Ochratoxin A

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Ochratoxin A
Ochratoxin A.svg
Ochratoxin A 3D BS.png
Names
IUPAC name
N-[(3R)-5-Chloro-8-hydroxy-3-methyl-1-oxo-3,4-dihydro-1H-2-benzopyran-7-carbonyl]-L-phenylalanine
Systematic IUPAC name
(2S)-2-[(3R)-5-Chloro-8-hydroxy-3-methyl-1-oxo-3,4-dihydro-1H-2-benzopyran-7-carboxamido]-3-phenylpropanoic acid
Other names
(R)-N- [(5-Chloro- 3,4-dihydro- 8-hydroxy- 3-methyl- 1-oxo- 1H-2-benzopyran-7-yl) -carbonyl]- L- phenylalanine
(−)-N- [(5-Chloro- 8-hydroxy- 3-methyl- 1-oxo- 7-isochromanyl) carbonyl]- 3-phenylalanine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.005.586 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 206-143-7
KEGG
PubChem CID
UNII
UN number 2811
  • InChI=1S/C20H18ClNO6/c1-10-7-12-14(21)9-13(17(23)16(12)20(27)28-10)18(24)22-15(19(25)26)8-11-5-3-2-4-6-11/h2-6,9-10,15,23H,7-8H2,1H3,(H,22,24)(H,25,26)/t10-,15+/m1/s1 Yes check.svgY
    Key: RWQKHEORZBHNRI-BMIGLBTASA-N Yes check.svgY
  • InChI=1/C20H18ClNO6/c1-10-7-12-14(21)9-13(17(23)16(12)20(27)28-10)18(24)22-15(19(25)26)8-11-5-3-2-4-6-11/h2-6,9-10,15,23H,7-8H2,1H3,(H,22,24)(H,25,26)/t10-,15+/m1/s1
    Key: RWQKHEORZBHNRI-BMIGLBTABQ
  • O=C(O)[C@@H](NC(=O)c1c(O)c2c(c(Cl)c1)C[C@H](OC2=O)C)Cc3ccccc3
Properties
C20H18ClNO6
Molar mass 403.813
Melting point 169 °C (336 °F; 442 K)
Hazards
GHS labelling:
GHS-pictogram-skull.svg GHS-pictogram-exclam.svg GHS-pictogram-pollu.svg
Danger
H300, H351, H413
P203, P260, P264, P264+P265, P270, P271, P273, P280, P284, P301+P316, P304+P340, P305+P351+P338, P316, P318, P320, P321, P330, P337+P317, P403+P233, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Ochratoxin A—a toxin produced by different Aspergillus and Penicillium species — is one of the most-abundant food-contaminating mycotoxins. [1] It is also a frequent contaminant of water-damaged houses and of heating ducts. [2] [3] Human exposure can occur through consumption of contaminated food products, particularly contaminated grain and pork products, as well as coffee, wine grapes, and dried grapes. [4] [5] [6] The toxin has been found in the tissues and organs of animals, including human blood and breast milk. [7] Ochratoxin A, like most toxic substances, has large species- and sex-specific toxicological differences. [5]

Impact on human and animal health

Carcinogenicity

Ochratoxin A is potentially carcinogenic to humans (Group 2B), and has been shown to be weakly mutagenic, possibly by induction of oxidative DNA damage. [8]

The evidence in experimental animals is sufficient to indicate carcinogenicity of ochratoxin A. It was tested for carcinogenicity by oral administration in mice and rats. It slightly increased the incidence of hepatocellular carcinomas in mice of each sex. [9] and produced renal adenomas and carcinomas in male mice and in rats (carcinomas in 46% of males and 5% of females). [10] In humans, very little histology data is available, so a relationship between ochratoxin A and renal cell carcinoma has not been found. However, the incidence of transitional cell (urothelial) urinary cancers seems abnormally high in Balkan endemic nephropathy patients, especially for the upper urinary tract. [11] The molecular mechanism of ochratoxin A carcinogenicity has been under debate due to conflicting literature, however this mycotoxin has been proposed to play a major role in reducing antioxidant defenses. [12]

