This page is being written
Ochratoxins are secondary metabolites of certain types of fungi. Ochratoxins occur in nature as Ochratoxin A (OTA), B (OTB), and C (OTC). Ochratoxin A is the most prevalent ochratoxin and the most toxic followed by OTB and OTC. Ochratoxin A, B and C are produced by Penicillium and Aspergillus species of mold. Two of the major producers are Aspergillus ochraceus and Penicillium verrucosum.
Ochratoxins are described as consisting of a para-chlorophenolic moiety containing a dihydroiso-coumarin group that is amide-linked to L–phenylalanine.
Ochratoxin B (OTB), a secondary metabolite of Aspergillus ochraceus, is the nonchlorinated analogue of the mycotoxin ochratoxin A (OTA), which is one of the most potent kidney carcinogens in rodents. Despite the closely related structure, OTB is considered to be of much lower toxicity. OTA is poorly metabolized and slowly eliminated, and this may play an important role in OTA toxicity, carcinogenicity, and organ specificity.
OTA and OTB have a similar potential to induce cytotoxicity in vitro, but large differences in their potential to induce nephrotoxicity in rodents. OTB is more extensively metabolized and more rapidly eliminated than OTA. The lack of specific retention of OTB in the kidneys and the differences in toxicokinetics may therefore provide an explanation for the lower toxicity of OTB. Biotransformation/detoxification and nephrotoxicity of ochratoxin B in rats. PMID: 15963343 [PubMed - indexed for MEDLINE]
Ochratoxin A is produced by Aspergillus ochraceus, research shows oxidative stress may be a major mechanism for the toxicity of Ochratoxin A (OTA). It is a mycotoxin that has long been studied as a nephrotoxin, immunotoxin, teratogen and carcinogen. Molds associated with the production of OTA include Aspergillus ochraceus, Aspergillus niger and Aspergillus carbonarius, Penicillium verrucosum, and species of Penicillium, Petromyces, and Neopetromyces. Concerns regarding exposure to ochratoxin have primarily centered on exposure to food contaminated with OTA such as wine, beer, coffee, dried vine fruit, grape juices, pork, poultry, dairy, spices, and chocolate . Toxicity from ochratoxin is considered serious enough that it is among approximately 20 mycotoxins monitored in food.
OTA causes decreased 5-oxoproline. Decreased 5-oxoproline is seen with Mild glutathione synthetase deficiency. Moderate deficiency can cause hemolytic anemia, elevated acidity – metabolic acidosis. Severe deficiency can cause neurological sxs such as seizures, decreased physical reactions, movements and speech, intellectual disability and loss of coordination. Some people with severe deficiency experience recurrent bacterial infections.
Ochratoxin A (OTA), first discovered in 1965 in Aspergillus ochraceus has been subsequently reported in several Aspergillus and Penicillium species.
Aspergillus niger, Aspergillus, and species of Penicillium, Petromyces, and Neopetromyces. OTA is a nephrotoxic, genotoxic, immunotoxic, and neurotoxic mycotoxin which is a known carcinogen in animals and a class 2B, possible human carcinogen. Associations have been found with human kidney disease including Balkan endemic nephropathy and focal segmental glomerulosclerosis.
Ochratoxin A is preferentially distributed in liver, kidney, muscle and fat. Pharmacokinetics of ochratoxin A in animals. PMID: 1820333 [PubMed - indexed for MEDLINE]
Where Are Ochratoxins Found
Exposure to ochratoxins is largely through food contamination and the most common food to be contaminated is grains. Ochratoxins have been found in corn, wheat, barley, flour, coffee, rice, oats, rye, beans, peas, and mixed feeds, and are more likely to be present in wine, grape juice, and dried vine fruits. Coffee and wines are the most likely suspect for ochratoxins.
Ochratoxins can also contaminate animal-derived products, such as meat and milk, and are even found in human milk
Skin contact and inhalation are known to also cause toxicity. Inhalation is usually from dust in commercial areas where grains are being stored and/or processed. Researchers found people working in environments where coffee, cocoa beans and spices are processed are at risk since these are foods that tend to be more likely to have ochratoxins on them. The other working environment that would lead to exposure would be found in environments where farmers or processers are working with grains. There are also ochratoxins that have been associated with water-damaged buildings.
OTA-producing Aspergillus species, A. carbonarius and A. niger (which produces OTA more rarely), grow well at high temperatures and produce dark colored hyphae and spores, making these species resistant to UV light. Therefore, Aspergillus carbonarius is commonly found in grapes and similar types of fruits that mature in sunlight and at high temperatures
Although Aspergillus is found more commonly in conditions of high humidity and temperature, Penicillium species are a source of ochratoxin in cool temperate regions.
