Skip to main content

Advertisement

SpringerLink
Log in

Ochratoxin A–induced genotoxic and epigenetic mechanisms lead to Alzheimer disease: its modulation with strategies

  • Environmental Pollutants and the Risk of Neurological Disorders
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Ochratoxin A (OTA) is a naturally occurring mycotoxin mostly found in food items including grains and coffee beans. It induces DNA single-strand breaks and has been considered to be carcinogenic. It is recognized as a serious threat to reproductive health both in males and females. OTA is highly nephrotoxic and carcinogenic, and its potency changes evidently between species and sexes. There is a close association between OTA, mutagenicity, carcinogenicity, and genotoxicity, but the underlying mechanisms are not clear. Reports regarding genotoxic effects in relation to OTA which leads to the induction of DNA adduct formation, protein synthesis inhibition, perturbation of cellular energy production, initiation of oxidative stress, induction of apoptosis, influences on mitosis, induction of cell cycle arrest, and interference with cytokine pathways. All these mechanisms are associated with nephrotoxicity, hepatotoxicity, teratotoxicity, immunological toxicity, and neurotoxicity. OTA administration activates various mechanisms such as p38 MAPK, JNKs, and ERKs dysfunctions, BDNF disruption, TH overexpression, caspase-3 and 9 activation, and ERK-1/2 phosphorylation which ultimately lead to Alzheimer disease (AD) progression. The current review will focus on OTA in terms of recent discoveries in the field of molecular biology. The main aim is to investigate the underlying mechanisms of OTA in regard to genotoxicity and epigenetic modulations that lead to AD. Also, we will highlight the strategies for the purpose of attenuating the hazards posed by OTA exposure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abdel-Hadi, A., 2011. Molecular ecology of Aspergillus section flavi species: approaches to understand the role of aflatoxin genes in aflatoxin biosynthesis

  • Abdel-Wahhab MA, Nada SA, Arbid MS (1999) Ochratoxicosis: prevention of developmental toxicity by L-methionine in the rats. J Appl Toxicol 19:7–12

    CAS  Google Scholar 

  • Abdel-Wahhab MA, Abdel-Galil MM, El-Lithey M (2005) Melatonin counteracts oxidative stress in rats fed an ochratoxin A contaminated diet. J Pineal Res 38(2):130–135

    CAS  Google Scholar 

  • Abdel-Wahhab MA, Abdel-Azim SH, El-Nekeety AA (2008) Inula crithmoides extract protects against ochratoxin A-induced oxidative stress, clastogenic and mutagenic alterations in male rats. Toxicon 52(4):566–573

    CAS  Google Scholar 

  • Abdel-Wahhab MA, Aljawish A, Kenawy AM, Hamed HS, El-Nekeety AA, Abdel-Aziem SH (2016) Grafting of gallic acid onto chitosan enhances antioxidant activities in vitro and protects against ochratoxin A toxicity in catfish (Clarias gariepinus). Environ Toxicol Pharmacol 41:279–288

    CAS  Google Scholar 

  • Abdel-Wahhab MA, Aljawish A, El-Nekeety AA, Abdel-Aziem SH, Hassan NS (2017) Chitosan nanoparticles plus quercetin suppress the oxidative stress, modulate DNA fragmentation and gene expression in the kidney of rats fed ochratoxin A-contaminated diet. Food Chem Toxicol 99:209–221

    CAS  Google Scholar 

  • Abdu, S.B., 2011. The protective role of ajwa date against the hepatotoxicity induced by ochratoxin A Egyp J Natural Toxins 8

  • Abrunhosa L, Santos L, Venâncio A (2006) Degradation of ochratoxin A by proteases and by a crude enzyme of Aspergillus niger. Food Biotechnol 20:231–242

    CAS  Google Scholar 

  • Adler M, Müller K, Rached E, Dekant W, Mally A (2009) Modulation of key regulators of mitosis linked to chromosomal instability is an early event in ochratoxin A carcinogenicity. Carcinogenesis 30(4):711–719

    CAS  Google Scholar 

  • Aiko V, Mehta A (2015) Occurrence, detection and detoxification of mycotoxins. J Biosci 40:943–954

    CAS  Google Scholar 

  • Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P., 2002. Chromosomal DNA and its packaging in the chromatin fiber. In Molecular Biology of the Cell. 4th edition. Garland Science

  • Alshannaq A, Yu JH (2017) Occurrence, toxicity, and analysis of major mycotoxins in food. Int J Environ Res Public Health 14(6):632

