Advertisement

Mycotoxin Research

, Volume 34, Issue 4, pp 241–255 | Cite as

A reproductive and developmental screening study of the fungal toxin ochratoxin A in Fischer rats

  • Genevieve S. Bondy
  • Laurie Coady
  • Nikia Ross
  • Don Caldwell
  • Anne Marie Gannon
  • Keri Kwong
  • Stephen Hayward
  • David E. Lefebvre
  • Virginia Liston
  • Jayadev Raju
  • Peter Pantazopoulos
  • Ivan Curran
Original Article
  • 145 Downloads

Abstract

The presence of the mycotoxin ochratoxin A (OTA) in cereal grains is due to the growth of toxigenic Penicillium mold on stored crops. Human exposure to OTA is higher in infants, toddlers, and children than in adolescents and adults, based on exposure assessments of ng OTA consumed/kg body weight/day. Ochratoxin A is nephrotoxic and teratogenic in animals, but its effects on juveniles exposed during the reproduction and development period have not been studied. To address this, Fischer rats were exposed to 0, 0.16, 0.4, 1.0, or 2.5 mg OTA/kg diet throughout breeding, gestation, and lactation and its adverse effects were assessed in adult rats and their offspring on postnatal day (PND) 21. There were no effects on implantation but post-implantation fetotoxicity was observed in the 2.5 mg/kg dose group, corresponding to a calculated dose of 167.0 μg/kg bw/day in dams. Adverse effects on body and kidney weights and on clinical parameters indicative of renal toxicity were significant in adult rats exposed to 1.0 mg OTA/kg diet (55.2 and 73.3 μg/kg bw/day in adult males and females, respectively) and in PND21 rats at the 0.4 mg/kg dose (33.9 μg/kg bw/day in dams), suggesting that weanling rats were more sensitive to OTA than adults. Overall, nephrotoxicity was the primary effect of OTA in weanling rats exposed throughout gestation and lactation at sub-fetotoxic concentrations in diet.

Keywords

Fetotoxic Kidney Ochratoxin A Rat Reproduction 

Notes

Acknowledgements

The authors would like to acknowledge the valuable assistance and input from the following: Jennifer Eastwood, Mark Feeley, Zoe Gillespie, Marnie Taylor, Christine Bourque, Gerard Cooke, Santokh Gill, and the staff of Health Canada’s animal facility, as well as Dan Cyr and Mary Gregory (INRS-Institut Armand Frappier, Université du Québec, Laval, Quebec, Canada).

Source of funding

This research was funded by the Food Directorate, Health Canada.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare and have agreed to allow the journal to review the data in this manuscript.

