The involvement of mycotoxins in the development of endemic nephropathy

  • Maja Peraica
  • Ana-Marija Domijan
  • Marica Miletić-Medved
  • Radovan Fuchs
Review Article

Summary

Endemic nephropathy is a human kidney disease that still escapes scientific explanation. It is accompanied by a high incidence of urothelial tumors in rural populations in endemic areas, which suggests that a natural nephrotoxic and carcinogenic compound may be involved in the etiology. The most imputed causative agent of endemic nephropathy is the mycotoxin ochratoxin A (OTA), because of its confirmed nephrotoxic and carcinogenic action. This paper presents a review of studies of OTA in food collected in the endemic areas and in blood and urine of their residents. Data on the co-occurrence of OTA and other nephrotoxic and carcinogenic mycotoxins such as citrinin and fumonisin B1 in food are also presented. Unfortunately, there is no study on the co-occurrence of OTA and other mycotoxins in humans and there is only one study on fumonisin B1 exposure in endemic areas. The paper also presents experimental data on cultured cells and laboratory animals treated with combinations of OTA and other nephrotoxic mycotoxins, because most such combinations show a synergistic effect. The occurrence of OTA- and aristolochic acid-DNA adducts is also presented.

Keywords

Aristolochic acid Citrinin Fumonisin B1 Nephrotoxicity Ochratoxin A 

Die Rolle von Mykotoxinen bei der endemischen Nephropathie

Zusammenfassung

Die endemische Nephropathie (EN) ist eine Nierenerkrankung, die noch immer nicht wissenschaftlich erklärt werden kann. Die EN wird von einer hohen Prävalenz von urothelialen Tumoren bei der ländlichen Bevölkerung der endemischen Region begleitet. Man vermutet daher, dass eine natürlich vorkommende nephrotoxische und karzinogene Substanz in die Ätiologie involviert ist. Am meisten wird das Mykotoxin Ochratoxin A (OTA) als schuldige Substanz verdächtigt, da dieses eine gesicherte nephrotoxische und karzinogene Wirkung hat. Die vorliegende Arbeit bringt eine Übersicht über alle relevanten Studien über OTA in der Nahrung beziehungsweise im Blut und im Harn der Bewohner der betroffenen Endemie-Gebiete. Es werden auch Daten über das gleichzeitige Vorkommen von OTA mit anderen Mykotoxinen, wie Zitronin und Fumonisin B1 (FB1) in der Nahrung vorgestellt. Leider existieren keine Studien über das gemeinsame Vorkommen von OTA und anderen Mykotoxinen beim Menschen, und es gibt nur eine Studie über die Exposition mit FB1 in endemischen Gebieten. Diese Übersicht berichtet auch über experimentelle Daten, die in Zellkulturen und Labortieren erhoben wurden, die mit OTA und anderen nephrotoxischen Mykotoxinen (da die meisten Mykotoxin-Kombinationen synergistische Wirkung zeigten) behandelt worden sind. Es wird auch das Vorkommen von OTA- und Aristolochia-Säure-bedingten DNA-Veränderungen diskutiert.