    Google Scholar 

  • Alvarez-Erviti L, Leache C, Gonzalez-Penas E, De Cerain AL (2005) Alterations induced in vitro by ochratoxin A in rat lymphoid cells. Hum Exp Toxicol 24(9):459–466

    CAS  Google Scholar 

  • Amezqueta S, Gonzalez-Penas E, Lizarraga T, Murillo-Arbizu M, De Cerain AL (2008) A simple chemical method reduces ochratoxin A in contaminated cocoa shells. J Food Prot 71:1422–1426

    CAS  Google Scholar 

  • Angioni A, Caboni P, Garau A, Farris A, Orro D, Budroni M, Cabras P (2007) In vitro interaction between ochratoxin A and different strains of Saccharomyces cerevisiae and Kloeckera apiculata. J Agric Food Chem 55:2043–2048

    CAS  Google Scholar 

  • Arbillaga L, Azqueta A, Ezpeleta O, Cerain AL (2007a) Oxidative DNA damage induced by ochratoxin A in the HK-2 human kidney cell line: evidence of the relationship with cytotoxicity. Mutagenesis. 22(1):35–42

    CAS  Google Scholar 

  • Arbillaga L, Azqueta A, Van Delft JH, De Cerain AL (2007b) In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol Appl Pharmacol 220(2):216–224

    CAS  Google Scholar 

  • Arrúa AA, Mendes JM, Arrúa P, Ferreira FP, Caballero G, Cazal C, Kohli MM, Peralta I, Ulke G, Fernández Ríos D (2019) Occurrence of deoxynivalenol and ochratoxin A in beers and wines commercialized in Paraguay. Toxins 11(6):308

    Google Scholar 

  • Asrani, R., Patial, V., Thakur, M., 2016. Ochratoxin A: possible mechanisms of toxicity. Biosynt Detec Toxic 57

  • Atroshi F, Biese I, Saloniemi H, Ali-Vehmas T, Saari S, Rizzo A, Veijalainen P (2000) Significance of apoptosis and its relationship to antioxidants after ochratoxin A administration in mice. J Pharm Pharm Sci 3(3):281–291

    CAS  Google Scholar 

  • Aydin, S., Palabiyik, Ş.S., Erkekoglu., P., Sahin, G., Başaran, N., Giray, B.K., 2013. The carotenoid lycopene protects rats against DNA damage induced by Ochratoxin A. Toxicon 73, 96–103

  • Baldi A, Losio M, Cheli F et al (2004) Evaluation of the protective effects of α-tocopherol and retinol against ochratoxin A cytotoxicity. Br J Nutr 91(4):507–512

    CAS  Google Scholar 

  • Bannister, A.J. and Kouzarides, T., 2011. Regulation of chromatin by histone modifications. Cell Res. 21(3), p.381

  • Barcelo JM, Barcelo RC (2018) Post-harvest practices linked with ochratoxin A contamination of coffee in three provinces of Cordillera Administrative Region, Philippines. Food Addit Contam Part A 35:328–340

    CAS  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297

    CAS  Google Scholar 

  • Baudrimont I, Betbeder AM, Gharbi A, Pfohl-Leszkowicz A, Dirheimer G, Creppy E (1994) Effect of superoxide dismutase and catalase on the nephrotoxicity induced by subchronical administration of ochratoxin A in rats. Toxicol. 89(2):101–111

    CAS  Google Scholar 

  • Baudrimont I, Murn M, Betbeder A, Guilcher J, Creppy E (1995) Effect of piroxicam on the nephrotoxicity induced by ochratoxin A in rats. Toxicol. 95(1–3):147–154

    CAS  Google Scholar 

  • Baudrimont I, Betbeder A, Creppy E (1997) Reduction of the ochratoxin A-induced cytotoxicity in Vero cells by aspartame. Arch Toxicol 71(5):290–298

    CAS  Google Scholar 

  • Becker PB, Workman JL (2013) Nucleosome remodeling and epigenetics. Cold Spring Harb Perspect Biol 5(9):a017905

    Google Scholar 

  • Bejaoui H, Mathieu F, Taillandier P, Lebrihi A (2006) Biodegradation of ochratoxin A by Aspergillus section Nigri species isolated from French grapes: a potential means of ochratoxin A decontamination in grape juices and musts. FEMS Microbiol Lett 255:203–208

