Measures against Toxic of Ochratoxin A: History
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Contributor:
Stoycho Stoev

Ochratoxin A (OTA), which is a frequent contaminant in feeds/foods for animals and humans all over the world, is defined by IARC as a possible human carcinogen and belongs to group 2B mycotoxins, which is based on various experimental studies with rats or mice. Therefore, there are still some disputes among the research community in regard to the real potential of OTA to be carcinogenic for animals, poultry or humans because the mentioned above studies address mainly laboratory animals, such as mice or rats, whereas the data for humans, farm animals and poultry are still limited.

  • feed additives
  • ochratoxin A
  • carcinogenic effect
  • risk assessment
  • prevention

1. Common Spontaneous Neoplastic Changes Characteristic for Advanced Age of the Respective Animals/Poultry

It is well-known that mice or rats are often used to evaluate the carcinogenic action of target toxic and carcinogenic substances. In this regard, historical data and strain sensitivities were considered to be important for adequate interpretation of the induced neoplasia [1][2]. The authors of such studies usually make a comparison between their results and the data from historical control groups in order to take into account the incidences of some spontaneously arisen tumors, characteristic for the advanced age of the used animal strain [3][4].
In this regard, it is important to evaluate only historical control data from the target animal species involved in the respective experiments and to use the same assessment criteria [4][5]. This approach is helpful in the case of evaluation of high incidence of uncommon neoplastic changes in the respective strain of mice/rats. For example, having in mind that above 90% of all spontaneous neoplasia in old Wistar rats are seen in the endocrine (42–48%), integumentary (26%), reproductive (9–11%) and hematopoietic/lymphatic (5.6–7%) systems [6][7][8], such neoplasia should not be considered to be specific as the same are not a consequence of carcinogenic effect of ochratoxin A  (OTA); this mycotoxin is eliminated usually through the kidneys or liver and intestine, provoking direct toxic or neoplastic effects on the same tissues (Table 1).
Table 1. Neoplasia in various tissues and organs in experimental laboratory animals or poultry and their attributability to OTA.
Neoplasia in Various Tissues and Organs in Experimental Laboratory Animals or Poultry
Mainly attributed to OTA Possibly attributed to OTA Not attributed to OTA but to age
References [1][2][9][10][11][12] References [1][2][11] References [3][4][5][6][7][8]
kidneys lung endocrine system
liver ureters reproductive system
intestine subcutaneous tissue hematopoietic system
intestinal mesenterium muscle lymphatic system
  eyes integumentary system
On the other hand, the neoplasia in the liver, kidneys, lung, skin and intestine should be attributed to the carcinogenic action of OTA as the same are not characteristic for the advanced age of rats and could be seen rarely (incidence is below 3–4%) [6][7][8]. Therefore, neoplasia in the urinary (below 0.4% in the rats of advanced age) or muscular (below 0.4% in the rats of advanced age) system, which are not characteristic for Wistar rats in advanced age [7][8][13], could be considered to be due to the cancerogenic effect of OTA [9][10].
It is known that squamous cell carcinoma of the eye is rarely seen in rats in advanced age [14]; however, the same tumor was recently found in rats exposed to 10 ppm OTA for a period of 2 years and is likely due to the carcinogenic effect of OTA or to a direct action of OTA-contaminated feed particles on the eyes’ surface [2]. The lung neoplasia could be also attributed to the intensive OTA-containing blood circulation in some organs, such as the lungs (Table 1).
The species and strain of the experimental mice are also important when investigate the carcinogenic effects of some substances. The BALB/c mouse is the most important laboratory strain for such experimental studies as neoplastic changes are uncommon and can be rarely found up to 22 months of age in BALB/c mice, mainly in the lung and mammary gland [15], and such tumors should be excluded as representative tumors in regards to the carcinogenicity of investigated substances, e.g., OTA. On the other hand, the mean lifespan of BALB/c mice sometimes can reach 29 months depending on the particular strain of mice [16], and thus the BALB/c strain is often used for long-term carcinogenic studies.
In a recent study with BALB/c mice, the carcinogenic effect of OTA when combined with PA was also proven [1]. In regards to the common spontaneous tumors, only myoepithelioma, rhabdomyosarcoma, testicular tumors, lymphoma and mammary tumors were found with a low rate of 0.5–1% of the control BALB/c mice [17][18].

