Ochratoxin A

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]

Ochratoxin A
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
KEGG
UNII
  • 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 checkY
    Key: RWQKHEORZBHNRI-BMIGLBTASA-N checkY
  • 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)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Infobox references

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 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.[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. 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.

Dietary guidelines
Concentrations of ochratoxin in usual foods
Source Median
in μg/kg
of food		 Median
in ng/kg
of food		 Weight
in kg		 Diet 1 Diet 1+
Liquorice extract 26.30 26,300
Ginger 5.50 5,500 0.005 27.50
Nutmeg 2.27 2,265 0.005 11.33
Paprika 1.32 1,315 0.005 6.58
Pig liver 1.10 1,100
Ginseng 1.10 1,100
Raisins dry 0.95 950 0.1 95.00
Pig kidney 0.80 800 0.2 160
Liquorice confectionery 0.17 170
Coffee 0.13 125 0.3 37.50
Cereals 0.09 87.5 0.5 43.75
Peanuts 0.08 79 0.2 15.80
Wine 0.05 50 0.5 25
Pulses 0.05 49.5 0.5 24.75
Beer 0.05 49
Salami 0.05 49 0.3 14.70
Total in ng 286.11 461.91

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. 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
Gender Weight
in kg		 Tolerable OTA
in ng
male 86 430
female 74 370