    CAS  Google Scholar 

  • Belmadani A, Tramu G, Betbeder AM, Creppy EE (1998a) Subchronic effects of ochratoxin A on young adult rat brain and partial prevention by aspartame, a sweetener. Hum Exp Toxicol 17:380–386. https://doi.org/10.1177/096032719801700704

    Article  CAS  Google Scholar 

  • Belmadani A, Tramu G, Betbeder AM, Steyn PS, Creppy EE (1998b) Regional selectivity to ochratoxin A, distribution and cytotoxicity in rat brain. Arch Toxicol 72:656–662. https://doi.org/10.1007/s002040050557

    Article  CAS  Google Scholar 

  • Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ et al (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868. https://doi.org/10.1126/science.1120972

    Article  CAS  Google Scholar 

  • Bhasin M, Reinherz EL, Reche PA (2006) Recognition and classification of histones using support vector machine. J Comput Biol 13(1):102–112

    CAS  Google Scholar 

  • Bhat PV, Pandareesh MD, Khanum F, Tamatam A (2016) Cytotoxic effects of ochratoxin A in neuro-2a cells: role of oxidative stress evidenced by N-acetylcysteine. Front Microbiol 7:1142

    Google Scholar 

  • Bizaj E, Mavri J, Čuš F, Raspor A (2016) Removal of ochratoxin A in Saccharomyces cerevisiae liquid cultures. South African J Enol Viticulture 30:151–155

    Google Scholar 

  • Boesch-Saadatmandi C, Loboda A, Jozkowicz A et al (2008) Effect of ochratoxin A on redox-regulated transcription factors, antioxidant enzymes and glutathione-S-transferase in cultured kidney tubulus cells. Food Chem Toxicol 46(8):2665–2671

    CAS  Google Scholar 

  • Boesch-Saadatmandi C, Wagner A, Graeser A, Hundhausen C, Wolffram S, Rimbach G (2009) Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus cells. J Anim Physiol Anim Nutr 93(5):547–554

    CAS  Google Scholar 

  • Böhm J, Grajewski J, Asperger H, Cecon B, Rabus B, Razzazi E (2000) Study on biodegradation of some A-and B-trichothecenes and ochratoxin A by use of probiotic microorganisms. Mycotoxin Res 16:70

    Google Scholar 

  • Boone, S., 2017. Improved coffee cherry processing. Google Patents

  • Bortoli, G., Fabian, M., 2001. A process to remove mycotoxins from green coffee, ASIC Congress, Trieste

  • Caccamo A, Maldonado MA, Bokov AF, Majumder S, Oddo S (2010) CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 107:22687–22692. https://doi.org/10.1073/pnas.1012851108

    Article  Google Scholar 

  • Cariddi LN, Sabini MC, Escobar FM et al (2015) Polyphenols as possible bioprotectors against cytotoxicity and DNA damage induced by ochratoxin A. Environ Toxicol Pharmacol 39(3):1008–1018

    CAS  Google Scholar 

  • Cavin C, Delatour T, Marin-Kuan M et al (2006) Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. Toxicol Sci 96(1):30–39

    Google Scholar 

  • Chakraborty D, Verma R (2010) Ameliorative effect of Emblica officinalis aqueous extract on ochratoxin-induced lipid peroxidation in the kidney and liver of mice. International J. Occup Med Environ Health 23(1):63–73

    Google Scholar 

  • Chang X, Wu Z, Wu S, Dai Y, Sun C (2015) Degradation of ochratoxin A by Bacillus amyloliquefaciens ASAG1. Food Add Contam Part A 32(4):564–571

    CAS  Google Scholar 

  • Chen C, Wu F (2017) The need to revisit ochratoxin A risk in light of diabetes, obesity, and chronic kidney disease prevalence. Food Chem Toxicol 103:79–85

    CAS  Google Scholar 

  • Chen W, Li C, Zhang B, Zhou Z, Shen Y, Liao X, Yang J, Wang Y, Li X, Li Y (2018a) Advances in biodetoxification of ochratoxin AA review of the past five decades. Front Microbiol 9

  • Chen L, Gao Y, Zhu L, Song H, Zhao L, Liu A, Zhang G, Shi G (2018b) Establishment and characterization of a GES-1 human gastric epithelial cell line stably expressing miR-23a. Oncol Lett 16(1):977–983

    Google Scholar 

  • Cho SM, Jeong SE, Lee KR, Sudhani HP, Kim M, Hong S-Y, Chung SH (2016) Biodegradation of ochratoxin A by Aspergillus tubingensis isolated from Meju. J Microbiol Biotechnol 26:1687–1695