2. The Possible Preventive Measures of Some Feed Additives against Toxic and Carcinogenic Effects of Ochratoxin A 

The most potent protector against OTA toxicity was thought to be PHE as such a protective effect was found against an OTA-induced decrease in serum glucose or serum protein, in addition to the carcinogenic effect of OTA in rats. However, such protection was not always found with respect to OTA-induced changes in serum enzyme activity [2].
The histopathological changes in the Wistar rats exposed to 5 or 10 ppm OTA for a period of 2 weeks were seen in many internal organs; however, the same were not so strong in the rats additionally supplemented with PHE [2]. However, the protective effect of PHE against the carcinogenic effect of OTA was still controversial and only partially proven as seen from the number of OTA-induced neoplasia in the group of rats additionally supplemented with PHE. It is important to emphasize that the number of neoplasia in PHE-supplemented rats exposed to 10 ppm OTA via the feed is approximately the same as in the rats exposed to two times lower OTA concentration in the feed of 5 ppm, which suggests that protective effect of PHE is not as strong as expected [2].
Similarly, the reported carcinogenic or toxic effect of OTA on some internal organs and the suppressed egg production of Plymouth Rock hens was not ameliorated, when the same hens were supplemented with 25 ppm PHE in addition to 5 ppm OTA during the one-year experimental period [11][19]. Moreover, the number of OTA-induced neoplasias was similar between the group of hens additionally supplemented with PHE and the group only treated with the same feed level of 5 ppm OTA, which suggests that PHE cannot serve as a good protector against OTA carcinogenicity or against decreased egg production in hens [11][19].
It is thought that the strong toxicity of OTA is likely due to its structural homology with PHE and the subsequent suppression of protein synthesis or to the damaged production of tyrosine from PHE and also to the inhibition of enzymes participating in the PHE metabolism [20][21]. Some authors proposed that suppling the feed with enough PHE could prevent OTA-induced suppression of protein synthesis, which is responsible for the disruption of some lipoprotein formations, e.g., cellular membranes, lysosomes and mitochondria [2][20]. Such damage in membrane integrity could be responsible for the increased permeability of lysosomes and subsequent leakage of target autolytic enzymes into the cytosol of cells and the expected degenerative changes in the same cells. In this regard, feed supplementation with PHE should prevent or at least ameliorate the same cellular OTA provoked damage.
Unfortunately, some recent experiments with poultry and rats clearly showed that the protective effect of PHE was lower than the expectations of the authors [2][11][19][22]. A probable cause for such disruption of protective effect of PHE against OTA toxicity could be the circumstance that PHE-supplementation in mice was found to elevate the OTA-content in serum and liver by about four to eight times due to increasing its gastrointestinal absorption [23]. It appears that the observed decrease in protective effect of PHE against OTA toxicity could be due to the circumstance that the induced by PHE increase in the intestinal OTA-absorption counteract this protection. This is possibly the main cause for the slight protective effect of PHE as PHE cannot overwhelm the increased toxicity of the higher OTA levels.
In order to define the right protective measures against the toxic or carcinogenic effect of OTA, some other target mechanisms of OTA-toxicity have to be taken into account, e.g., the inhibition of mitochondrial transport and the increase in lipid peroxidation in addition to the observed genotoxic effect and DNA-adduct formation [24][25][26], which could be responsible for its carcinogenic effect. It was reported that OTA can suppress the macrophage phagocytic activity of natural killer cells and T-killer cells via decreasing of the basal inteferon and is partly responsible for cancerogenic effect of OTA [27].
The strong immunosuppressive effect of OTA on humoral and cellular immune response and the observed suppression of the activity in natural killer cell [28][29] could also disrupt the regular destroying of tumor cells [1][2][11]; however, the same should be prevented by target feed additives, e.g., immune boosters. The possible mechanism of immunosuppression could be due to the known inhibition of protein synthesis and subsequent delay of the division of the immunocompetent cells of the immune system provoked by OTA [27].
Such an impairment of protein synthesis in lymphocytes might lead to respective impairment in their proliferation and differentiation [30][31]. The OTA-induced suppression of humoral and cellular immune response, which is known in principle, was demonstrated in practice by an experimental study with pigs. It was shown that the immunosuppressive effect of OTA was the first expressed toxic effect of OTA, which induced the development of target secondary microbial infections in pigs at low contamination levels of 1 ppm OTA in the diet [29].
OTA was found to suppress cell-mediated and humoral immune responses in feed levels of 2–4 ppm in pigs [27][29][32] and chicks [33]; however, no immunosuppressive effect was found at feed levels of 1 ppm [22]. The immunosuppressive effect of OTA was seen to be stronger when chicks or animals were simultaneously treated with PA at low contamination levels of 0.2–0.8 ppm OTA [28], which suggested a stronger immunosuppressive and carcinogenic effect of the same toxins, when ingested together as happens in practice and was recently proven in mice experiments [1].
In such a way, the toxicity and carcinogenicity of various OTA-producing strains could be different and often not correlating with the capacity of OTA production. It seems that moldy feed contaminated with OTA and other mycotoxins as happen in the field could be much more dangerous because such feed was found to be more toxic or carcinogenic for laboratory and farm animals [1][28][34][35].
