause extensive leakage of electrons in mitochondrial complexes responsible for oxidative phosphorylation during the generation of ATP energy. The leaked electrons from EMF exposure could be the major source of ROS and increased oxidative stress [39].
Proton leakage in mitochondria is the major source of the superoxide ROS, while increased ROS can cause more electron leakage. Hence, ROS in mitochondria has the potential to become a self-reinforcing positive feedback loop that causes disease in various tissues and organs. Mitochondria isolated from hearts of patients with ischaemia / reperfusion injury showed significantly higher rates of proton leakage [40].
EMF has been shown in many studies to activate voltage-gated calcium channels (VGCCs) [41], however, the effects of VGCC activation appear to be controversial as some studies showed negative effects while others showed positive effects [41]. The reason for these discrepancies may be due to the fact that membranes, especially mitochondrial membranes, may respond differently to different intensities and frequencies of EMF [42]. Regardless, one common mechanism underlies all EMF effects on cell membranes.
EMF Causes Membrane Depolarization
Calcium ion movement across voltage ‐ gated calcium channels (VGCCs) is ALWAYS preceded by membrane depolarization. Depolarization opens VGCCs allowing ion movements across the channels [43]. In cells and mitochondria, depolarization of the membrane causes loss of membrane potential (ΔΨm), where the membrane charge state changes from a negative to a positive one. This change has a direct impact on the ability of mitochondria to produce energy because the collapse of the membrane potential causes protons to leak back into the matrix instead of being driven through the ATP synthase, rotating the synthase in the process [44].
By causing proton leakage, membrane depolarization can increase ROS and oxidative stress in mitochondria [45]. The inability to repolarize plasma membranes, or the sustained depolarization of membranes, may result in energy depletion in mitochondria, as well as increased ROS leading to apoptosis [46].
900 MHz frequency has been observed to cause apoptosis and oxidative stress via mitochondrial depolarization in breast cancer cells [47]. Another experiment found mice exposed to 900 MHz produced extensive DNA damage and cell cycle arrest in testicular germ cells as a result of mitochondria membrane depolarization that destabilized cellular redox homeostasis [48]. Studies discovered that 900 MHz could modulate surface charge distribution, changing the orientation of hydrophilic phospholipids in plasma membranes [49].
EMF May Enhance Cytotoxicity of Mycotoxins
The ability of EMF to alter lipid membrane dynamics is similar to how mycotoxins cause membrane damage via increased lipid peroxidation from oxidative stress. Magnetic fields have been demonstrated to increase ROS in human, mouse, rat cells, and tissues [50]. Lipid bilayers of membranes exhibiting peroxidation showed conformational changes in the lipids, resulting in membrane permeability that eventually damage cell membranes [51]. What is also interesting is that lipid peroxidation can also activate ion channels that result in membrane depolarization, similar to effects from exposure to EMF [52].
It is becoming quite clear that cytotoxicity of mycotoxins are reinforced and exacerbated by EMF, while the damage from EMF can be increased significantly from exposure to mycotoxins. This positive feedback between EMF and mycotoxins is further exacerbated by the depletion of the important ancient molecule melatonin, as a result of suppression by light at night [53], as well as constant exposure to man-made magnetic fields such as electricity [54] .
Melatonin is Your Best Friend Against Mycotoxins
Different in vitro and in vivo studies have reported melatonin to be an effective protective agent against toxicity induced by mycotoxins [55-57]. How does melatonin accomplish this remarkable feat? Very simply, melatonin can attenuate ALL the damages exerted by various mycotoxins. Take a look at the following diagrams showing how melatonin can suppress pathways activated by different mycotoxins.
[Source: Milad Iranshahy, Leila Etemad, Abolfazl Shakeri, et al. Protective activity of melatonin against mycotoxins-induced toxicity: a reviewToxicological & Environmental Chemistry Volume 101, 2019 - Issues 9-10 DOI: 10.1080/02772248.2020.1731751]
[Source: Milad Iranshahy, Leila Etemad, Abolfazl Shakeri, et al. Protective activity of melatonin against mycotoxins-induced toxicity: a reviewToxicological & Environmental Chemistry Volume 101, 2019 - Issues 9-10 DOI: 10.1080/02772248.2020.1731751]
[Source: Milad Iranshahy, Leila Etemad, Abolfazl Shakeri, et al. Protective activity of melatonin against mycotoxins-induced toxicity: a reviewToxicological & Environmental Chemistry Volume 101, 2019 - Issues 9-10 DOI: 10.1080/02772248.2020.1731751]
Melatonin Inhibits Lipid Peroxidation Induced by Oxidative Stress
Melatonin is a potent scavenger of free radicals. Its ability to prevent lipid peroxidation was clearly elucidated more than two decades ago. An in vivo experiment on animals with organ damage induced by lipid peroxidation from ethanol free radical oxidative stress revealed that melatonin supplementation significantly reversed lipid peroxidation to protect brains, hearts, lungs and heads from ethanol toxicity. In fact, melatonin treatment rescued tissue lipid peroxidation and returned levels to those of control animals [58].