    CAS  Google Scholar 

  • Costa S, Utan A, Cervellati R, Speroni E, Guerra M (2007) Catechins: natural free-radical scavengers against ochratoxin A-induced cell damage in a pig kidney cell line (LLC-PK1). Food Chem Toxicol 45(10):1910–1917

    CAS  Google Scholar 

  • Costa JG, Saraiva N, Guerreiro PS et al (2016) Ochratoxin A-induced cytotoxicity, genotoxicity and reactive oxygen species in kidney cells: an integrative approach of complementary endpoints. Food Chem Toxicol 87:65–76

    CAS  Google Scholar 

  • Creppy EE, Schlegel M, Röschenthaler R, Dirheimer G (1980) Phenylalanine prevents acute poisoning by ochratoxin-a in mice. Toxicol Lett 6(2):77–80

    CAS  Google Scholar 

  • Creppy EE, Röschenthaler R, Dirheimer G (1984) Inhibition of protein synthesis in mice by ochratoxin A and its prevention by phenylalanine. Food Chem Toxicol 22(11):883–886. https://doi.org/10.1016/0278-6915(84)90170-4

    Article  CAS  Google Scholar 

  • Creppy E, Baudrimont I, Belmadani A, Betbeder A (1996) Aspartame as a preventive agent of chronic toxic effects of ochratoxin A in experimental animals. J Toxicol Toxin Rev 15(3):207–221

    CAS  Google Scholar 

  • Creppy EE, Baudrimont I, Marie A (1998) How aspartame prevents the toxicity of ochratoxin A. J Toxicol Sci 23:165–172

    CAS  Google Scholar 

  • Creppy EE, Moukha S, Bacha H, Carratu MR (2005) How much should we involve genetic and environmental factors in the risk assessment of mycotoxins in humans? Int J Environ Res Public Health 2(1):186–193

    CAS  Google Scholar 

  • Cui J, Xing L, Li Z, Wu S, Wang J, Liu J, Wang J, Yan X, Zhang X (2010) Ochratoxin A induces G2 phase arrest in human gastric epithelium GES-1 cells in vitro. Toxicol Lett 193(2):152–158

    CAS  Google Scholar 

  • Cui J, Liu J, Wu S et al (2013) Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro. Arch Toxicol 87(10):1829–1840

    CAS  Google Scholar 

  • Czakai K, Müller K, Mosesso P et al (2011) Perturbation of mitosis through inhibition of histone acetyltransferases: the key to ochratoxin a toxicity and carcinogenicity? Toxicol Sci 122(2):317–329

    CAS  Google Scholar 

  • Dai J, Sullivan BA, Higgins JM (2006) Regulation of mitotic chromosome cohesion by Haspin and Aurora B. Dev Cell 11(5):741–750

    CAS  Google Scholar 

  • Dai Q, Zhao J, Qi X et al (2014) MicroRNA profiling of rats with ochratoxin A nephrotoxicity. BMC Genomics 15(1):333

    Google Scholar 

  • Darif Y, Mountassif D, Belkebir A et al (2016) Ochratoxin A mediates MAPK activation, modulates IL-2 and TNF-α mRNA expression and induces apoptosis by mitochondria-dependent and mitochondria-independent pathways in human H9 T cells. J Toxicol Sci 41(3):403–416

    CAS  Google Scholar 

  • De Bellis P, Tristezza M, Haidukowski M, Fanelli F, Sisto A, Mulè G, Grieco F (2015) Biodegradation of ochratoxin A by bacterial strains isolated from vineyard soils. Toxins 7:5079–5093

    Google Scholar 

  • De Felice D, Solfrizzo M, De Curtis F, Lima G, Visconti A, Castoria R (2008) Strains of Aureobasidium pullulans can lower ochratoxin A contamination in wine grapes. Phytopathol. 98:1261–1270

    Google Scholar 

  • De Oliveira MR, Nabavi SM, Braidy N, Setzer WN, Ahmed T, Nabavi SF (2016) Quercetin and the mitochondria: a mechanistic view. Biotechnol Adv 34(5):532–549

    Google Scholar 

  • Di Giacomo C, Acquaviva R, Piva A et al (2007) Protective effect of cyanidin 3-O-β-d-glucoside on ochratoxin A-mediated damage in the rat. Br J Nutr 98(5):937–943

    Google Scholar 

  • Domijan AM, Želježić D, Kopjar N, Peraica M (2006) Standard and Fpg-modified comet assay in kidney cells of ochratoxin A-and fumonisin B 1-treated rats. Toxicol. 222(1):53–59

