Mold 102 - Ochratoxin A

This article is not medical or healthcare advice. Before you start any health related regimen you should the advice of your Primary Care Physician or an M.D.

Ochratoxin A is perhaps one of the most common mycotoxins, both to be tested for and to be present in urine based test results from Moasic, Real Time, or my favorite Vibrant America. It is commonly found in "relatively" low amounts in grains, nuts, legumes, teas, coffees, and root vegetables. Of course it is also found in water damaged buildings. This article will be expanded over time, and there will be an article on each of the main mycotoxins later.

Ochratoxin A (OTA) is a mycotoxin produced by several fungal species including Aspergillus ochraceus, A. carbonarius, A. niger and Penicillium verrucosum. [1]. Organic Acids tests commonly test for aspergillus colonization in the gut - which can happen when exposed to mold.

Some of the more common foods that have been associated with Ochratoxin A include:

"Smoked and salted dried fish, dried beans, biltong, soya beans, chickpeas, rapeseed, pepper, dried fruit, and sesame seeds, nuts, cereals rice, barley, maize, wheat, flour, and bran, coffee beans. Grapes and grape products, including table grapes, wines, and dried vine fruits. Nuts, apples, pears, peaches, citrus, grapes, figs, strawberries, mangoes, tomatoes, melons, onions, garlic, and yams. Cereal crops; cheese, meat products." [1] To simplify, think of products that are stored in bulk, in dark damp places, that may have come with some minor mold from the earth, etc. Grains, nuts, legumes, dried beans, fruits, etc.

Ochratoxin A is a neuro toxin, and commonly causes neurological based issues. Beyond that it inhibits a very important gene called HMOX1. Why is this important ? A very small sampling of what HMOX1 does:

1. Takes iron and puts it into long term iron stores as ferritin (low ferritin anybody?)

2. Controls mast cell activation (insert clearing of throat)

3. Controls angiotensin 2 which if unregulated leads to high aldosterone (potassium excretion, marks on ankles from socks), and then stimulates NADPH Oxidase - causing mast cell issues, immune upregulation (NFKB, TNFA, IL-6, etc), and depletion of NAD.

4. Inhibits TNFA

5. Inhibits NFKB

6. Inhibits IL-6

7. Stimulates billiverdin which makes billirubin

8. Is a key player in the Keap 1 - NrF2 pathway which enables a number genes like NQO1 (NAD recycling), as well as anti oxdant genes like SOD1, SOD2, SOD3, CAT, GPX1-8 (Glutathione Peroxidase), and GSR (Glutathione Recycling).

Luckily there are several known herbs and compounds that can counter this by upregulating HMOX1:).

Renal, Testes, Intestinal Disease:

Ochratoxin A is also implicated in kidney damage. OTA causes nephrotoxicity and renal tumors in a variety of animal species; 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]

Technically Speaking - Ochratoxin A Jacks You Up - Detox Pathways - Anti Oxidant Agents [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 covalently bound to DNA. This could interfere with the DNA repair systems and cell cycle controls systems and serve as an initiating point of carcinogenesis.

Oxidative stress is another component 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.

The Gut MicroBiome Also Plays A Role In The BioTransformation and Metabolism Of Ochratoxin A

"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]

Some Agents Can Help With Ochratoxin A Toxicity - Melatonin, Licorice, Phenylalinine [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. It is significant in this study that the histopathological abnormalities were seen in this relatively short 28 day exposure and showed degenerative symptoms in the proximal tubules, congestion in renal tissue, and a remarkable infiltration of inflammatory cells consistent with OTA nephropathy.

Phenylalanine 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 nonsteroidal anti inflammatory drug/NSAID) and ethyl biscoumacetate (vitamin K antagonist/coumarin) and was less toxic when administered with sulfamethoxypridazine (a sulfonamide antibiotic) ."

Now The Brain - And Neuro Degenerative Diseases:

"In vitro and in vivo research has demonstrated cerebellar, hippocampal, and other adverse neurological effects due to OTA . A single dose of OTA 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]

Pase 2 Detox Pathways:

The primary phase 2 pathways used by Ochratoxin A is Glucuronidation, and to a lesser extent the amino acid, sulfation, and acetylation phase 2 detox pathways.

Binding Agents:

When selecting a binding agent to drag the toxin out of the GI tract, the primary considerations are : charge, size of binding sites on the binder, and the number of right sized binding sites on the binder per molecule. Cholystyramine, Welchol, and chitosan, all have the same charge, nearly identical sized binding sites, and very similar density of right sized binding sites per molecule. They are not identical compounds technically, but for binding purposes to Ochratoxin A - they are mimics. Chitosan is made from ground up shell fish, so allergies can be a consideration, but it is a fraction of the cost of the two prescription agents as alternatives.

Impact On Immunity / 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]ych

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 on line.

As the days go by, i will post other mold related blogs on Citrin, and Gliotoxin (both inhibit IL-10 which is a key regulator of, yep, 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 B3, Aflotoxin, Verrucarin J, STC, Chaetoglobosin A, 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 approach each corner in the hallway of life, we can never know what is around that corner - but being open to the possibility, in a split second, everything can change, just like 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 2024 be a blessed one for you and your families.

References:

1. 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.

2. A Review of the Diagnosis and Treatment of Ochratoxin A Inhalational Exposure Associated with Human Illness and Kidney Disease including Focal Segmental Glomerulosclerosis.

3. 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

4. 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