References

  1. Pleština R (1992) Some features of Balkan endemic nephropathy. Food Chem Toxicol 30: 177–181CrossRefPubMedGoogle Scholar
  2. Miletic-Medved M, Peraica M, Domijan AM (2005) Recent data on endemic nephropathy and related urothelial tumors in Croatia. Wien Klin Wochenschr 117: 604–609CrossRefPubMedGoogle Scholar
  3. Božic Z, Duancic V, Belicza M, Kraus O, Skljarov I (1995) Balkan endemic nephropathy: still a mysterious disease. Eur J Epidemiol 11: 235–238CrossRefPubMedGoogle Scholar
  4. Krogh P (1974) Mycotoxin porcine nephropathy: a possible model for Balkan endemic nephropathy. In: Puchlev A (ed) Endemic nephropathy. Proceedings of the Second International Symposium on Endemic Nephropathy; 1972 Nov 9–11; Sofia (Bulgaria), Bulgarian Academy of Science, Sofia, pp 266–270Google Scholar
  5. Peraica M, Domijan A-M, Fuchs R, Lucic A, Radic B (1999) The occurrence of ochratoxin A in blood in general population of Croatia. Toxicol Lett 110: 105–112CrossRefPubMedGoogle Scholar
  6. Fuchs R, Peraica M (2005) Ochratoxin A in human kidney diseases. Food Addit Contam 22 [Suppl 1]: 53–57CrossRefPubMedGoogle Scholar
  7. International Agency for Research on Cancer (IARC) (1993) Some naturally occurring substances: food items and constituents, heterocyclic aromatic amines and mycotoxins. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 56. IARC, LyonGoogle Scholar
  8. International Agency for Research on Cancer (IARC) (1986) Some naturally occurring and synthetic food components, furocoumarins and ultraviolet radiation. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 40. IARC, LyonGoogle Scholar
  9. International Agency for Research on Cancer (IARC) (2002) Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol 82. IARC, LyonGoogle Scholar
  10. Pavlović M, Pleština R, Krogh P (1979) Ochratoxin A contamination of foodstuffs in an area with Balkan (endemic) nephropathy. Acta Path Microbiol Scand Sect B 87: 243–246Google Scholar
  11. Puntarić D, Bošnir J, Šmit Z, Škes I, Baklaić Ž (2001) Ochratoxin A in corn and wheat: geographical association with endemic nephropathy. Croat Med J 42: 175–180PubMedGoogle Scholar
  12. Petkova-Bocharova T, Castegnaro M (1985) Ochratoxin A contamination of cereals in an area of high incidence of Balkan endemic nephropathy in Bulgaria. Food Addit Contam 2: 267–270CrossRefPubMedGoogle Scholar
  13. Petkova-Bocharova T, Castegnaro M, Michelon J, Maru V (1991) Ochratoxin A and other mycotoxins in cereals from an area of Balkan endemic nephropathy and urinary tract tumours in Bulgaria. In: Castegnaro M, Pleština R, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxins, endemic nephropathy and urinary tract tumors. IARC, Lyon, IARC Scientific Publications 115: 83–87Google Scholar
  14. Jurjevic Ž, Solfrizzo M, Cvjetkovic B, Avantaggiato G, Visconti A (1999) Ochratoxin A and fumonisins (B1 and B2) in maize from Balkan nephropathy endemic and non endemic areas of Croatia. Mycotox Res 15: 67–80CrossRefGoogle Scholar
  15. Vrabcheva T, Usleber E, Dietrich R, Martlbauer E (2000) Co-occurrence of ochratoxin A and citrinin in cereals from Bulgarian villages with a history of Balkan endemic nephropathy. J Agric Food Chem 48: 2483–2488CrossRefPubMedGoogle Scholar
  16. Abouzied MM, Horvath AD, Podlesny PM, Regina NP, Metodiev VD, Kamenova-Tozeva RM, et al (2002) Ochratoxin A concentration in food and feed from a region with Balkan endemic nephropathy. Food Addit Contam 19: 755–764CrossRefPubMedGoogle Scholar
  17. Vrabcheva T, Petkova-Bocharova T, Grosso F, Nikolov I, Chernozemsky IN, Castegnaro M, et al (2004) Analysis of ochratoxin A in foods consumed by inhabitants from an area with Balkan endemic nephropathy: a 1 month follow-up study. J Agric Food Chem 52: 2404–2410CrossRefPubMedGoogle Scholar
  18. Castegnaro M, Canadas D, Vrabcheva T, Petkova-Bocharova T, Chernozemsky IN, Pfohl-Leszkowicz A (2006) Balkan endemic nephropathy: role of ochratoxins A through biomarkers. Mol Nutr Food Res 50: 519–529CrossRefPubMedGoogle Scholar
  19. Studer-Rohr I, Schlatter J, Dietrich DR (2000) Kinetic parameters and intraindividual fluctuations of ochratoxin A plasma levels in humans. Arch Toxicol 74: 499–510CrossRefPubMedGoogle Scholar