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

References
  1. Al-Anati L, Petzinger E (2006). "Immunotoxic activity of ochratoxin A". J. Vet. Pharmacol. Ther. 29 (2): 79–90. doi:10.1111/j.1365-2885.2006.00718.x. PMID 16515661.
  2. Polizzi V, et al. (2009). "Fungi, mycotoxins and volatile organic compounds in mouldy interiors from water-damaged buildings". Journal of Environmental Monitoring. 11 (10): 1849–1858. doi:10.1039/b906856b. PMID 19809708.
  3. Richard JL; at al. (1999). "The occurrence of ochratoxin A in dust collected from a problem household". Mycopathologia. 146 (2): 99–103. doi:10.1023/A:1007056627296. PMID 10822509. S2CID 31557794.
  4. Pfohl-Leszkowicz A, Manderville RA (2007). "Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans". Mol Nutr Food Res. 51 (1): 61–99. doi:10.1002/mnfr.200600137. PMID 17195275.
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  6. Blesa J, et al. (2006). "Factors affecting the presence of ochratoxin A in wines". Critical Reviews in Food Science and Nutrition. 46 (6): 473–8. doi:10.1080/10408390500215803. PMID 16864140. S2CID 45392770.
  7. Clark HA, Snedeker SM (2006). "Ochratoxin A: its cancer risk and potential for exposure". Journal of Toxicology and Environmental Health Part B: Critical Reviews. 9 (3): 265–96. doi:10.1080/15287390500195570. PMID 16621780. S2CID 41761053.
  8. Palma N, et al. (2007). "Ochratoxin A-Induced Mutagenesis in Mammalian Cells Is Consistent with the Production of Oxidative Stress". Chemical Research in Toxicology. 20 (7): 1031–1037. doi:10.1021/tx700027j. PMC 2367102. PMID 17567156.
  9. Bendele AM, et al. (1985). "Ochratoxin A Carcinogenesis in the (C57BL/6J X C3H) F1mouse". J Natl Cancer Inst. 75 (4): 733–42. PMID 3862905.
  10. Gary A. Boorman. "Toxicology and Carcinogenesis studies of Ochratoxin A in F344/N rats". National Toxicology Program, May 1989, NTP TR 358.
  11. Basic-Jukic N, et al. (2007). "Renal transplantation in patients with Balkan endemic nephropathy". Transplant Proc. 39 (5): 1432–1435. doi:10.1016/j.transproceed.2006.11.019. PMID 17580155.
  12. C. Cavin; T. Delatour; M. Marin-Kuan; D. Holzhauser; L. Higgins; C. Bezencon (2007). "REduction in antioxidant defences may contribute to ochratoxin A toxicity and carcinogenicity". Toxicological Sciences. 96 (1): 30–39. doi:10.1093/toxsci/kfl169. PMID 17110534.
  13. Belmadani A, et al. (1999). "Selective toxicity of ochratoxin A in primary cultures from different brain regions". Arch Toxicol. 73 (2): 108–114. doi:10.1007/s002040050594. PMID 10350191. S2CID 19714271.
  14. Sava V, et al. (2006). "Acute neurotoxic effects of the fungal metabolite ochratoxin A". Neurotoxicology. 27 (1): 82–92. doi:10.1016/j.neuro.2005.07.004. PMID 16140385.
  15. Xiangnan Zhang; et al. (2009). "Ochratoxin A induces apoptosis in neuronal cells". Genes Nutr. 4 (1): 41–48. doi:10.1007/s12263-008-0109-y. PMC 2654052. PMID 19148691.
  16. Kunio Doi; Koji Uetsuka (2011). "Mechanisms of Mycotoxin-Induced Neurotoxicity through Oxidative Stress-Associated Pathways". International Journal of Molecular Sciences. 12 (8): 5213–5327. doi:10.3390/ijms12085213. PMC 3179161. PMID 21954354.
  17. Aleckovic M, et al. (2010). "Glomerular filtration rate in examined population of Bosnian Posavina – region of Balkan Endemic Nephropathy". Bosn J Basic Med Sci. 10 (3–4): 256–61. doi:10.17305/bjbms.2010.2652. PMC 5627717. PMID 20433435.
  18. Djukanovic L, et al. (2010). "Investigation of Balkan endemic nephropathy in Serbia: how to proceed?". Srp Arh Celok Lek. 138 (Suppl. 1): S68–72. doi:10.2298/SARH1004256D. PMID 20499513.
  19. Castegnaro M, et al. (2006). "Balkan endemic nephropathy: role of ochratoxins A through biomarkers" (PDF). Mol Nutr Food Res. 50 (6): 519–29. doi:10.1002/mnfr.200500182. PMID 16715544.
  20. Long DT, Voice TC (2007). "Role of exposure analysis in solving the mystery of Balkan endemic nephropathy". Croat. Med. J. 48 (3): 300–11. PMC 2080532. PMID 17589972.
  21. Abouzied MM, Horvath AD, Podlesny PM, et al. (2002). "Ochratoxin A concentrations in food and feed from a region with Balkan Endemic Nephropathy". Food Additives and Contaminants. 19 (8): 755–64. doi:10.1080/02652030210145036. PMID 12227939. S2CID 44838516.
  22. Fink-Gremmels J. (29 June – 1 July 2005). "Conclusions from the workshops on Ochratoxin A in Food: recent developments and significance". Organized by ILSI Europe in Baden (Austria).
  23. Krogh P, et al. (1976). "Experimental porcine nephropathy: changes of renal function and structure peroraly induced by crystalline ochratoxin A". Acta Pathol Microbiol Scand A. 84 (5): 429–34. PMID 970130.
  24. Hope JH, Hope BE (2012). "A Review of the Diagnosis and Treatment of Ochratoxin A Inhalational Exposure Associated with Human Illness and Kidney Disease including Focal Segmental Glomerulosclerosis". Journal of Environmental and Public Health. 2012: 1–10. doi:10.1155/2012/835059. PMC 3255309. PMID 22253638. Article ID 835059.
  25. Niemiec, J.; Borzemska, W. (1994). "The effect of Ochratoxin A on egg quality development of embryos and the level of toxin in egg and tissue of hens and chicks". Journal of Animal and Feed Sciences. 3 (4): 309–316. doi:10.22358/jafs/69844/1994.
  26. Battacone G. Nudda A. Pulina G. (2010). "Effects of Ochratoxin A on Livestock Production". Toxins. 2 (7): 1796–1824. doi:10.3390/toxins2071796. PMC 3153269. PMID 22069661.
  27. Scientific Panel on Contaminants in the Food Chain (2006). "Opinion of the Scientific Panel on Contaminants in the Food Chain on a request from the Commission related to Ochratoxin A in Food, Question N° EFSA-Q-2005-154, Adopted on 4 April 2006". The EFSA Journal. 365: 1–56.
  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.
  29. De Stefani; et al. (1998). "Meat intake, mate drinking and renal cell cancer in Uruguay: a case-control study". Br J Cancer. 78 (9): 1239–1243. doi:10.1038/bjc.1998.661. PMC 2062999. PMID 9820187.
  30. Rashidkhani B, et al. (2005). "Major dietary patterns and risk of Renal Cell Carcinoma in a prospective cohort of Swedish women". J. Nutr. 135 (7): 1757–1762. doi:10.1093/jn/135.7.1757. PMID 15987861.
  31. Boonen, Jente; Malysheva, Svetlana V.; Taevernier, Lien; Diana Di Mavungu, José; De Saeger, Sarah; De Spiegeleer, Bart (2012). "Human skin penetration of selected model mycotoxins". Toxicology. 301 (1–3): 21–32. doi:10.1016/j.tox.2012.06.012. PMID 22749975.
  32. Woolf LI (1975). "Phenylketonuria as a balanced polymorphism: the nature of the heterozygote advantage". Annals of Human Genetics. 38 (4): 461–469. doi:10.1111/j.1469-1809.1975.tb00635.x. PMID 1190737. S2CID 970755.
  33. Withrock, Isabelle C.; Anderson, Stephen J.; Jefferson, Matthew A.; McCormack, Garrett R.; Mlynarczyk, Gregory S.A.; Nakama, Aron; Lange, Jennifer K.; Berg, Carrie A.; Acharya, Sreemoyee; Stock, Matthew L.; Lind, Melissa S.; Luna, K.C.; Kondru, Naveen C.; Manne, Sireesha; Patel, Bhavika B.; de la Rosa, Bierlein M.; Huang, Kuei-Pin; Sharma, Shaunik; Hu, Hilary Z.; Kanuri, Sri Harsha; Carlson, Steve A. (2015). "Genetic diseases conferring resistance to infectious diseases". Genes & Diseases. 2 (3): 247–254. doi:10.1016/j.gendis.2015.02.008. PMC 6150079. PMID 30258868.
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