References

  1. Al-Anati L, Petzinger E (2006) Immunotoxic activity of ochratoxin A. J Vet Pharmacol Ther 29:79–90CrossRefPubMedGoogle Scholar
  2. Álvarez L, Gil AG, Ezpeleta O, Garcia-Jalón JA, de Cerain AL (2004) Immunotoxic effects of ochratoxin A in Wistar rats after oral administration. Food Chem Toxicol 42:825–834CrossRefPubMedGoogle Scholar
  3. Battacone G, Nudda A, Pulina G (2010) Effects of ochratoxin a on livestock production. Toxins (Basel) 2:1796–1824CrossRefGoogle Scholar
  4. Bendele AM, Carlton WW, Krogh P, Lillehoj EB (1985) Ochratoxin A carcinogenesis in the (C57BL/6J x C3H)F1 mouse. J Nat Cancer Inst 75:733–742PubMedGoogle Scholar
  5. Boorman GA, McDonald MR, Imoto S, Persing R (1992) Renal lesions induced by ochratoxin A exposure in the F344 rat. Toxicol Pathol 20:236–245CrossRefPubMedGoogle Scholar
  6. Brown MH, Szczech GM, Purmalis BP (1976) Teratogenic and toxic effects of ochratoxin A in rats. Toxicol Appl Pharmacol 37:331–338CrossRefPubMedGoogle Scholar
  7. Carson FL (1990) Histotechnology: a self-instructional text. ASCP Press, ChicagoGoogle Scholar
  8. Chang FC, Chu FS (1977) The fate of ochratoxin A in rats. Food Cosmet Tox 15:199–204CrossRefGoogle Scholar
  9. Creasy D, Bube A, de Rijk E, Kandori H, Kuwahara M, Masson R, Nolte T, Reams R, Regan K, Rehm S, Rogerson P, Whitney K (2012) Proliferative and nonproliferative lesions of the rat and mouse male reproductive system. Toxicol Pathol 40:40S–121SCrossRefPubMedGoogle Scholar
  10. Dietrich DR, Heussner AH, O’Brien E (2005) Ochratoxin A: comparative pharmacokinetics and toxicological implications (experimental and domestic animals and humans). Food Addit Contam Suppl 1:45–52CrossRefGoogle Scholar
  11. Dortant PM, Peters-Volleberg GWM, Van Loveren H, Marquardt RR, Speijers GJA (2001) Age-related differences in the toxicity of ochratoxin A in female rats. Food Chem Toxicol 39:55–65CrossRefPubMedGoogle Scholar
  12. Duarte SC, Pena A, Lino CM (2010) A review on ochratoxin A occurrence and effects of processing of cereal and cereal-derived food products. Food Microbiol 27:187–198CrossRefPubMedGoogle Scholar
  13. Everds NE (2015) Evaluation of clinical pathology data: correlating changes with other study data. Toxicol Pathol 43:90–97CrossRefPubMedGoogle Scholar
  14. Frazier KS, Seely JC, Hard GC, Betton G, Burnett R, Nakatsuji S, Nishikawa A, Durchfeld-Meyer B, Bube A (2012) Proliferative and nonproliferative lesions of the rat and mouse urinary system. Toxicol Pathol 40:14S–86SCrossRefPubMedGoogle Scholar
  15. Galtier P, Charpenteau J-L, Alvinerie M, Labouche C (1979) The pharmacokinetic profile of ochratoxin A in the rat after oral and intravenous administration. Drug Metab Dispos 7:429–434PubMedGoogle Scholar
  16. Hagelberg S, Hult K, Fuchs R (1989) Toxicokinetics of ochratoxin A in several species and its plasma-binding properties. J Appl Toxicol 9:91–96CrossRefPubMedGoogle Scholar
  17. Haley P, Perry R, Ennulat D, Frame S, Johnson C, Lapointe JM, Nyska A, Snyder P, Walker D, Walter G. S. T. P. I. W. Group (2005) STP position paper: best practice guideline for the routine pathology evaluation of the immune system. Toxicol Pathol 33:404–407CrossRefPubMedGoogle Scholar
  18. Hallén IP, Breitholtz-Emanuelsson A, Hult K, Olsen M, Oskarsson A (1998) Placental and lactational transfer of ochratoxin A in rats. Nat Toxins 6:43–49CrossRefPubMedGoogle Scholar