  20. Fillastre JP (1997) Néphrotoxicité expérimentale et humaine des ochratoxines. Bull Acad Natle Med 181: 1447–1463Google Scholar
  21. Maaroufi K, Achour A, Hammami M, El May M, Betbeder AM, Ellouz F, et al (1995) Ochratoxin A in human blood in relation to nephropathy in Tunisia. Hum Exp Toxicol 14: 609–615CrossRefPubMedGoogle Scholar
  22. Maaroufi K, Achour A, Betbeder AM, Hammami M, Ellouz F, Creppy EE, Bacha H (1995) Foodstuffs and human blood contamination by the mycotoxin ochratoxin A: correlation with chronic interstitial nephropathy in Tunisia. Arch Toxicol 69: 552–558CrossRefPubMedGoogle Scholar
  23. Wafa EW, Yahya RS, Sobh MA, Eraky I, El-Baz M, E-Gayar HAM, et al (1998) Human ochratoxicosis and nephropathy in Egypt: a preliminary study. Hum Exp Toxicol 17: 124–129CrossRefPubMedGoogle Scholar
  24. Hult K, Pleština R, Habazin-Novak V, Radic B, Ceovic S (1982) Ochratoxin A in human blood and Balkan endemic nephropathy. Arch Toxicol 51: 313–321CrossRefGoogle Scholar
  25. Radic B, Fuchs R, Peraica M, Lucic A (1997) Ochratoxin A in human sera in the area with endemic nephropathy in Croatia. Toxicol Lett 91: 105–109CrossRefPubMedGoogle Scholar
  26. Petkova-Bocharova T, Castegnaro M (1991) Ochratoxin A in human blood in relation to Balkan endemic nephropathy and urinary tract tumours in Bulgaria. In: Castegnaro M, Pleština R, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxins, endemic nephropathy and urinary tract tumors. IARC, Lyon. IARC Scientific Publications 115: 135–137Google Scholar
  27. Castegnaro M, Maru V, Petkova-Bocharova T, Nikolov I, Bartsch H (1991) Concentrations of ochratoxin A in the urine of endemic nephropathy patients and controls in Bulgaria: lack of detection of 4-hydroxyochratoxin A. In: Castegnaro M, Pleština R, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxins, endemic nephropathy and urinary tract tumors. IARC, Lyon. IARC Scientific Publications 115: 165–169Google Scholar
  28. Ribar S, Mesaric M, Bauman M (2001) High-performance liquid chromatographic determination of sphinganine and sphingosine in serum and urine of subjects from an endemic nephropathy area in Croatia. J Chromatogr B 754: 511–519CrossRefGoogle Scholar
  29. Speijers GJA, Speijers MHM (2004) Combined toxic effects of mycotoxins. Toxicol Lett 153: 91–98CrossRefPubMedGoogle Scholar
  30. Heussner AH, Dietrich DR, O'Brein E (2006) In vitro investigation of individual and combined cytotoxic effects of ochratoxin A and other selected mycotoxins on renal cells. Toxicol Vitro 20: 332–341CrossRefGoogle Scholar
  31. Diaz CT, Sogbe E, Ascanio E, Hernandez M (2001) Ochratoxin A and fumonisin B1 natural interactions in pigs. Clinical and pathological study. Rev Cient Fac Cien V 11: 314–321Google Scholar
  32. Creppy EE, Chiarappa P, Baudrimont I, Borracci P, Moukha S, Carratu MR (2004) Synergistic effects of fumonisin B1 and ochratoxin A: are in vitro cytotoxicity data predictive of in vivo acute toxicity? Toxicology 201: 115–123CrossRefPubMedGoogle Scholar
  33. Šegvić Klarić M, Pepeljnjak S, Domijan AM, Petrik J (2006) Lipid peroxidation and glutathione levels in porcine kidney PK15 cells after individual and combined treatment with fumonisin B1, beauvericin and ochratoxin A. Basic Clin Pharmacol Toxicol 100: 157–164Google Scholar
  34. Šegvić Klarić M, Rumora L, Ljubanović D, Pepeljnjak S (2008) Cytotoxicity and apoptosis induced by fumonisin B1, beauvericin and ochratoxin A in porcine kidney PK15 cells: effects of individual and combined treatment. Arch Toxicol DOI 10.1007/s00204-007-0245-yGoogle Scholar
  35. Kubena LF, Edrington TS, Harvey RB, Phillips TD, Sarr AB, Rottinghaus GE (1997) Individual and combined effects of fumonisin B1 present in Fusarium moniliforme culture material and diacetoxyscirpenol or ochratoxin A in turkey poults. Poultry Sci 76: 256–264CrossRefGoogle Scholar
  36. Domijan AM, Želježic D, Kopjar N, Peraica M (2006) Standard and Fpg-modified comet assay in kidney cells of ochratoxin A- and fumonisin B1-treated rats. Toxicology 222: 53–59CrossRefPubMedGoogle Scholar