    CAS  Google Scholar 

  • Domijan AM, Peraica M, Vrdoljak AL, Radić B, Žlender V, Fuchs R (2007) The involvement of oxidative stress in ochratoxin A and fumonisin B1 toxicity in rats. Mol Nutr Food Res 51(9):1147–1151

    CAS  Google Scholar 

  • Dutto I, Tillhon M, Cazzalini O, Stivala LA, Prosperi E (2015) Biology of the cell cycle inhibitor p21CDKN1A: molecular mechanisms and relevance in chemical toxicology. Arch Toxicol 89(2):155–178

    CAS  Google Scholar 

  • Dwivedi P, Burns RB (1984) Effect of ochratoxin A on immunoglobulins in broiler chicks. Res Vet Sci 36(1):117–121

    CAS  Google Scholar 

  • EFSA (2004) Opinion of the Scientific Panel on the Contaminants in the Food Chain on a request from the Commission related to ochratoxin A (OTA) as undesirable substance in animal feed. EFSA J 101:1–36

    Google Scholar 

  • Ehrlich V, Darroudi F, Uhl M et al (2002) Genotoxic effects of ochratoxin A in human-derived hepatoma (HepG2) cells. Food Chem Toxicol 40(8):1085–1090

    CAS  Google Scholar 

  • El-Nekeety AA, Abdel-Wahhab KG, Abdel-Aziem SH, Mannaa FA, Hassan NS, Abdel-Wahhab MA (2017) Papaya fruits extracts enhance the antioxidant capacity and modulate the genotoxicity and oxidative stress in the kidney of rats fed ochratoxin A-contaminated diet. J Appl Pharm Sci 7(07):111–121

    CAS  Google Scholar 

  • Engelhardt G (2002) Degradation of ochratoxin a and b by the white rot funguspleurotus ostreatus. Mycotoxin Res 18:37–43

    CAS  Google Scholar 

  • Essid E, Petzinger E (2011) Silibinin pretreatment protects against ochratoxin A-mediated apoptosis in primary rat hepatocytes. Mycotoxin Res 27(3):167–176

    CAS  Google Scholar 

  • Essid E, Dernawi Y, Petzinger E (2012) Apoptosis induction by OTA and TNF-α in cultured primary rat hepatocytes and prevention by silibinin. Toxins 4(11):1139–1156

    CAS  Google Scholar 

  • Ferguson-Smith AC (2011) Genomic imprinting: the emergence of an epigenetic paradigm. Nat Rev Genet 12(8):565

    CAS  Google Scholar 

  • Ferrante MC, Bilancione M, Raso GM et al (2006) Expression of COX-2 and hsp72 in peritoneal macrophages after an acute ochratoxin A treatment in mice. Life Sci 79(13):1242–1247

    CAS  Google Scholar 

  • Ferrante M, Raso GM, Bilancione M, Esposito E, Iacono A, Meli R (2008) Differential modification of inflammatory enzymes in J774A. 1 macrophages by ochratoxin A alone or in combination with lipopolysaccharide. Toxicol Lett 181(1):40–46

    CAS  Google Scholar 

  • Ferraz MB, Farah A, Iamanaka BT, Perrone D, Copetti MV, Marques VX, Vitali AA, Taniwaki MH (2010) Kinetics of ochratoxin A destruction during coffee roasting. Food Control 21:872–877

    CAS  Google Scholar 

  • Friedlander RM (2003) Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348:1365–1375

    CAS  Google Scholar 

  • Fuchs S, Sontag G, Stidl R, Ehrlich V, Kundi M, Knasmüller S (2008) Detoxification of patulin and ochratoxin A, two abundant mycotoxins, by lactic acid bacteria. Food Chem Toxicol 46:1398–1407

    CAS  Google Scholar 

  • Fusi E, Rebucci R, Pecorini C, Rossi L, D’Ambrosio F, Baldi A (2008) Evaluation of the damage induced by ochratoxin A and the protective role of α-tocopherol in cultured bovine mammary epithelial cells. Vet Res Commun 32(1):343–345

    Google Scholar 

  • Fusi E, Rebucci R, Pecorini C et al (2010) Alpha-tocopherol counteracts the cytotoxicity induced by ochratoxin a in primary porcine fibroblasts. Toxins 2(6):1265–1278

    CAS  Google Scholar 

  • Gagliano N, Dalle Donne I, Torri C et al (2006) Early cytotoxic effects of ochratoxin A in rat liver: a morphological, biochemical and molecular study. Toxicol. 225(2):214–224