  19. Hassan Z, Khan MZ, Saleemi MK, Khan A, Javed I, Bhatti SA (2012) Toxico-pathological effects of in ovo inoculation of ochratoxin A (OTA) in chick embryos and subsequently in hatched chicks. Toxicol Pathol 40:33–39CrossRefGoogle Scholar
  20. Hayes AW, Hood RD, Lee HL (1974) Teratogenic effects of ochratoxin A in mice. Teratology 9:93–98CrossRefPubMedGoogle Scholar
  21. Hood RD, Naughton MJ, Hayes AW (1976) Prenatal effects of ochratoxin A in hamsters. Teratology 13:11–14CrossRefPubMedGoogle Scholar
  22. Hooth MJ, Deangelo AB, George MH, Gaillard ET, Travlos GS, Boorman GA, Wolf DC (2001) Subchronic sodium chlorate exposure in drinking water results in a concentration-dependent increase in rat thyroid follicular cell hyperplasia. Toxicol Pathol 29:250–259CrossRefPubMedGoogle Scholar
  23. JECFA (2008) Safety evaluation of certain Food Addit Contam Sixty-eighth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Food Additives Series No. 59, p. 357–429. WHO, GenevaGoogle Scholar
  24. Krogh P, Elling F, Friis C, Hald B, Larsen AE, Lillehøj EB, Madsen A, Mortensen P, Rasmussen F, Ravnskov U (1979) Porcine nephropathy induced by long-term ingestion of ochratoxin A. Vet Pathol 16:466–475CrossRefPubMedGoogle Scholar
  25. Kuiper-Goodman T, Hilts C, Billiard SM, Kiparissis Y, Richard IDK, Hayward S (2010) Health risk assessment of ochratoxin A for all age-sex strata in a market economy. Food Addit Contam 27:212–240CrossRefGoogle Scholar
  26. Lane-Petter W (1968) Cannibalism in rats and mice. Proc R Soc Med 61:1295–1296PubMedPubMedCentralGoogle Scholar
  27. Magan N, Aldred D (2007) Post-harvest control strategies: minimizing mycotoxins in the food chain. Int J Food Microbiol 119:131–139CrossRefPubMedGoogle Scholar
  28. Mally A (2012) Ochratoxin A and mitotic disruption: mode of action analysis of renal tumor formation by ochratoxin A. Toxicol Sci 127:315–330CrossRefPubMedGoogle Scholar
  29. Marin S, Ramos AJ, Cano-Sancho G, Sanchis V (2013) Mycotoxins: occurrence, toxicology, and exposure assessment. Food Chem Toxicol 60:218–237CrossRefPubMedGoogle Scholar
  30. Mayura K, Reddy RV, Hayes AW, Berndt WO (1982) Embryocidal, fetotoxic and teratogenic effects of ochratoxin A in rats. Toxicology 25:175–185CrossRefPubMedGoogle Scholar
  31. Mayura K, Hayes AW, Berndt WO (1983) Effects of dietary protein on teratogenicity of ochratoxin A in rats. Toxicology 27:147–157CrossRefPubMedGoogle Scholar
  32. Mitchell NJ, Chen C, Palumbo JD, Bianchini A, Cappozzo J, Stratton J, Ryu D, Wu F (2017) A risk assessment of dietary ochratoxin A in the United States. Food Chem Toxicol 100:265–273CrossRefPubMedGoogle Scholar
  33. Munro IC, Moodie CA, Kuiper-Goodman T, Scott PM, Grice HC (1974) Toxicologic changes in rats fed graded dietary levels of ochratoxin A. Toxicol Appl Pharm 28:180–188CrossRefGoogle Scholar
  34. NTP (1989) Toxicology and carcinogenesis studies of ochratoxin A (CAS No. 303-47-9) in F344/N rats (gavage studies). NTP TR 358, NIH Publication No. 89-2813. U.S. Department of Health and Human Services, Research Triangle ParkGoogle Scholar
  35. Patil RD, Dwivedi P, Sharma AK (2006) Critical period and minimum single oral dose of ochratoxin A for inducing developmental toxicity in pregnant Wistar rats. Reprod Toxicol 22:679–687CrossRefPubMedGoogle Scholar
  36. Rached E, Hard GC, Blumbach K, Weber K, Draheim R, Lutz WK, Özden S, Steger U, Dekant W, Mally A (2007) Ochratoxin A: 13-week oral toxicity and cell proliferation in male F344/N rats. Toxicol Sci 97:288–298CrossRefPubMedGoogle Scholar
