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Ochratoxin A—a toxin produced by Aspergillus ochraceus, Aspergillus carbonarius, and Penicillium verrucosum—is one of the most-abundant food-contaminating mycotoxins. It is also a frequent contaminant of water-damaged houses and of heating ducts. 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. The toxin has been found in the tissues and organs of animals, including human blood and breast milk. Ochratoxin A, like most toxic substances, has large species- and sex-specific toxicological differences. While its exact mechanism of toxicity is controversial, it has been postulated to inhibit cellular energy production and a variety of other vital pathways as well as having a genotoxic effect forming radical DNA adducts.

Contamination Sources
Ochratoxin A was originally isolated from colonies of Aspergillus ochraceus in 1965, but more recent studies have discovered its production in other fungal genera Aspergillus carbonarius, and Penicillium verrucosum. Countries in hot and wet climate conditions (particularly African, South Asian, and South American nations) typically are prone to more toxic filamentous fungi contamination, and therefore also fungi that produce ochratoxins and other mycotoxins. However, countries of Northern Europe are especially contaminated with ochratoxin A produced by fungi belonging to the Penicillium genera which thrives in Europe's colder climates.

Nearly half of all ochratoxin A exposure occurs due to cereal and grain contamination. The second highest source of ochratoxin A exposure is from wine or grape products, such as dried grapes, at 10-15% of total. Though other sources of contamination occur in agricultural products such as coffee beans, pulses, spices, meat and cheese products, and even beer.

Biosynthesis


Not much is known about the fungal biosynthesis of ochratoxin A. Moiety analysis of the molecular strucure of the toxin has suggested key enzymes such as polyketide synthase, an enzyme involved in other mycotoxin biosynthesis pathway. Some studies have attempted to discern potential pathways to the toxin. Huff and Hamilton proposed a potential synthesis pathway originating from simple metabolites acetyl CoA and malonate which form a polyketide. Under this hypothetical biosynthetic pathway to ochratoxin A, a cyclic mellein molecule undergoes convergent synthesis with phenylalanine found on the final ochratoxin A molecule, and the two join through peptide linkage and ultimately producing the final product through esterase activity. Cloning and genetic studies to find the gene cluster for enzymes in the biosythetic pathway are currently undergoing, but show promising results based on other mycotoxin biosynthetic examples.

Legislation and legal limits
General concern for the potential effects of mycotoxins has been growing in recent years. As of early 2010, a considerable amount of countries have mandated monitoring and controlling mycotoxin levels like ochratoxin A in commodities. . Many scientific committees in the United States and globally have attempted to investigate the safe daily intake amount of ochratoxin A in recent decades. In 2004, the European Commission Regulation (EC) amended its previous regulations to limit ochratoxin A intake to 1.2-14 ng/kg daily.

Dietary guidelines
The European Food Safety Authority EFSA established the following table in 2006 for the "tolerable weekly intake" (TWI) of ochratoxin A (on advice of the Scientific Panel on Contaminants in the Food Chain) at 120 ng/kg., equivalent to a tolerable daily intake (TDI) of 14 ng/kg. One such ruling was the toxin contamination in unprocessed cereal was limited to 5 μg/kg, with cereal-derived products limited to 3 μg/kg. . Other organizations have established even lower limits for intake of ochratoxin A, based on the consumption habits of the population. 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. 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.

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 ochratoxin A exposure generally involve reduction in weight gains, poor feed conversion, reduced egg production, and poor egg shell quality. 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. However, contamination of milk is a possibility. Since liver of animals with ochratoxin A exposure retain the toxin, its use in feed has been significantly reduced.

Toxicity
Ochratoxin A has been termed “the continuing enigma” in terms of its mechanism of toxicity in humans. It is not yet clear the nature of the predominant cellular mechanism of this toxin.

Carcinogenicity
Ochratoxin A is thought to be carcinogenic to humans (Group 2B), though no causal relationship has been found yet. The evidence in experimental animals is sufficient to indicate carcinogenicity of ochratoxin A for legislative studies, however. Oral administration of the toxin in mice and rats slightly increased the incidence of hepatocellular carcinomas in mice of each sex. and produced renal adenomas and carcinomas in male mice and in rats (carcinomas in 46% of males and 5% of females). In humans, however, very little histology data are 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. High rates of ochratoxin A exposure in the Balkans, a region with a strong agricultural presence, and cancer suggests an association of between ochratoxin A and cancer.

Neurotoxicity
Ochratoxin A has a strong affinity for the brain, especially the cerebellum, ventral mesencephalon, and hippocampal structures. 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 neurobiological deficiency of Parkinson's disease, but it did not cause cell death in any of brain regions examined. 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. The developing brain is very susceptible to ochratoxin, hence the need for caution during pregnancy.

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.

Renal Toxicity
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 renal failure that requires dialysis or transplantation. The initial symptoms of BEN are those of a nephritis of the sort met with after toxic aggressions to the proximal convoluted tubules in the kidney. Such symptoms include hallmark kidney dysfunction problems, including high urine sugar content (glycosuria) without hyperglycemia, poor urine concentration capacity, impaired urine acidification, and long-lasting normal creatinine clearance.

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 tumors. However, insufficient information is currently available to conclusively link ochratoxin A to BEN. As is common in other toxins, ochratoxin A may require synergistic interactions with predisposing genetic risk factors or other environmental toxicants to induce this nephropathy. 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. This porcine nephropathy bears typical signs of toxicity to the proximal tubules of the kidney common to BEN such as loss of ability to concentrate urine, high sugar content in foods, and cellular kidney 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 inhalation exposure: such a glomerulopathy with noteworthy excess protein in the urine has been described 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).

Dermal toxicity
Studies have shown ochratoxin A can permeate through the human skin. Although no significant health risk is expected after dermal contact in agricultural or residential environments, skin exposure to ochratoxin A should nevertheless be limited.

Genotoxic Effects
The molecular mechanism of ochratoxin A toxicity has been under debate due to conflicting literature, however this mycotoxin has been proposed to play a major role in reducing antioxidant defenses. and has been shown to be weakly mutagenic, possibly by induction of oxidative DNA damage. Recent studies have summarized the multiple pathways which describe the formation of DNA adducts by ochratoxin A. First, the toxin can undergo oxidation by Cytochrome P450 to form derivative metabolites. These various metabolites can then bind to and be activated by various enzymes like peroxidase which can add electrons to these metabolites to form toxic radicals. These electrophilic or radicalized derivatives may then bind to DNA and negatively affect DNA replication and transcription events, causing mutations.

Treatment
Since ochratoxin A binds to serum albumin, a molecular which allows passage of lipids through the blood, with high affinity, it remains in blood serum for extended periods while producing toxic affects throughout the body. This limits any potential treatment since the toxin may continually have delayed release from serum throughout blood flow. Research has instead focused on limiting its damage where the toxin does appear, rather than prevent its transport. Studies aimed at reducing its oxidative damage have been successful at reducing some of its toxic affects, such as cytotoxicity and DNA damage. Cell-based assays of ochratoxin A exposure treated with anti-oxidant treatments such as Vitamin C, Vitamin E, or Vitamin A have shown promising results. Other studies have attempted limiting ochratoxin A capability to inhibit cellular energy production through diosmetin or carotenoid treatment. Regardless, since the exact target and mechanism of primary toxicity of ochratoxin A is unknown, the efficacy of treatments is significantly lower than required to revert acute exposure.