    CAS  Google Scholar 

  • Gallo A, Giuberti G, Frisvad JC, Bertuzzi T, Nielsen KF (2015) Review on mycotoxin issues in ruminants: occurrence in forages, effects of mycotoxin ingestion on health status and animal performance and practical strategies to counteract their negative effects. Toxins 7:3057–3111

    CAS  Google Scholar 

  • Gan F, Xue H, Huang Y, Pan C, Huang K (2015) Selenium alleviates porcine nephrotoxicity of ochratoxin A by improving selenoenzyme expression in vitro. PLoS One 10(3):e0119808

    Google Scholar 

  • Gan F, Zhou Y, Hou L, Qian G, Chen X, Huang K (2017) Ochratoxin A induces nephrotoxicity and immunotoxicity through different MAPK signaling pathways in PK15 cells and porcine primary splenocytes. Chemosphere 182:630–637

    CAS  Google Scholar 

  • Gan F, Zhou Y, Qian G et al (2018) PCV2 infection aggravates ochratoxin A-induced nephrotoxicity via autophagy involving p38 signaling pathway in vivo and in vitro. Environ Pollut 238:656–662

    CAS  Google Scholar 

  • Garcia A, Avila E, Rosiles R, Petrone V (2003) Evaluation of two mycotoxin binders to reduce toxicity of broiler diets containing ochratoxin A and T-2 toxin contaminated grain. Avian Dis 47(3):691–699

    CAS  Google Scholar 

  • Gautier JC, Holzhaeuser D, Markovic J, Gremaud E, Schilter B, Turesky RJ (2001) Oxidative damage and stress response from ochratoxin A exposure in rats. Free Radic Biol Med 30(10):1089–1098

    CAS  Google Scholar 

  • Gayathri L, Dhivya R, Dhanasekaran D, Periasamy VS, Alshatwi AA, Akbarsha MA (2015) Hepatotoxic effect of ochratoxin A and citrinin, alone and in combination, and protective effect of vitamin E: In vitro study in HepG2 cell. Food Chem Toxicol 83:151–163

    CAS  Google Scholar 

  • Gazin C, Wajapeyee N, Gobeil S, Virbasius CM, Green MR (2007) An elaborate pathway required for Ras-mediated epigenetic silencing. Nature. 449:1073–1077

    CAS  Google Scholar 

  • Giromini C, Rebucci R, Saccone F, Fusi E, Baldi A (2015) Cytotoxicity, DNA integrity and methylation in mammary and kidney epithelial cell lines exposed to Ochratoxin A. Ital J Anim Sci 14(suppl. 1):44–44

    Google Scholar 

  • Gordon EM, Ravicz JR, Liu S, Chawla SP, Hall FL (2018) Cell cycle checkpoint control: the cyclin G1/Mdm2/p53 axis emerges as a strategic target for broad-spectrum cancer gene therapy-A review of molecular mechanisms for oncologists. Mol Clin Oncol 9(2):115–134

    CAS  Google Scholar 

  • Grosse Y, Chekir-Ghedira L, Huc A et al (1997) Retinol, ascorbic acid and α-tocopherol prevent DNA adduct formation in mice treated with the mycotoxins ochratoxin A and zearalenone. Cancer Lett 114(1):225–229

    CAS  Google Scholar 

  • Guerra M, Galvano F, Bonsi L et al (2005) Cyanidin-3-O-β-glucopyranoside, a natural free-radical scavenger against aflatoxin B1-and ochratoxin A-induced cell damage in a human hepatoma cell line (Hep G2) and a human colonic adenocarcinoma cell line (CaCo-2). Br J Nutr 94(2):211–220

    CAS  Google Scholar 

  • Ha TH (2015) Recent advances for the detection of ochratoxin A. Toxins 7(12):5276–5300

    CAS  Google Scholar 

  • Hadjeba-Medjdoub K, Tozlovanu M, Pfohl-Leszkowicz A, Frenette C, Paugh RJ, Manderville RA (2012) Structure–activity relationships imply different mechanisms of action for Ochratoxin A-mediated cytotoxicity and genotoxicity. Chem Res Toxicol 25(1):181–190

    CAS  Google Scholar 

  • Hameed MR, Khan MZ, Saleemi MK et al (2017) Study of ochratoxin A (OTA)-induced oxidative stress markers in broiler chicks. Toxin Rev 36(4):270–274

