Mycotoxins: Ochratoxin A (1/3)
*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.
Ochratoxin A Overview
Ochratoxin A is a mold toxin (mycotoxin) produced by Aspergillus and Penicillium mold species. Because these molds commonly contaminate foods, relatively low levels of this toxin are often present in grains, nuts, legumes, and root vegetables, as well as in tea and coffee. These molds are also commonly present in water damaged buildings, making Ochratoxin A one of the most frequently discovered mycotoxins in urine-based mycotoxin testing offered by Mosaic, Real Time Labs, and Vibrant America. Ochratoxin A exposure can have serious health implications, as it has been linked to organ damage, neuroinflammation, and oxidative stress.
“In vitro and in vivo research has demonstrated cerebellar, hippocampal, and other adverse neurological effects due to Ochratoxin A (OTA) . A single dose of OTA to Swiss mice was associated with significant oxidative damage in six brain regions.”
Why Read This Article?
You may find this article valuable if you’re interested in:
Mold illness as it relates to chronic illness
The health implications of exposure to Aspergillus and Penicillium mold species
The impact of Ochratoxin A exposure on gene expression and how to address it
The impact of Ochratoxin A exposure on the brain, kidneys, and immune system
What to do if exposed to Ochratoxin A
The use of binders and other supplements in managing Ochratoxin A exposure
Ochratoxin A (OTA)
Ochratoxin A (OTA) is a mycotoxin produced by several mold species, including Aspergillus ochraceus, A. carbonarius, A. niger and Penicillium verrucosum. [1]. These molds are some of the most commonly encountered food-contaminating molds. Simply put, products that are stored in bulk and in dark, damp places are those most at risk of being contaminated. Some foods that have been commonly associated with Ochratoxin A contamination include [1]:
Smoked and salted dried fish
dried beans, biltong, soya beans, chickpeas, yams
rapeseed, pepper, dried fruit
sesame seeds, nuts, cereals rice, barley, maize, wheat, flour, and bran
coffee beans, nuts
Grapes and grape products, including table grapes, wines, and dried vine fruits
Apples, pears, peaches, citrus, grapes, figs, strawberries, mangoes, tomatoes, melons, onions, garlic
Cereal crops [1]
Health Implications of Ochratoxin A
Impact of Ochratoxin A on Gene Expression
Ochratoxin A inhibits a very important gene called HMOX1. Functionally, HMOX1 is important because it:
Facilitates the process of storing iron as ferritin
Controls mast cell activation
Controls angiotensin 2 which, if unregulated, leads to high aldosterone (potassium excretion, marks on ankles from socks); it then stimulates NADPH Oxidase causing mast cell issues, immune up-regulation (NFKB, TNFA, IL-6, etc), and depletion of NAD
Inhibits TNFA, a key regulator of the immune system and the inflammatory response
Inhibits NFKB, a protein complex that controls DNA transcription, cell survival, and cytokine production
Inhibits IL-6, a protein that plays a key role in the functioning of the immune system, the inflammatory cascade, metabolism, and more
Stimulates billiverdin, which makes billirubin
Is a key player in the Keap 1 - NrF2 pathway, which enables a number of genes like NQO1 (NAD recycling), as well as antioxdant genes like SOD1, SOD2, SOD3, CAT, GPX1-8 (Glutathione Peroxidase), and GSR (Glutathione Recycling)
As you can see, inhibition of HMOX1 has some potentially serious consequences. Fortunately, there are several herbs and other compounds that are known to up-regulate HMOX1 and counter the inhibition caused by OTA. They will be discussed later in the article.
Links Between Ochratoxin A Exposure and Kidneys and Testes Disease
Ochratoxin A is also considered to be nephrotoxic. Its ability to cause kidney damage and kidney tumors in a variety of animal species has been documented; however, human health effects are less well-characterized. Various studies have linked OTA exposure with the human diseases Balkan endemic nephropathy (BEN) and chronic interstitial nephropathy (CIN), as well as other renal diseases. [1]
"Several studies in animals have confirmed a causal connection between OTA exposure and cancers of the urinary tract, liver, and mammary glands. Striking similarities have been noted between OTA-induced porcine nephropathy in pigs and BEN in humans. The main nephrotoxic effect is in the postproximal nephron and proximal tubule which have been reported as a self-enhancing effect.
A recent study in Sri Lanka measuring mycotoxin levels in the urine of patients with kidney disease demonstrated the presence of Ochratoxin in 93.5 percent of patients tested, although Ochratoxin was also found in individuals without kidney disease.
A correlation of consumption of foods known to contain OTA and the incidence of testicular cancer in 20 countries has suggested the possibility of OTA being related to an increased incidence of testicular carcinoma. The authors also report that there is correlation of pork and coffee intake with testicular carcinoma. In addition, animals exposed to OTA contain OTA in the testes and OTA causes adducts in testicular DNA.