Ochratoxin (OTA) is an other mycotoxin produced by Aspergillus. It is also produced by Penicillium. It is present in a large variety of foods because it is produced by several fungal strains of the Penicillium and Aspergillus species. It is most commonly found in wheat, corn and oats. Ochratoxin A is the most economically important form of ochratoxin; ochratoxins B and C are less toxic and less common. Ochratoxins may be transferred through milk, blood, and meat, so you will find it in dairy and meat products from animals that have consumed contaminated grains. OTA occurs in olives, beans, beer, wine, coffee, cocoa products, raisins, figs, licorice, pulses, pumpkin seeds, and tea. It has been found on such food as dried and smoked fish, dried fruit and tree nuts. It has also been found on grapes and grape products such as wine, raisens, wine vinegars. The WHO in 2001 reported that the main sources are cereals, wine, grape juice, coffee and pork for human exposure at levels of 58%, 21%, 7%, 5% and 3% of ochratoxin intake respectively. Red wines typically contain higher ochratoxin levels than white wines. Although coffee bean roasting lowers ochratoxin levels by 80% - 96%, it was shown to be fairly stable in processing of wheat and barley via dry milling and heat processing. Wet milling of corn resulted in reductions of corn grits and germ by 49% and 96 % respectively. Penicillium verrucosum is the leading cause of ochratoxin contamination of cereal grains in temperate climates. Grapes, raisins, and even wines may become contaminated with ochratoxins produced by Aspergillus carbonarius, the principal causal agent of grape black mold. A number of Aspergillus spp. may cause ochratoxin contamination in green and processed coffee, including A. ochraceus, A. carbonarius, and A. niger. Tree nuts and figs may be infested with A. ochraceus and A. melleus, the leading producers of ochratoxins in these commodities.
It seems one of the key points for growth of ochratoxins in grain is at the point where grain is being dried and stored. If grain is sufficiently dry with moisture content below 14.5% it is considered safe to prevent OTA produciton (Magan and Aldred, 2007).
the average concentration of OTA is reported to range from 0.1 to 100 ng/g. OTA concentration in black pepper, cayenne pepper, caraway, cardamom, coriander, chili powder, curcuma, and dried red pepper ranges from 1 to 100 ng/g.The levels of OTA in animal products are the levels of OTA range from 0.1 to 1 ng/g. I was reading through a list of European Union alerts regarding ochratoxin and saw that some pumpkin seeds from China were listed as having 20,000 ng/g and licorice root from Turkey had 434 ng/g.
There are numerous countries that limit the amount of ochratoxin A allowed in cereals (grains) and cereal products. The limits range from 3 micrograms/kilogram to 50 micrograms/kilogram. At the time of this writing I saw suggested limits on the FDA website but not any regulated limits.
Health Effects of Ochratoxins
The fact that OTA is such a potent mycotoxin relies on its ability to disturb cellular physiology in multiple ways, particularly byinhibiting the phenylalanyl-tRNA-synthetase (Baudrimontetal., 1997; Creppyet al., 1983a),
OTA acts as a nephrotoxin and an urothelial carcinogen as a result of both the oxidative stress and direct genotoxic mechanisms. Strikingly, chronic exposure to low OTA doses could be even more damaging than acute exposure to a high dose
OTA is nephrotoxic, hepatotoxic, embryotoxic, teratogenic, neurotoxic, immunotoxic, genotoxic, and carcinogenic in many species of animals with species and sex-related differences Ochratoxin A (OTA) is a known nephrotoxic, immunotoxic, and carcinogenic mycotoxin in animals [1, 2] that has long been studied for its role in animal and human disease. Molds associated with the production of OTA include Aspergillus ochraceus, Aspergillus niger and Aspergillus carbonarius, Penicillium verrucosum, and species of Penicillium, Petromyces, and Neopetromyces . Concerns regarding exposure to ochratoxin have primarily centered on exposure to food contaminated with OTA such as wine, beer, coffee, dried vine fruit, grape juices, pork, poultry, dairy, spices, and chocolate . Toxicity from ochratoxin is considered serious enough that it is among approximately 20 mycotoxins monitored in food.
In the blood, OTA binds to albumin and the bound fraction constitutes a mobile reserve of OTA . The relative contribution of each excretory route is influenced by the degree of serum macromolecular binding as well as differences in the enterohepatic recirculation of OTA . Elimination of OTA in urine and feces is felt to be relatively slow and has been shown to vary by species and gender as well as specific genotype that may affect the biotransformation of OTA.
Ochratoxin has been found in liver, muscle, fat, skin, gastric mucosa, the heart muscles bone marrow, as well as the adrenal medulla and cortex in animals. Ochratoxin is considered toxic to the kidneys, immune system, damages the growing fetus and is a possible carcinogen. Ochratoxin poisoning is thought to be the cause of a chronic kidney disease in humans known as Balkan endemic nephropathy. Recent studies have provided a link between ochratoxin exposure and human testicular cancer in Europe.