    CAS  Google Scholar 

  • Hassen W, Ayed-Boussema I, Bouslimi A, Bacha H (2007) Heat shock proteins (Hsp 70) response is not systematic to cell stress: case of the mycotoxin ochratoxin A. Toxicology. 242(1):63–70

    CAS  Google Scholar 

  • Hennemeier I, Humpf HU, Gekle M, Schwerdt G (2014) Role of microRNA-29b in the ochratoxin A-induced enhanced collagen formation in human kidney cells. Toxicology. 324:116–122

    CAS  Google Scholar 

  • Hibi D, Kijima A, Kuroda K et al (2013) Molecular mechanisms underlying ochratoxin A-induced genotoxicity: global gene expression analysis suggests induction of DNA double-strand breaks and cell cycle progression. J Toxicol Sci 38(1):57–69

    CAS  Google Scholar 

  • Hoehler D, Marquardt RR (1996) Influence of vitamins E and C on the toxic effects of ochratoxin A and T-2 toxin in chicks. Poult Sci 75(12):1508–1515

    CAS  Google Scholar 

  • Hoehler D, Marquardt RR, McIntosh AR, Xiao H (1996) Free radical generation as induced by ochratoxin A and its analogs in bacteria (Bacillus brevis). J Biol Chem 271(44):27388–27394

    CAS  Google Scholar 

  • Hoehler D, Marquardt RR, McIntosh AR, Hatch GM (1997) Induction of free radicals in hepatocytes, mitochondria and microsomes of rats by ochratoxin A and its analogs. Biochim Biophys Acta-Mol Cell Res 1357(2):225–233

    CAS  Google Scholar 

  • Holzapfel, W., Brost, I., Farber, P., Geisen, R., Bresch, H., Jany, K., Mengu, M., Jakobsen, M., Steyn, P., Teniola, D., 2002. Actinomycetes for breaking down aflatoxin B1, ochratoxin A, and/or zearalenon. Patent Number WO02/099142 A3

  • Hooper DG, Bolton VE, Guilford FT, Straus DC (2009) Mycotoxin detection in human samples from patients exposed to environmental molds. Int J Mol Sci 10(4):1465–1475

    CAS  Google Scholar 

  • Hope, J.H., Hope, B.E., 2012. A review of the diagnosis and treatment of ochratoxin A inhalational exposure associated with human illness and kidney disease including focal segmental glomerulosclerosis J Environ Public Health 2012

  • Hou L, Gan F, Zhou X et al (2018) Immunotoxicity of ochratoxin A and aflatoxin B1 in combination is associated with the nuclear factor kappa B signaling pathway in 3D4/21 cells. Chemosphere 199:718–727

    CAS  Google Scholar 

  • Hu H, Jia X, Wang Y, Liang Z (2018) Removal of ochratoxin A by a carboxypeptidase and peptides present in liquid cultures of Bacillus subtilis CW14. World Mycotoxin J:1–12

  • Huang FJ, Chan WH (2016) Effects of ochratoxin a on mouse oocyte maturation and fertilization, and apoptosis during fetal development. Environ Toxicol 31(6):724–735

    CAS  Google Scholar 

  • Hundhausen C, Bösch-Saadatmandi C, Augustin K, Blank R, Wolffram S, Rimbach G (2005) Effect of vitamin E and polyphenols on ochratoxin A-induced cytotoxicity in liver (HepG2) cells. J Plant Physiol 162(7):818–822

    CAS  Google Scholar 

  • Jennings P, Weiland C, Limonciel A et al (2012) Transcriptomic alterations induced by ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol 86(4):571–589

    CAS  Google Scholar 

  • Kamp HG, Eisenbrand G, Janzowski C et al (2005a) Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats. Mol Nutr Food Res 49(12):1160–1167

    CAS  Google Scholar 

  • Kamp HG, Eisenbrand G, Schlatter J, Würth K, Janzowski C (2005b) Ochratoxin A: induction of (oxidative) DNA damage, cytotoxicity and apoptosis in mammalian cell lines and primary cells. Toxicology 206(3):413–425

    CAS  Google Scholar 

  • Karlovsky P, Suman M, Berthiller F, De Meester J, Eisenbrand G, Perrin I, Oswald IP, Speijers G, Chiodini A, Recker T (2016) Impact of food processing and detoxification treatments on mycotoxin contamination. Mycotoxin Res 32:179–205