Several studies on Tunisians with and without renal disease have shown elevations in serum OTA levels in both populations, with higher levels being found in those with renal disease. In one report, the mean value of OTA for the healthy control population was 3.3 ± 1.5 ng/mL (ppb) compared to a mean value of 18 ± 7 ng/mL (ppb) in those with chronic interstitial nephropathy of unknown origin. Another study of OTA in human blood samples comparing persons with various types of chronic kidney disease to controls showed elevations in serum ochratoxin which were greatest in those diagnosed with chronic interstitial nephropathy at mean values of 25–59 ng/mL (ppb) compared to 0.7–7.8 ng/mL (0.7–7.8 ppb) in the general population and 6–18 ng/mL (ppb) in those with other types of kidney disease." [2]
The Impact of the Microbiome on the Metabolism and Biotransformation of OTA
"Intestinal microflora also appear to contribute significantly to the metabolism of OTA via hydrolyzation to the less toxic ochratoxin alpha in rats. Inhibition of microflora in the lower GI tract of rats by neomycin results in decreased hydrolysis of OTA to ochratoxin alpha resulting in elevated levels of OTA . In addition, administration of radiolabeled OTA to rats indicated that effective metabolism of OTA was lacking in most tissues other than the intestines. The importance of digestion in the detoxication of OTA is also supported by the observation that OTA does not readily accumulate in ruminants due to rapid detoxification in the extensive ruminant stomach ." [2]
OTA Compromises Detoxification, Antioxidant Pathways, and DNA Repair [2]
"Individual genetic differences affect the biotransformation and relative toxicity of OTA, with enzymatic hydrolysis and cytochrome p450 induction felt to play a role in toxicity. Studies have indicated that the biotransformation of OTA can be effected by CYP 3A4, CYP 1A1, and CYP 2C9-1, while conflicting results have been found for CYP 1A2.
DNA adducts also occur in animals exposed to OTA in all available studies. DNA adducts consist of a chemical that is bound to DNA by a covalent bond. This could interfere with the DNA repair systems and cell cycle control systems, and may serve as an initiating point of carcinogenesis.
Increased oxidative stress is another consequence of OTA toxicity. Pretreatment of rats with retinol (vitamin A), ascorbic acid (vitamin C), or alpha tocopherol (vitamin E) before OTA administration significantly decreased the number of DNA adducts formed in the kidney by 70 percent, 90 percent, and 80 percent, respectively. In addition, lipid peroxidation and enzymes involved in arachidonic acid metabolism affect the biotransformation of OTA. More recently, it is been shown in rodents that mTOR/AKT pathways are significantly deregulated after exposure to OTA, possibly contributing to carcinogenicity in kidney cells.
Supplements in Ochratoxin A Toxicity - Melatonin, Licorice, Phenylalanine [2]
"Various substances have been found to either increase or decrease the toxicity of OTA. In mice, pretreatment with phenobarbital decreased the toxicity of OTA with significant increases in LD50 seen. Administration of piperonyl butoxide was also shown to significantly decrease the LD50 of OTA thus increasing toxicity.
A protective effect of melatonin and licorice plant extract was demonstrated in rats exposed to OTA for 28 days and alleviated most of the biochemical abnormalities associated with the exposure. The results of this study are significant in that histopathological abnormalities were identified within the relatively short 28 day exposure, including evidence of degeneration in the proximal tubules, congestion in renal tissue, and a remarkable infiltration of inflammatory cells consistent with OTA nephropathy.
Phenylalinine prevents acute poisoning by OTA in mice. Aspartame, a structural analogue of phenylalanine, is also a powerful inhibitor of OTA toxicity, at least in animals. In male rats, OTA was more toxic in the presence of phenylbutazone (a non-steroidal anti-inflammatory drug/NSAID) and ethyl biocoumacetate (vitamin K antagonist/coumarin), and was less toxic when administered with sulfamethoxypridazine (a sulfonamide antibiotic)."
The Impact of Ochratoxin A On the Brain and Its Link To Neurodegeneration
Ochratoxin A is a known neurotoxin that can cross the blood brain barrier where it has the potential to cause neurodegeneration.
