Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity

Christophe Cavin, Thierry Delatour, Maricel Marin-Kuan, Daisy Holzhäuser, Larry Higgins, Claudine Bezençon, Gabriela Guignard, Sylviane Junod, Janique Richoz-Payot, Eric Gremaud, John D. Hayes, Sandra Nestler, Peter Mantle, Benoît Schilter

    Research output: Contribution to journalArticle

    98 Citations (Scopus)

    Abstract

    Ochratoxin A (OTA) is a renal carcinogen in rodents. Its human health significance is unclear. It likely depends upon the mechanism of carcinogenesis. In a previous microarray study a reduction in nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)-dependent gene expression was observed in the kidney but not in the liver of rats fed OTA up to 12 months. Nrf2 regulates detoxification and antioxidant gene expression. The present report shows that OTA decreased the protein expression of several markers of the Nrf2-regulated gene battery in kidney in vivo indicating that the effects observed at mRNA level may be of biological significance. The OTA-mediated Nrf2 response could be reproduced in an NRK renal cell line and in primary hepatocyte cultures. In in vitro systems, an OTA-mediated inhibition of Nrf2 activity was demonstrated by electrophoretic mobility shift and Antioxidant Regulatory Element-driven luciferase reporter assays. The reduction of Nrf2-regulated gene expression resulted in oxidative DNA damage as evidenced by formation of abasic sites in vitro and confirmed in kidney in vivo. All OTA-mediated effects observed were prevented by pretreatment of cell cultures with inducers of Nrf2 activity. Our data suggest that reduction of cellular defense against oxidative stress by Nrf2 inhibition may be a plausible mechanism of OTA nephrotoxicity and carcinogenicity.
    Original languageEnglish
    Pages (from-to)30-9
    Number of pages10
    JournalToxicological Sciences
    Volume96
    Issue number1
    DOIs
    Publication statusPublished - 2007

    Fingerprint

    Toxicity
    Antioxidants
    Kidney
    Gene expression
    Gene Expression
    Cell culture
    Electrophoretic mobility
    Detoxification
    Oxidative stress
    Microarrays
    ochratoxin A
    Luciferases
    Carcinogens
    Liver
    DNA Damage
    Rats
    Hepatocytes
    Rodentia
    Assays
    Carcinogenesis

    Cite this

    Cavin, C., Delatour, T., Marin-Kuan, M., Holzhäuser, D., Higgins, L., Bezençon, C., ... Schilter, B. (2007). Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. Toxicological Sciences, 96(1), 30-9. https://doi.org/10.1093/toxsci/kfl169
    Cavin, Christophe ; Delatour, Thierry ; Marin-Kuan, Maricel ; Holzhäuser, Daisy ; Higgins, Larry ; Bezençon, Claudine ; Guignard, Gabriela ; Junod, Sylviane ; Richoz-Payot, Janique ; Gremaud, Eric ; Hayes, John D. ; Nestler, Sandra ; Mantle, Peter ; Schilter, Benoît. / Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. In: Toxicological Sciences. 2007 ; Vol. 96, No. 1. pp. 30-9.
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    abstract = "Ochratoxin A (OTA) is a renal carcinogen in rodents. Its human health significance is unclear. It likely depends upon the mechanism of carcinogenesis. In a previous microarray study a reduction in nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)-dependent gene expression was observed in the kidney but not in the liver of rats fed OTA up to 12 months. Nrf2 regulates detoxification and antioxidant gene expression. The present report shows that OTA decreased the protein expression of several markers of the Nrf2-regulated gene battery in kidney in vivo indicating that the effects observed at mRNA level may be of biological significance. The OTA-mediated Nrf2 response could be reproduced in an NRK renal cell line and in primary hepatocyte cultures. In in vitro systems, an OTA-mediated inhibition of Nrf2 activity was demonstrated by electrophoretic mobility shift and Antioxidant Regulatory Element-driven luciferase reporter assays. The reduction of Nrf2-regulated gene expression resulted in oxidative DNA damage as evidenced by formation of abasic sites in vitro and confirmed in kidney in vivo. All OTA-mediated effects observed were prevented by pretreatment of cell cultures with inducers of Nrf2 activity. Our data suggest that reduction of cellular defense against oxidative stress by Nrf2 inhibition may be a plausible mechanism of OTA nephrotoxicity and carcinogenicity.",
    author = "Christophe Cavin and Thierry Delatour and Maricel Marin-Kuan and Daisy Holzh{\"a}user and Larry Higgins and Claudine Bezen{\cc}on and Gabriela Guignard and Sylviane Junod and Janique Richoz-Payot and Eric Gremaud and Hayes, {John D.} and Sandra Nestler and Peter Mantle and Beno{\^i}t Schilter",
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    Cavin, C, Delatour, T, Marin-Kuan, M, Holzhäuser, D, Higgins, L, Bezençon, C, Guignard, G, Junod, S, Richoz-Payot, J, Gremaud, E, Hayes, JD, Nestler, S, Mantle, P & Schilter, B 2007, 'Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity', Toxicological Sciences, vol. 96, no. 1, pp. 30-9. https://doi.org/10.1093/toxsci/kfl169

    Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. / Cavin, Christophe; Delatour, Thierry; Marin-Kuan, Maricel; Holzhäuser, Daisy; Higgins, Larry; Bezençon, Claudine; Guignard, Gabriela; Junod, Sylviane; Richoz-Payot, Janique; Gremaud, Eric; Hayes, John D.; Nestler, Sandra; Mantle, Peter; Schilter, Benoît.

    In: Toxicological Sciences, Vol. 96, No. 1, 2007, p. 30-9.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity

    AU - Cavin, Christophe

    AU - Delatour, Thierry

    AU - Marin-Kuan, Maricel

    AU - Holzhäuser, Daisy

    AU - Higgins, Larry

    AU - Bezençon, Claudine

    AU - Guignard, Gabriela

    AU - Junod, Sylviane

    AU - Richoz-Payot, Janique

    AU - Gremaud, Eric

    AU - Hayes, John D.

    AU - Nestler, Sandra

    AU - Mantle, Peter

    AU - Schilter, Benoît

    PY - 2007

    Y1 - 2007

    N2 - Ochratoxin A (OTA) is a renal carcinogen in rodents. Its human health significance is unclear. It likely depends upon the mechanism of carcinogenesis. In a previous microarray study a reduction in nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)-dependent gene expression was observed in the kidney but not in the liver of rats fed OTA up to 12 months. Nrf2 regulates detoxification and antioxidant gene expression. The present report shows that OTA decreased the protein expression of several markers of the Nrf2-regulated gene battery in kidney in vivo indicating that the effects observed at mRNA level may be of biological significance. The OTA-mediated Nrf2 response could be reproduced in an NRK renal cell line and in primary hepatocyte cultures. In in vitro systems, an OTA-mediated inhibition of Nrf2 activity was demonstrated by electrophoretic mobility shift and Antioxidant Regulatory Element-driven luciferase reporter assays. The reduction of Nrf2-regulated gene expression resulted in oxidative DNA damage as evidenced by formation of abasic sites in vitro and confirmed in kidney in vivo. All OTA-mediated effects observed were prevented by pretreatment of cell cultures with inducers of Nrf2 activity. Our data suggest that reduction of cellular defense against oxidative stress by Nrf2 inhibition may be a plausible mechanism of OTA nephrotoxicity and carcinogenicity.

    AB - Ochratoxin A (OTA) is a renal carcinogen in rodents. Its human health significance is unclear. It likely depends upon the mechanism of carcinogenesis. In a previous microarray study a reduction in nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)-dependent gene expression was observed in the kidney but not in the liver of rats fed OTA up to 12 months. Nrf2 regulates detoxification and antioxidant gene expression. The present report shows that OTA decreased the protein expression of several markers of the Nrf2-regulated gene battery in kidney in vivo indicating that the effects observed at mRNA level may be of biological significance. The OTA-mediated Nrf2 response could be reproduced in an NRK renal cell line and in primary hepatocyte cultures. In in vitro systems, an OTA-mediated inhibition of Nrf2 activity was demonstrated by electrophoretic mobility shift and Antioxidant Regulatory Element-driven luciferase reporter assays. The reduction of Nrf2-regulated gene expression resulted in oxidative DNA damage as evidenced by formation of abasic sites in vitro and confirmed in kidney in vivo. All OTA-mediated effects observed were prevented by pretreatment of cell cultures with inducers of Nrf2 activity. Our data suggest that reduction of cellular defense against oxidative stress by Nrf2 inhibition may be a plausible mechanism of OTA nephrotoxicity and carcinogenicity.

    U2 - 10.1093/toxsci/kfl169

    DO - 10.1093/toxsci/kfl169

    M3 - Article

    VL - 96

    SP - 30

    EP - 39

    JO - Toxicological Sciences

    JF - Toxicological Sciences

    SN - 1096-6080

    IS - 1

    ER -