Neurotoxicity

Ochratoxin A has a strong affinity for the brain, especially the cerebellum (Purkinje cells), ventral mesencephalon, and hippocampal structures. [13] The affinity for the hippocampus could be relevant to the pathogenesis of Alzheimer's disease, and subchronic administration to rodents induces hippocampal neurodegeneration. Ochratoxin causes acute depletion of striatal dopamine, which constitutes the bed of Parkinson's disease, but it did not cause cell death in any of brain regions examined. [14] Teams from Zheijiang Univ. and Kiel Univ. hold that ochratoxin may contribute to Alzheimer's and to Parkinson's diseases. Nonetheless, their study was performed in vitro and may not extrapolate to humans. [15] The developing brain is very susceptible to ochratoxin, hence the need for caution during pregnancy. [16]

Immunosuppression and immunotoxicity

Ochratoxin A can cause immunosuppression and immunotoxicity in animals. The toxin's immunosuppressant activity in animals may include depressed antibody responses, reduced size of immune organs (such as the thymus, spleen, and lymph nodes), changes in immune cell number and function, and altered cytokine production. Immunotoxicity probably results from cell death following apoptosis and necrosis, in combination with slow replacement of affected immune cells due to inhibition of protein synthesis. [1]

Balkan endemic nephropathy (BEN), a slowly progressive renal disease, appeared in the middle of the 20th century, highly localized around the Danube, but only hitting certain households. Patients over the years develop kidney failure that requires dialysis or transplantation. The initial symptoms are those of a tubulointerstitial nephritis of the sort met with after toxic aggressions to the proximal convoluted tubules. Such proximal tubule nephropathies can be induced by aluminium (e.g. in antiperspirants), antibiotics (vancomycin, aminosides), tenofovir (for AIDS), and cisplatin[ citation needed ]. Their symptoms are well known to nephrologists: glycosuria without hyperglycemia, microalbuminuria, poor urine concentration capacity, impaired urine acidification, and yet long-lasting normal creatinine clearance. [17] In BEN, renal biopsy shows acellular interstitial fibrosis, tubular atrophy, and karyomegaly in proximal convoluted tubules. [18] A number of descriptive studies have suggested a correlation between exposure to ochratoxin A and BEN, and have found a correlation between its geographical distribution and a high incidence of, and mortality from, urothelial urinary tract tumours. [19] However, insufficient information is currently available to conclusively link ochratoxin A to BEN. [20] The toxin may require synergistic interactions with predisposing genotypes or other environmental toxicants to induce this nephropathy. [21] Ochratoxin possibly is not the cause of this nephropathy, and many authors are in favor of aristolochic acid, that is contained in a plant: birthwort (Aristolochia clematitis). Nevertheless, although many of the pieces of scientific evidence are lacking and/or need serious re-evaluation, it remains that ochratoxin, in pigs, demonstrates direct correlation between exposure and onset and progression of nephropathy. [22] This porcine nephropathy [23] bears typical signs of toxicity to proximal tubules: loss of ability to concentrate urine, glycosuria, and histological proximal tubule degeneration.

Other nephropathies, although not responding to the "classical" definition of BEN, may be linked to ochratoxin. Thus, this could in certain circumstances be the case for focal segmental glomerulosclerosis after inhalational exposure: such a glomerulopathy with noteworthy proteinuria has been described [24] in patients with very high urinary ochratoxin levels (around 10 times levels that can be met with in "normal" subjects, i.e. around 10 ppb or 10 ng/ml).

Food animal industry impact

Ochratoxin-contaminated feed has its major economic impact on the poultry industry. Chickens, turkeys, and ducklings are susceptible to this toxin. Clinical signs of avian ochratoxicosis generally involve reduction in weight gains, poor feed conversion, reduced egg production, and poor egg shell quality. [25] Economic losses occur also in swine farms, linked to nephropathy and costs for the disposal of carcasses.