"In vitro and in vivo research has demonstrated cerebellar, hippocampal, and other adverse neurological effects due to OTA . A single dose of OTA administered to Swiss mice was associated with significant oxidative damage in six brain regions—the cerebellum, hippocampus, caudate putamen, pons medulla, substantia nigra, and cerebral cortex. Peak effects were observed in the midbrain, caudate/putamen, and hippocampus. In addition, striatal dopamine was decreased after a single exposure to OTA. In vitro experiments have shown decreased proliferation of neural progenitor stem cells in the hippocampal region of mice after exposure to OTA leading the authors to speculate that problems impairing hippocampal neurogenesis in vivo could contribute to the memory problems and depression commonly seen in humans exposed to mycotoxins. In another study evaluating the neurotoxicity of ochratoxin A, primary neurons and neuronal cells were incubated with increasing concentrations of OTA. A dose-dependent increase in cytotoxicity was found in both cell types resulting from apoptosis and accompanied by a loss of mitochondrial membrane potential. Based on these data, the authors speculated that OTA may contribute to the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s in which apoptotic processes are centrally involved."[2]
Ochratoxin A and Its Impact On Immunity and the Gut
"OTA is known to be immunotoxic in animal studies. The immunosuppressant activity of OTA in animals has been characterized by size reduction of vital immune organs like the thymus, spleen and lymph nodes, depression of antibody responses, alterations in the number and functions of immune cells, and modulation of cytokine production. There are also complex relationships between Aspergillus, T regulatory lymphocytes, and candidiasis, which can be clinically relevant in humans."[2].
"According to the studies described to date, OTA can affect gut dysbiosis, including increasing gut permeability, immunity, and bacterial translocation, and can eventually lead to gut and other organ injury. Although there are many studies investigating the effects of OTA on the gut health of poultry, further studies are needed to better characterize the underlying mechanisms of action and develop preventative or therapeutic interventions for mycotoxicosis in poultry."[4]
Detoxification and Binding of Ochratoxin A
Detoxification
Ochratoxin A is primarily metabolized in the liver via glucuronidation, a phase 2 detoxification pathway, where it is transformed into a water soluble form that is then excreted by the kidneys through the urine. To a lesser extent, the amino acid, sulfation, and acetylation detox pathways are also used.
Ochratoxin A Binding Agents
Ochratoxin A can be eliminated via gastrointestinal excretion with the help of a binding agent. When selecting a binding agent, the primary considerations include the electrical charge of the binder, size of binding sites on the binder, and the number of correctly sized binding sites on the binder per molecule. Cholystyramine and Welchol (prescription binders), and chitosan (OTC supplement), all have the same charge, nearly identical sized binding sites, and very similar density of correctly sized binding sites per molecule. Technically, they are not chemically identical compounds, but when it comes to binding Ochratoxin A, they behave the same. Chitosan is made from ground up shell fish, so its potential as a food allergen should be noted. However, chitosan is a fraction of the cost of the two prescription agents, which can be an important factor to consider.
Closing Thoughts
I encourage you to check out the reference articles and dive in for more details.
If you would like to review your genetics associated with HMOX1, the relevant phase 1 (CYP 450) and phase 2 detox pathways associated with Ochratoxin A, or discuss potential strategies to help test, remove, and counter the effects of Ochratoxin A, please schedule an appointment online.
I will post other mold related blogs on Citrin, and Gliotoxin (both inhibit IL-10 which is a key regulator of, heme synthesis), Zearalanone (perhaps the nastiest one when combined with Long Haul or ME CFS), and how it can lead to b2 depletion, blood glucose issues, and a process called ferroptosis - unmitigated cell death that results in massive weight loss), Patulin, Riordin A, Fumonisms, Aflatoxin, Verrucarin, STC, Chaetoglobosin, Mychophenolic Acid, etc. For reference, i have found about 40% of the folks who i work with who come to me with Long Haul, have had mold exposure, and significant levels of mycotoxins when tested.
Never lose hope, as we walk through the hallway of life, we can never know what is around the corner - but being open to the possibility that, in a split second, everything can change as quickly as the snap of your fingers. The lesson is like life: two sides of the coin, never take anything for granted, and never lose hope. May the coming months and year be a blessed one for you and your families.
References:
Ochratoxin A and human health risk: a review of the evidence. By Travis R Bui-Klimke 1, Felicia Wu. Crit Rev Food Sci Nutr. . 2015;55(13):1860-9.
A Review of the Diagnosis and Treatment of Ochratoxin A Inhalational Exposure Associated with Human Illness and Kidney Disease including Focal Segmental Glomerulosclerosis.
Ochratoxin A: 50 Years of Research. Frantisek Malir, Vladimir Ostry, et al. Department of Biology, Faculty of Science, University of Hradec Kralove, Hradec Kralove 50003, Czech Republic. National Reference Center for Microfungi and Mycotoxins in Food Chains, Center of Health, Nutrition and Food in Brno, National Institute of Public Health in Prague, Brno 61242, Czech Republic. Toxins 2016, 8(7), 191; https://doi.org/10.3390/toxins8070191
Ochratoxin A: its impact on poultry gut health and microbiota, an overview. Shuangshuang Zhai,∗ Yongwen Zhu. Poult Sci. 2021 May; 100(5): 101037. Published online 2021 Feb 11. doi: 10.1016/j.psj.2021.101037. PMCID: PMC8005833. PMID: 33752074