Melatonin Enhances Mitophagy and Modulates Apoptosis Signaling Pathways
Mycotoxins and EMF can damage mitochondria. In yeast models, cells with enhanced mitophagy showed higher resistance against toxic effects of mycotoxins [17]. In vitro studies demonstrated that melatonin is able to upregulate mitophagy in mitochondria and prolong cell survival under conditions of oxidative stress [59]. Mitochondria targeted by Trichothecenes mycotoxins are challenged by increased oxidative stress, but effective degradation of mitochondria damaged by mycotoxins via mitophagy can increase cell survival [17].
Various mycotoxins, including satratoxin can trigger programmed cell death by activating apoptotic signaling pathways including caspase-3 [21, 22]; p38 MAPK [23, 24], and ERK [25, 26]. Melatonin is a potent modulator of apoptotic signaling pathways. In rodents with diabetic retinopathy, melatonin was found to suppress the MAPK signaling pathway to inhibit inflammation and apoptosis [60]. Melatonin was also found to maintain the activation of the ERK MAPK survival pathway to counter apoptosis triggered by UVB damage vitro [61].
Melatonin Protects DNA from Damage by Increasing p53 Tumor Suppressor
DNA is the known target of mycotoxins after they are metabolized in the liver by cytochrome p450 enzymes. Binding to DNA creates a covalent adduct that leads to a carcinogenic lesion [13]. Melatonin is well known as an anticancer agent. High levels of melatonin can prevent cells from malignant development. Melatonin can prevent DNA damage accumulation and cell proliferation in tumorigenesis by activating p53 tumor suppressor pathways via phosphorylation of p53 [62].
Yet the most exciting discovery in the study of melatonin and mycotoxins is the work by Maroli published in 2020 [63].
Melatonin Inhibits T-2 Toxicity by Competitive Binding to AChE and CYP450
Mycotoxins bind to AChE and CYP450 to cause detrimental health effects. Mycotoxins like aflatoxin and T-2 trichothecenes can bind to AChE resulting in various neurological dysfunctions [8, 9]. T-2 and other mycotoxins, through binding to acetylcholinesterase (AChE) and cytochrome P450 receptors can significantly alter their functions, leading to carcinogenesis, teratogenesis, hepatotoxicity, nephrotoxicity, immunotoxicity and neurotoxicity.
Maroli definitively showed that melatonin can bind to both acetylcholinesterase (AChE) and CYP450 with greater affinity and stability than the super toxic T-2 trichothecene [63]. That means if there is adequate melatonin present, the molecule can prevent mycotoxins from binding to important enzymes and receptors to cause significant damage and oxidative stress. The chart below shows that the negative free energy is greater when melatonin binds to AChE and CYP450 compared to mycotoxins. A greater negative free energy = more efficient binding and stability.
Take a look at the diagrams "a" to "d" below.
Diagrams a, b, show the exact binding locations of melatonin and mycotoxin T-2 trichothecene in AChE, respectively.
Diagrams c, d show the binding locations of melatonin and mycotoxin T-2 trichothecene in CYP450, respectively.
[Source: Nikhil Maroli Melatonin Protects T-2 toxin-induced neuronal stress through Acetylcholinesterase & Cytochrome P450 receptor-mediated signaling bioRxiv preprint doi: https://doi.org/10.1101/2020.03.28.013573]
The diagrams above imply that if melatonin occupies the same binding positions but with higher stability and affinity than T-2, then T-2 will be blocked from binding to these important enzymes and receptors to cause cytotoxicity. This is probably the most exciting discovery in the field of mycotoxin treatment by natural small molecules.
Melatonin is an ancient molecule that has evolved with living systems for more than 3 billion years. It has not failed to protect living organisms from endogenous and exogenous stress, and will continue to do so given the opportunity. Our light environment at night strongly suppresses melatonin production. Together with increased oxidative stress from constant EMF exposure, exogenous melatonin supplementation may be required to support deficiencies. It is time for melatonin to gain wide acceptance across all health disciplines as it is truly a miraculous molecule.
Have you had your AA and MEL today?
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