Having in mind that OTA is only a part of the complex of many other mold metabolites, e.g., PA, citrinine, and fumonisin B1, which might be synergistic with it in immunosuppressive or carcinogenic effects, special attention should be paid to the level of OTA interaction with other target metabolites in commercial chicken/pig diet or human food because such low contaminations levels of OTA could be dangerous when ingested together with other target metabolites in the same spontaneously contaminated feeds/foods [36][37][38][39].
In addition to PHE, significant protective effects against the growth inhibitory effects of OTA and associated pathomorphological changes were seen for some other feed additives, e.g., water extract of artichoke, sesame seeds (rich in PHE) and Roxazyme-G (polyenzyme complement produced by fungi ‘Trichoderma’) [22][28][40]. The protective effect of Roxazyme-G and sesame seeds was well expressed in regards to OTA-provoked changes in the kidneys and liver.
Surprisingly, the protective effect of sesame seed and artichoke extract was found to be better expressed against 5 ppm OTA-induced suppression of humoral immune response as compared to PHE in the same experimental study. This could be due to the improved protein synthesis, which is damaged in OTA-treated animals and also to the improved division of the cells of the immune system, which is known to be destroyed in OTA-exposed animals as has been found [22][28][40].
That circumstance suggests that the same additives could be used to protect against the carcinogenic effects of OTA via protecting against the immunosuppressive effect of OTA on cellular immune response and the suppression of the activity in natural killer cells [28][29], which is responsible for the regular destruction of tumor cells [1][2][11]. The observed protection of the same additives against an OTA-induced decrease in the lymphoid organs’ weight in chicks suggests such a mechanism of protection [22][28][40].
Sesame seeds, which are rich in proteins (about 20%) and PHE (about 4.3%), present a cheaper way to supply animals with PHE and also to avoid the increased absorption of OTA from the gastrointestinal tract provoked by pure PHE [23]. Sesame seeds can also increase the energy metabolism in animals, which usually is damaged in OTA-exposed animals [41]. Similarly, Roxazyme-G can increase the digestive dissimilation of polysaccharides, which could improve digestible energy production by 8–13% and in such a way to improve the energy metabolism, which is impaired in OTA-treated animals.
On the other hand, artichoke-extract is recommended as a diuretic agent and was found to increase the urinary excretion of OTA [22][28][40][42]. It was also found that cynarine and flavonoids content in such extracts could increase the metabolism of cholesterol and decrease serum urea and lipids by improving the diuresis and biliary secretion, which can improve the hepatobiliary route of excretion of OTA in chicks (OTA is excreted via the bile and urine) [22][28][40]. In addition, cynarine and flavonoids content in artichoke-extract possess a strong protective effect on the liver [43][44][45] protecting against hepatocellular damages induced by OTA in chicks. The high levels of vitamin C in the artichoke-extract could also have a protective effect against OTA as it was found that ascorbic acid supplementation (300 mg/kg) to the diet of laying hens can reduce OTA toxicity [46].
Some experimental studies with poultry exposed to OTA and supplemented with various herbs or herbal products given as feed additives also revealed significant protection against the toxic and immunosuppressive effects of OTA. The OTA-induced damages in various internal organs and immunosuppression were less pronounced in the chicks/animals protected by certain target herbs or herbal products, e.g., Silybum marianum, Withania somnifera and Silymarin, whereas slight protection was seen for the herbs Centella asiatica, Glycyrrhiza glabra and Tinospora cordifolia. The protective effect of the same herbs was mainly seen on the kidneys, liver and immune system, which are usually compromised by OTA [47][48][49][50].
Clearly, some of the mentioned above protective additives, e.g., sesame seeds and artichoke-extract or target herbs or herbal products and extracts, could be used as possible supplements to the feeds in order to ameliorate the toxic and carcinogenic effects of OTA in animals or poultry. However, this possibility should be further investigated and analyzed, particularly in regards to the economic efficiency of each target additive to be used as a practical approach for safe utilization of OTA-contaminated fodder avoiding the condemnation of such fodder.
For preventing possible human exposure to this dangerous and relatively heat stable mycotoxin having a strong carcinogenic- and toxic effect on farm animals or humans, some preventive measures have been recently suggested to be undertaken at slaughterhouses [36][51][52]. For example, in order to prevent the contamination of chicken meat with OTA, the period of feed deprivation of chickens before slaughter could be prolonged.
In addition, a possible change in the feed source for a several days in chicken or for a week in pigs before slaughter time in farms with mycotoxic nephropathy could decrease tissue contamination with OTA because OTA has a short half-life in chicks (4 h) [22] and pigs (72–120 h) [36]. In already slaughtered pigs and chicks, the prevention of tissue contamination with OTA may include a condemnation of the kidneys and liver (in chicks) or kidneys (in pigs) as OTA is accumulated in the same target organs in high levels.

This entry is adapted from the peer-reviewed paper 10.3390/toxins14060380

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