  37. Seely JC (2017) A brief review of kidney development, maturation, developmental abnormalities, and drug toxicity: juvenile animal relevancy. J Toxicol Path 30:125–133CrossRefGoogle Scholar
  38. Shreeve BJ, Patterson DS, Pepin GA, Roberts BA, Wrathal AE (1977) Effect of feeding ochratoxin A to pigs during early pregnancy. Br Vet J 133:412–417CrossRefPubMedGoogle Scholar
  39. Stoev SD (2010) Studies on carcinogenic and toxic effects of ochratoxin A in chicks. Toxins (Basel) 2:649–664CrossRefGoogle Scholar
  40. Sugita-Konishi Y, Kamata Y, Sato T, Yoshinari T, Saito S (2013) Exposure and risk assessment for ochratoxin A and fumonisins in Japan. Food Add Contam Part A 30:1392–1401CrossRefGoogle Scholar
  41. Thoolen B, Maronpot RR, Harada T, Nyska A, Rousseaux C, Nolte T, Malarkey DE, Kaufmann W, Kuttler K, Deschl U, Nakae D, Gregson R, Vinlove MP, Brix AE, Singh B, Belpoggi F, Ward JM (2010) Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system. Toxicol Path 38:5S–81SCrossRefGoogle Scholar
  42. Thuvander A, Breitholtz-Emanuelsson A, Olsen M (1995) Effects of ochratoxin A on the mouse immune system after subchronic exposure. Food Chem Toxicol 33:1005–1011CrossRefPubMedGoogle Scholar
  43. Thuvander A, Breitholtz-Emanuelsson A, Brabencova D, Gadhasson I (1996) Prenatal exposure of Balb/c mice to ochratoxin A: effects on the immune system in the offspring. Food Chem Toxicol 34:547–554CrossRefPubMedGoogle Scholar
  44. van der Merwe KJ, Steyn PS, Fourie L, Scott De B, Theron JJ (1965) Ochratoxin A, a toxic metabolite produced by Aspergillus ochraceus Wilh. Nature 205:1112–1113CrossRefPubMedGoogle Scholar
  45. Varga J, Rigo K, Téren J, Mesterházy Á (2001) Recent advances in ochratoxin research. I. Production, detection and occurrence of ochratoxins. Cereal Res Commun 29:85–92Google Scholar
  46. Wangikar PB, Dwivedi P, Sinha N (2004) Teratogenic effects of ochratoxin A in rabbits. World Rabbit Sci 12:159–171Google Scholar
  47. Weiss G, Goodnough LT (2005) Anemia of chronic disease. New Engl J Med 352:1011–1023CrossRefPubMedGoogle Scholar
  48. World Health Organization (1980) In: Castegnaro M, Hunt DC, Sansone EB, Schuller PL, Siriwardana MG, Telling GM, van Egmond HP, Walker EA (eds) Laboratory decontamination and destruction of aflatoxins B1, B2, G1, G2 in laboratory wastes. International Agency for Research on Cancer, Lyon, pp 1–59Google Scholar
  49. Zoetis T, Hurtt ME (2003) Species comparison of anatomical and functional renal development. Birth Defect Res (Pt B) 68:111–120CrossRefGoogle Scholar

Copyright information

© Society for Mycotoxin Research and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Genevieve S. Bondy
    • 1
  • Laurie Coady
    • 1
  • Nikia Ross
    • 1
  • Don Caldwell
    • 1
  • Anne Marie Gannon
    • 1
  • Keri Kwong
    • 2
  • Stephen Hayward
    • 3
  • David E. Lefebvre
    • 1
  • Virginia Liston
    • 1
  • Jayadev Raju
    • 1
  • Peter Pantazopoulos
    • 2
  • Ivan Curran
    • 1
  1. 1.Bureau of Chemical Safety, Food Directorate, Health Products and Food BranchHealth CanadaOttawaCanada
  2. 2.Ontario Food Laboratory, Laboratories Directorate, Regulatory Operations and Regions BranchHealth CanadaTorontoCanada
  3. 3.Bureau of Food Surveillance and Science Integration, Food Directorate, Health Products and Food BranchHealth CanadaOttawaCanada

Personalised recommendations