Toxicity does not seem to constitute a problem in cattle, as the rumen harbors protozoa that hydrolyze OTA. [26] However, contamination of milk is a possibility.[ citation needed ]

Dietary guidelines

Concentrations of ochratoxin in usual foods
SourceMedian
in μg/kg
of food		Median
in ng/kg
of food		Weight
in kg		Diet 1Diet 1+
Liquorice extract26.3026,300
Ginger5.505,5000.00527.50
Nutmeg2.272,2650.00511.33
Paprika1.321,3150.0056.58
Pig liver1.101,100
Ginseng1.101,100
Raisins dry0.959500.195.00
Pig kidney0.808000.2160
Liquorice confectionery0.17170
Coffee0.131250.337.50
Cereals0.0987.50.543.75
Peanuts0.08790.215.80
Wine0.05500.525
Pulses0.0549.50.524.75
Beer0.0549
Salami0.05490.314.70
Total in ng286.11461.91

EFSA established in 2006 the "tolerable weekly intake" (TWI) of ochratoxin A (on advice of the Scientific Panel on Contaminants in the Food Chain) at 120 ng/kg., [27] equivalent to a tolerable daily intake (TDI) of 14 ng/kg. Other organizations have established even lower limits for intake of ochratoxin A, based on the consumption habits of the population. [28] For USA, the FDA considers a TDI of 5 ng/kg. In the US, mean body weight for men is 86 kg, and for women 74 kg.[ citation needed ] Hence, the TDI for men is 430 ng and for women is 370 ng. In the joined table "weight in kg" is the weight eaten per day of each of the listed foodstuffs. Diet 1, with small quantities of ginger, nutmeg, and paprika, a good serving of dry raisins, a reasonable amount of coffee, cereals, wine, pulses, and salami, amounts to a safe diet (as for ochratoxin, at least), with 286 ng per day. However, it would be easy to go into excessive levels (Diet 1+), just by eating 200 g of pig kidney and 200 g of peanuts, which would lead to a total of nearly 462 ng of ochratoxin. This shows how delicate a safe diet can be.

Tolerable daily intake 5 ng/kg
GenderWeight
in kg		Tolerable OTA
in ng
male86430
female74370

Although ochratoxin A is not held as of today as responsible for renal cell carcinoma (RCC), the most frequent renal cancer, it is frequently written that dietary pattern might decrease or increase the risk of RCC. A Uruguayan case-control study [29] correlates intake of meat with occurrence of RCC. A very large prospective cohort in Sweden [30] explores correlations between RCC occurrence, diets rich in vegetables and poultry (so-called "healthy diets"), and diets rich in meat (especially processed meat: salami, black pudding). The thesis defended is that more fruit and vegetables might have a protective role. Fruit (except raisins and dried fruit) are very poor in ochratoxin, and processed meat can be rich in ochratoxin.

Dermal exposure

Ochratoxin A can permeate through the human skin. [31] Although no significant health risk is expected after dermal contact in agricultural or residential environments, skin exposure to ochratoxin A should nevertheless be limited.

Genetic resistance

In 1975, Woolf et al. [32] proposed that the inherited disorder phenylketonuria protects against ochratoxin A poisoning through the production of high levels of phenylalanine. Ochratoxin is a competitive inhibitor of phenylalanine in the phenylalanyl-tRNA-synthetase-catalyzed reaction thus preventing protein synthesis, which can be reversed by introducing phenylalanine, which is in excess in PKU individuals. [33]

See also

Related Research Articles

<span class="mw-page-title-main">Aflatoxin</span> Group of poisons produced by moulds