  37. Cosyns JP, Jadoul M, Squifflet JP, De Plaen JF, Ferluga D, Van Ypersele de Strihou C (1994) Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Inter 45: 1680–1688CrossRefGoogle Scholar
  38. Vanherweghem JL, Depierreux M, Tielmans C, Abramowicz D, Dratwa M, Jadoul M, Richard C, Vandervelde D, Verbeelen D, Vanhaelen-Fastre R, Vanhaelen M (1993) Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 341: 387–391CrossRefPubMedGoogle Scholar
  39. Peraica M, Domijan A-M, Šarić M (2008) Mycotoxic and aristolochic acid theories of the development of endemic nephropathy. Arh Hig Rada Toksikol 59: 59–65CrossRefPubMedGoogle Scholar
  40. Vanherweghem JL, Abramowicz D, Tielmans C, Depierreux M (1996) Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis; a pilot study in Chinese herbs nephropathy. Am J Kidney Dis 27: 209–215CrossRefPubMedGoogle Scholar
  41. Hranjec T, Kovac A, Kos J, Mao W, Chen JJ, Grollman AP, Jelakovic B (2005) Endemic nephropathy: the case for chronic poisoning by Aristolochia. Croat Med J 46: 116–125PubMedGoogle Scholar
  42. Pfohl-Leszkowicz A, Chakor K, Creppy EE, Dirheimer G (1991) DNA adduct formation in mice treated with ochratoxin A. In: Castegnaro M, Pleština R, Dirheimer G, Chernozemsky IN, Bartsch H (eds) Mycotoxins, endemic nephropathy and urinary tract tumors. IARC, Lyon. IARC Scientific Publications 115: 245–253Google Scholar
  43. Pfohl-Leszkowicz A, Grosse Y, Kane A, Creppy EE, Dirheimer G (1993) Differential DNA adduct formation and disappearance in three mouse tissues after treatment with the mycotoxin ochratoxin A. Mutat Res 289: 265–273CrossRefPubMedGoogle Scholar
  44. Schmeisser HH, Schoepe KB, Wiessler M (1988) DNA adduct formation of aristolochic acid I and II in vitro and in vivo. Carcinogenesis 9: 297–303CrossRefGoogle Scholar
  45. Gautier J-C, Richoz J, Welti H, Markovic J, Gremaud E, Guengerich FP, Turesky RJ (2001) Metabolism of ochratoxin A: absence of formation of genotoxic derivatives by human and rat enzymes. Chem Res Toxicol 14: 34–45CrossRefPubMedGoogle Scholar
  46. Mally A, Zepnik H, Wanek P, Eder E, Dingley K, Ihmels H, Völker W, Dekant W (2004) Ochratoxin A: lack of formation of covalent DNA adducts. Chem Res Toxicol 17: 234–242CrossRefPubMedGoogle Scholar
  47. Arlt VM, Ferluga D, Stiborova M, Pfohl-Leszkowicz, Vukelic M, Ceovic S, Schmeiser HH, Cosyns JP (2002) Is aristolochic acid a risk factor for Balkan endemic nephropathy-associated urothelial cancer? Int J Cancer 101: 500–502CrossRefPubMedGoogle Scholar
  48. Pfohl-Leszkowicz A, Grosse Y, Castegnaro M, Petkova-Bocharova T, Nicolov IG, Chernozemsky IV, Bartsch H, Betbeder AM, Creppy EE, Dirheimer G (1994) Similarity between ochratoxin A induced DNA adducts in mice and DNA adducts in urinary tract tumours in humans with Balkan endemic nephropathy. In: Scudamore K (ed) Occurrence and significance of mycotoxins. Central Science Laboratory, London, pp 239–243Google Scholar
  49. Nortier JL, Munitz Martinez MC, Schmeiser HH, Arlt VM, Bieler CH, Petein M, Depierreux MF, De Pauw L, Abramowicz D, Vereerstraeten P, Vanherweghem JL (2000) Urothelial carcinoma associated with the use of Chinese herb (Aristolochia fangchi). N Engl J Med 342: 1686–1692CrossRefPubMedGoogle Scholar
  50. Pfohl-Leszkowicz A, Tozlovanu M, Manderville R, Peraica M, Castegnaro M, Stefanovic V (2007) New molecular and field evidence for the implication of mycotoxins but not aristolochic acid in human nephropathy and urinary tract tumor. Molec Nutr Food Res 51: 1131–1146CrossRefGoogle Scholar
  51. Grollman AP, Shibutani S, Moriya M, Miller F, Wu L, Moll U, Suzuki N, Fernandes A, Tosenquist T, Medverec Z, Jakovina K, Brdar B, Slade N, Turesky RJ, Goodenough AK, Rieger R, Vukelic M, Jelakovic B (2007) Aristolochic acid and the etiology of endemic (Balkan) nephropathy. PNAS 104: 12129–12134CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Maja Peraica
    • 1
  • Ana-Marija Domijan
    • 1
  • Marica Miletić-Medved
    • 2
  • Radovan Fuchs
    • 1
  1. 1.Institute for Medical Research and Occupational HealthZagrebCroatia
  2. 2.Institute of Public Health of Brodsko-Posavska CountySlavonski BrodCroatia

Personalised recommendations