Interest in the mechanism of action of mycotoxins and especially OTA has increased with the availability of a Clinical Laboratory Improvement Amendments (CLIA) regulation-compliant registered laboratory test, which has identified OTA in the urine of humans with chronic illness . One of the clinical studies identified OTA in 83% of over 100 individuals tested with chronic illness and a history of water-damaged building exposure.
Oxidative stress may be a possible key facctor in the toxicity and genotoxicity of OTA. Oxidative DNA damage has been seen in vitro with OTA and in the kidney and liver of rats. OTA was shown to increase the formation of oxidative products of lipds, with increased production of malondialdehyde, in creased reactive oxygen species levels as well as 8-oxoguanine formation and deplted cellular glutathione levels. A study showed OTA could be decreased by maintaining glutathione production through pretreating the in vitro cell with the glutathione rater limiting amino acid, N-acetyl cysteine, which decreased reactive oxygen species and 8-oxoguanine formation. These are in vitro studies but they lead us to believe glutahione may be protective in ochratoxin damage. It is thought that both DNA adduct-mediated damage by ochratoxin as well as oxidatative stress are causes of OTA induced carcinogenicity. Aflatoxin appears to have similar mechanisms where-by it induces cancer.
OTA lowers the level of phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis. The toxin also enhances lipid peroxidation both in vivo and in vitro, which is probably responsible for its adverse affects on mitochondrial function. OTA also forms DNA adducts in the kidney, liver and spleen that results in single-strand breaks (OTA, 2002).
OTA has been detected in human blood and milk.
The estimated tolerable dosage in humans was estimated at 0.2 to 4.2 ng/kg body weight based upon NTP carcinogenicity study in rats. Following intravenous administration, OTA is eliminated with a half-life from body in vervet monkeys in 19-21 days (Stander et al, 2001).
The oral LD50 of OTA ranges from 3 to 20 mg/kg in different animals.
Ochratoxin is acutely toxic to the kidneys and the liver. There are reports of Ochratoxin being toxic to the nervous system, immune syste, the DNA, to embryos and causing birth defects in humans and animals both.
The International Agency For Research On Cancer has listed Ochratoxin as a Group 2B (possible human carcinogen). It is also thought to cause Blakan Endemic Nephropahty.
Balkan endemic nephropathy (BEN) is a chronic disease associated with ochratoxin exposure. It is a chronic interstitial nephropathy that initially has changes in kidney epithelial cells without any noticable anatomical changes to the eye. After chronic exposure, kidneys have interstitial fibrosis and they are smaller. Towards the end of this process the impairment of kidney function leads to polyuria (pee a lot) accompanied with red tongue, thirst, and a bitter taste. Neither edema nor hypertension that is noticed with other kidney diseases is observed. Other symptoms such as headaches, lower back pain, weakness, and anemia (iron deficiency) have been noted.
Ochratoxin as many mycotoxins is fat soluble and has been shown to accumulate in tissues of animals, especially pigs.
Ochratoxin has a similar molecular structure as the essential amino acid phenlalanine. It has been shown to interfere with phenylalanine hydroxylase activity in the liver and kidney, which inhibits normal creation of proteins and inhibits creation of RNA/DNA.
Urine is the main excretion route for both OTA and OTα, which is a metabolic degradation product of OTA. The amount excreted in the urine is thought to be dependent of the free OTA concerntration. Since OTA binds to serum albumin, many other things that bind to albumin could change how much free OTA is availble to be excreted. Anything affecting serum albumin would also affect the amount of OTA free to be excreted after ingestion. This may be why some studies find the ingested amount of OTA is not related to the amount that is found in the urine. Men tend to have 27% more positive urine samples than women when groups of people are studied.
Ochratoxin is also excreted in human milk. Yes, this means moms exposed to OTA will expose their breast fed infants. The amount in milk is less than that found in blood though. Sudies report as much as ten times less.
Ruminant animals are not as sensitive to ochratoxin A as are non-ruminants. In fact only 2-6.5% of the toxin appears to be absorbed into the animals system. The highest measured has been 10%. This protection appears to be largely due to protozoan content of their rumen. It also appears that the protozoans will decrease in number if the ruminant is fed grains. When I read the research on protozoans assisting in ochratoxin removal from the ruminants, I immediately started wondering about the role of blastocystis which is now being called a commensual. Is it possible that people who are eating ochratoxin contaminated food on a regular basis, (too many of these folks) and have blastocystis in their intestine might be getting assistance from the blastocystis in removing the ochratoxin?