Aflatoxins are various poisonous carcinogens and mutagens that are produced by certain molds, particularly Aspergillus species mainly by Aspergillus flavus and Aspergillus parasiticus. According to the USDA, "They are probably the best known and most intensively researched mycotoxins in the world." The fungi grow in soil, decaying vegetation and various staple foodstuffs and commodities such as hay, maize, peanuts, coffee, wheat, millet, sorghum, cassava, rice, chili peppers, cottonseed, tree nuts, sesame seeds, sunflower seeds, and various cereal grains and oil seeds. In short, the relevant fungi grow on almost any crop or food. When such contaminated food is processed or consumed, the aflatoxins enter the general food supply. They have been found in both pet and human foods, as well as in feedstocks for agricultural animals. Animals fed contaminated food can pass aflatoxin transformation products into milk, milk products, and meat. For example, contaminated poultry feed is the suspected source of aflatoxin-contaminated chicken meat and eggs in Pakistan.

<span class="mw-page-title-main">Proximal tubule</span> Segment of nephron in kidneys

The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s capsule abruptly transition to proximal tubule epithelial cells (PTECs). The proximal tubule can be further classified into the proximal convoluted tubule (PCT) and the proximal straight tubule (PST).

A mycotoxin is a toxic secondary metabolite produced by fungi and is capable of causing disease and death in both humans and other animals. The term 'mycotoxin' is usually reserved for the toxic chemical products produced by fungi that readily colonize crops.

<span class="mw-page-title-main">T-2 mycotoxin</span> Chemical compound

T-2 mycotoxin is a trichothecene mycotoxin. It is a naturally occurring mold byproduct of Fusarium spp. fungus which is toxic to humans and other animals. The clinical condition it causes is alimentary toxic aleukia and a host of symptoms related to organs as diverse as the skin, airway, and stomach. Ingestion may come from consumption of moldy whole grains. T-2 can be absorbed through human skin. Although no significant systemic effects are expected after dermal contact in normal agricultural or residential environments, local skin effects can not be excluded. Hence, skin contact with T-2 should be limited.

Acute tubular necrosis (ATN) is a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. Because necrosis is often not present, the term acute tubular injury (ATI) is preferred by pathologists over the older name acute tubular necrosis (ATN). ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. Common causes of ATN include low blood pressure and use of nephrotoxic drugs. The presence of "muddy brown casts" of epithelial cells found in the urine during urinalysis is pathognomonic for ATN. Management relies on aggressive treatment of the factors that precipitated ATN. Because the tubular cells continually replace themselves, the overall prognosis for ATN is quite good if the underlying cause is corrected, and recovery is likely within 7 to 21 days.

<span class="mw-page-title-main">Fumonisin B1</span> Chemical compound

Fumonisin B1 is the most prevalent member of a family of toxins, known as fumonisins, produced by multiple species of Fusarium molds, such as Fusarium verticillioides, which occur mainly in maize (corn), wheat and other cereals. Fumonisin B1 contamination of maize has been reported worldwide at mg/kg levels. Human exposure occurs at levels of micrograms to milligrams per day and is greatest in regions where maize products are the dietary staple.

<span class="mw-page-title-main">Ochratoxin</span> Group of chemical compounds

Ochratoxins are a group of mycotoxins produced by some Aspergillus species and some Penicillium species, especially P. verrucosum. Ochratoxin A is the most prevalent and relevant fungal toxin of this group, while ochratoxins B and C are of lesser importance.

<span class="mw-page-title-main">Trichothecene</span> Large family of chemically related mycotoxins

The trichothecenes are a large family of chemically related mycotoxins. They are produced by various species of Fusarium, Myrothecium,Trichoderma, Podostroma, Trichothecium, Cephalosporium, Verticimonosporium, and Stachybotrys. Chemically, trichothecenes are a class of sesquiterpenes.

<span class="mw-page-title-main">Zearalenone</span> Chemical compound

Zearalenone (ZEN), also known as RAL and F-2 mycotoxin, is a potent estrogenic metabolite produced by some Fusarium and Gibberella species. Specifically, the Gibberella zeae, the fungal species where zearalenone was initially detected, in its asexual/anamorph stage is known as Fusarium graminearum. Several Fusarium species produce toxic substances of considerable concern to livestock and poultry producers, namely deoxynivalenol, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS) and zearalenone. Particularly, ZEN is produced by Fusarium graminearum, Fusarium culmorum, Fusarium cerealis, Fusarium equiseti, Fusarium verticillioides, and Fusarium incarnatum. Zearalenone is the primary toxin that binds to estrogen receptors, causing infertility, abortion or other breeding problems, especially in swine. Often, ZEN is detected together with deoxynivalenol in contaminated samples and its toxicity needs to be considered in combination with the presence of other toxins.

<span class="mw-page-title-main">Citrinin</span> Chemical compound

Citrinin is a mycotoxin which is often found in food. It is a secondary metabolite produced by fungi that contaminates long-stored food and it can cause a variety of toxic effects, including kidney, liver and cell damage. Citrinin is mainly found in stored grains, but sometimes also in fruits and other plant products.

<span class="mw-page-title-main">Balkan endemic nephropathy</span> Medical condition

Balkan endemic nephropathy (BEN) is a form of interstitial nephritis causing kidney failure. It was first identified in the 1920s among several small, discrete communities along the Danube River and its major tributaries, in the modern countries of Croatia, Bosnia and Herzegovina, Serbia, Kosovo, Romania, and Bulgaria. It is caused by small long-term doses of aristolochic acid in the diet. The disease primarily affects people 30 to 60 years of age. Doses of the toxin are usually low and people moving to endemic areas typically develop the condition only when they have lived there for 10–20 years. People taking higher doses of aristolochic acid have developed kidney failure after shorter durations of exposure.

Patulin is an organic compound classified as a polyketide. It is named after the fungus from which it was isolated, Penicillium patulum. It is a white powder soluble in acidic water and in organic solvents. It is a lactone that is heat-stable, so it is not destroyed by pasteurization or thermal denaturation. However, stability following fermentation is lessened. It is a mycotoxin produced by a variety of molds, in particular, Aspergillus and Penicillium and Byssochlamys. Most commonly found in rotting apples, the amount of patulin in apple products is generally viewed as a measure of the quality of the apples used in production. In addition, patulin has been found in other foods such as grains, fruits, and vegetables. Its presence is highly regulated.

Mycotoxicology is the branch of mycology that focuses on analyzing and studying the toxins produced by fungi, known as mycotoxins. In the food industry it is important to adopt measures that keep mycotoxin levels as low as practicable, especially those that are heat-stable. These chemical compounds are the result of secondary metabolism initiated in response to specific developmental or environmental signals. This includes biological stress from the environment, such as lower nutrients or competition for those available. Under this secondary path the fungus produces a wide array of compounds in order to gain some level of advantage, such as incrementing the efficiency of metabolic processes to gain more energy from less food, or attacking other microorganisms and being able to use their remains as a food source.

Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. Endotoxins most commonly refer to the lipopolysaccharide (LPS) or lipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. The botulinum toxin, which is primarily produced by Clostridium botulinum and less frequently by other Clostridium species, is the most toxic substance known in the world. However, microbial toxins also have important uses in medical science and research. Currently, new methods of detecting bacterial toxins are being developed to better isolate and understand these toxins. Potential applications of toxin research include combating microbial virulence, the development of novel anticancer drugs and other medicines, and the use of toxins as tools in neurobiology and cellular biology.

Aflatoxin B<sub>1</sub> Chemical compound

Aflatoxin B1 is an aflatoxin produced by Aspergillus flavus and A. parasiticus. It is a very potent carcinogen with a TD50 3.2 μg/kg/day in rats. This carcinogenic potency varies across species with some, such as rats and monkeys, seemingly much more susceptible than others. Aflatoxin B1 is a common contaminant in a variety of foods including peanuts, cottonseed meal, corn, and other grains; as well as animal feeds. Aflatoxin B1 is considered the most toxic aflatoxin and it is highly implicated in hepatocellular carcinoma (HCC) in humans. In animals, aflatoxin B1 has also been shown to be mutagenic, teratogenic, and to cause immunosuppression. Several sampling and analytical methods including thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), mass spectrometry, and enzyme-linked immunosorbent assay (ELISA), among others, have been used to test for aflatoxin B1 contamination in foods. According to the Food and Agriculture Organization (FAO), a division of the United Nations, the worldwide maximum tolerated levels of aflatoxin B1 was reported to be in the range of 1–20 μg/kg (or .001 ppm - 1 part-per-billion) in food, and 5–50 μg/kg (.005 ppm) in dietary cattle feed in 2003.