For those of you who want to see the science behind this, here it is: In ruminant animals such as cows, OTA goes through hydrolysis to a non-toxic ochratoxin alpha that takes place in their digestive system in the presence of the ruminant protozoa. This appears to remove the negative effects of the toxin. In one study aflatoxin A and DON were not degraded by rumen microorganisms, but ochratoxin A was cleaved mostly into ochratoxin alpha dand phenylalanine. (Ochratoxin alpha has been shown to be non harmful to pig kidneys) more than 90% of ZEA was degrade to zearalenol and about twice as much alpha zea (has 3-4 times more estrogenic activity as does the parent OTA compound although it may be easier to remove) and beta zea was formed. DAS was quickly and completely deacetylated to monoacetoxyscirpenol and T-2 toxin was deacetylated to HT-2 toxin.
Now the next thing that was identified was that feeding concentrates (largely grains) to ruminants could decrease this protective feature and increase the amount of absorbed mycotoxin. Feeding sheep grains along with their hay decreased the ability to degrade the ochratoxin A by 20%. There are two possible things that might be happening here. One is that the grains may have a lot of ochratoxin on them or the other is that the grains may make the rumen less hospitable for the protozoans. (When I use to have organic dairy goats, all of us raising goats organically knew that grains were not healthy to feed the animal and we kept them to a minimum. It is kind of like feeding candy to kids.) So, in comes another study which found feeding sheep grains decreased the protozoan in the rumen and caused an increase in OTA that was not degraded and ended up being absorbed by the sheep where it was detected in their serum.
Preventing Ochratoxins Exposure
Regulation Of Aflatoxins
For Ochratoxin A:
- The U.S. FDA has no regulations around Ochratoxins.
- The European Union allows 2-10 micrograms/kilogram of Ochratoxin A in food.
- The foods more commonly assumed may have these mycotoxins and therefore more likely to be tested are cereals, dried vine fruits, wine, grapes, coffee, cocoa and cheese.
How Processing Affects Ochratoxin In Food
Ochratoxin A is partially destroyed by baking. Baking and roasting have been reported to reduce the toxin by only 20%. Treatment of grain by scouring while cleaning the grain for milling has resulted in as much as 50% reduction of ochratoxin A in wheat flour. Milling has little effect on OTA. Unfortunately ochratoxin is found in foods that go through high heat processing. Therefore, it is found in cereal products, roasted coffee and beer. Although it can be partially destroyed, it is simply not destroyed well by heat.
Testing For Ochratoxin Exposure
Ochratoxin can be measured in blood serum, in urine and in human kidneys (post-mortem of course) OTA in blood serum is a useful biomarker of OTA exposure due to its high-affinity binding to serum albumin or to other small proteins, which should result in higher serum OTA levels and long persistence of OTA in blood serum. Indeed, the OTA blood levels give a better idea of exposure over longer periods of time. Urine biomarkers are more relevant for day to day exposure. OTA derivatives have also been measured in the blood and urine.
In one study, The correlation between the blood plasma ochratoxin A levels and ochratoxin A consumption was not significant (95% confidence limit). However, a significant correlation was found between ochratoxin A consumption and the urine ochratoxin A concentration expressed as the total amount excreted.
Testing for ochratoxin in the urine can be obtained at these labs.
Urine testing should be 24 hour testing as the amount of toxin can change through-out the day.
PKU - Ochratoxin A Inhibits Phenylalanyl-tRNA Synthetase
The variation of the gene frequency for phenylketonuria (PKU) between races and geographical areas suggests that some regional environmental conditions may confer a selective advantage to the heterozygous state, as is the case with sickle cell anemia and glucose-6-phosphate dehydrogenase deficiency in regions with endemic malaria. Researchers have proposed that the heterozygote advantage in PKU consists in protection from the fungal toxin ochratoxin A, which is produced by some Aspergillus molds that cause food to rot.
Ochratoxin A competitively inhibits the coupling of phenylalanine to its cognate tRNA by the corresponding aminoacyl transferase and thereby disrupts protein synthesis. It is more toxic to fetuses than to adults. This appears to be due to the fetus having low levels of the enzymes that inactivate xenobiotics and toxins such as ochratoxin. Mothers who are heterozygous for PKU will have a somewhat higher level of phenylalanine, which will be shared with the fetus via the placenta. This will counter the inhibition of tRNA aminoacylation in the fetus and thereby afford it some measure of protection.
PKU is quite high in Ireland. This country has had repetative episodes of severe famine. Starving people will tend to eat rotten food rather than discard it. In Irish women, lower rates of abortion were found in those who were heterozygous for PKU.
Deotoxification of Ochratoxins With Biotransformation And Binders
Biotransformation of Ochratoxins
Binders and Bile to Remove Ochratoxins
Interaction of 2′R-ochratoxin A with Serum Albumins: Binding Site, Effects of Site Markers, Thermodynamics, Species Differences of Albumin-binding, and Influence of Albumin on Its Toxicity in MDCK Cells
Remember To Send This To Friends And Family Who Will Benefit From Reading It!