<span class="mw-page-title-main">Organic anion transporter 1</span> Protein-coding gene in the species Homo sapiens

The organic anion transporter 1 (OAT1) also known as solute carrier family 22 member 6 (SLC22A6) is a protein that in humans is encoded by the SLC22A6 gene. It is a member of the organic anion transporter (OAT) family of proteins. OAT1 is a transmembrane protein that is expressed in the brain, the placenta, the eyes, smooth muscles, and the basolateral membrane of proximal tubular cells of the kidneys. It plays a central role in renal organic anion transport. Along with OAT3, OAT1 mediates the uptake of a wide range of relatively small and hydrophilic organic anions from plasma into the cytoplasm of the proximal tubular cells of the kidneys. From there, these substrates are transported into the lumen of the nephrons of the kidneys for excretion. OAT1 homologs have been identified in rats, mice, rabbits, pigs, flounders, and nematodes.

<span class="mw-page-title-main">Riddelliine</span> Chemical compound

Riddelliine is a chemical compound classified as a pyrrolizidine alkaloid. It was first isolated from Senecio riddellii and is also found in a variety of plants including Jacobaea vulgaris, Senecio vulgaris, and others plants in the genus Senecio.

Aspergillus ochraceus is a mold species in the genus Aspergillus known to produce the toxin ochratoxin A, one of the most abundant food-contaminating mycotoxins, and citrinin. It also produces the dihydroisocoumarin mellein. It is a filamentous fungus in nature and has characteristic biseriate conidiophores. Traditionally a soil fungus, has now began to adapt to varied ecological niches, like agricultural commodities, farmed animal and marine species. In humans and animals the consumption of this fungus produces chronic neurotoxic, immunosuppressive, genotoxic, carcinogenic and teratogenic effects. Its airborne spores are one of the potential causes of asthma in children and lung diseases in humans. The pig and chicken populations in the farms are the most affected by this fungus and its mycotoxins. Certain fungicides like mancozeb, copper oxychloride, and sulfur have inhibitory effects on the growth of this fungus and its mycotoxin producing capacities.

Penicillium verrucosum is a psychrophilic fungus which was discovered in Belgium and introduced by Dierckx in 1901. Six varieties of this species have been recognized based primarily on differences in colony colour: P. verrucosum var. album, P. verrucosum var. corymbiferum, P. verrucosum var. cyclopium, P. verrucosum var. ochraceum, P. verrucosum var. melanochlorum and P. verrucosum var. verrucosum. This fungus has important implications in food, specifically for grains and other cereal crops on which it grows. Its growth is carefully regulated in order to reduce food spoilage by this fungi and its toxic products. The genome of P. verrucosum has been sequenced and the gene clusters for the biosyntheses of its mycotoxins have been identified.

<span class="mw-page-title-main">Nivalenol</span> Type of mycotoxin

Nivalenol (NIV) is a mycotoxin of the trichothecene group. In nature it is mainly found in fungi of the Fusarium species. The Fusarium species belongs to the most prevalent mycotoxin producing fungi in the temperate regions of the northern hemisphere, therefore making them a considerable risk for the food crop production industry.

References

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  28. ↑ Codex Alimentarius Commission (1999). "Codex Committee on Food Additives and Contaminants, Position paper on ochratoxin A, Thirty-first Session, The Hague, The Netherlands, 22-26 March 1999" (PDF). Joint FAO/WHO Food Standards Programme: 1–9. Archived from the original (PDF) on 2017-05-18.
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