    CAS  Google Scholar 

  • Kastner A, Hirsch EC, Herrero MT, Javoy-Agid F, Agid Y (1993) Immunocytochemical quantification of tyrosine hydroxylase at a cellular level in the mesencephalon of control subjects and patients with Parkinson’s and Alzheimer’s disease. J Neurochem 61:1024–1034. https://doi.org/10.1111/j.1471-4159.1993.tb03616.x

    Article  CAS  Google Scholar 

  • Kayoko M, Shigetoshi S, Tetsuro K, Mikio Y, Masayoshi K (1985) Reduction of ochratoxin A toxicity in mice treated with phenylalanine and phenobarbital. Toxicol Lett 25(1):1–5

    Google Scholar 

  • Kerkadi A, Barriault C, Marquardt RR et al (1999) Cholestyramine protection against ochratoxin A toxicity: role of ochratoxin A sorption by the resin and bile acid enterohepatic circulation. J Food Prot 62(12):1461–1465

    CAS  Google Scholar 

  • Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405. https://doi.org/10.1016/j.bbadis.2009.12.009

    Article  CAS  Google Scholar 

  • Knasmuller S, Cavin C, Chakraborty A et al (2004) Structurally related mycotoxins ochratoxin A, ochratoxin B, and citrinin differ in their genotoxic activities and in their mode of action in human-derived liver (HepG2) cells: implications for risk assessment. Nutr Cancer 50(2):190–197

    Google Scholar 

  • Kőszegi T, Poór M (2016) Ochratoxin A: molecular interactions, mechanisms of toxicity and prevention at the molecular level. Toxins 8(4):111

    Google Scholar 

  • Kumar R, Alam S, Chaudhari BP et al (2012) Ochratoxin A-induced cell proliferation and tumor promotion in mouse skin by activating the expression of cyclin-D1 and cyclooxygenase-2 through nuclear factor-kappa B and activator protein-1. Carcinogenesis 34(3):647–657

    Google Scholar 

  • Kumar M, Dwivedi P, Sharma AK, Sankar M, Patil RD, Singh ND (2014) Apoptosis and lipid peroxidation in ochratoxin A-and citrinin-induced nephrotoxicity in rabbits. Toxicol Ind Health 30(1):90–98

    CAS  Google Scholar 

  • Kumari D, Sinha S (1994) Effect of retinol on ochratoxin-produced genotoxicity in mice. Food Chem Toxicol 32(5):471–475

    CAS  Google Scholar 

  • La Pera L, Avellone G, Lo Turco V, Di Bella G, Agozzino P, Dugo G (2008) Influence of roasting and different brewing processes on the ochratoxin A content in coffee determined by high-performance liquid chromatography-fluorescence detection (HPLC-FLD). Food Addit Contam 25:1257–1263

    Google Scholar 

  • Lambert D, Padfield PJ, McLaughlin J, Cannell S, O’Neill CA (2007) Ochratoxin A displaces claudins from detergent resistant membrane microdomains. Biochem Biophys Res Commun 358(2):632–636

    CAS  Google Scholar 

  • Leite, G.M., 2013. Potential for control of spoilage and mycotoxigenic species using mixtures of anti-oxidants, aliphatic acids and molecular approaches using RNAi. http://dspace.lib.cranfield.ac.uk/handle/1826/8632

  • Li J, Yin S, Dong Y, Fan L, Hu H (2011) p53 activation inhibits ochratoxin A-induced apoptosis in monkey and human kidney epithelial cells via suppression of JNK activation. Biochem Biophys Res Commun 411(2):458–463

    CAS  Google Scholar 

  • Li X, Gao J, Huang K et al (2015) Dynamic changes of global DNA methylation and hypermethylation of cell adhesion-related genes in rat kidneys in response to ochratoxin A. World Mycotoxin J 8(4):465–476

    CAS  Google Scholar 

  • Liang R, Shen XL, Zhang B et al (2015) Apoptosis signal-regulating kinase 1 promotes ochratoxin A-induced renal cytotoxicity. Sci Report 5:8078

    Google Scholar 

  • Limonciel A, Jennings P (2014) A review of the evidence that ochratoxin A is an Nrf2 inhibitor: implications for nephrotoxicity and renal carcinogenicity. Toxins 6(1):371–379

    CAS  Google Scholar 

  • Liu Q, Zhang J, Zhu H, Qin C, Chen Q, Zhao B (2007) Dissecting the signaling pathway of nicotine-mediated neuroprotection in a mouse Alzheimer disease model. FASEB J 21:61–73. https://doi.org/10.1096/fj.06-5841com

    Article  CAS  Google Scholar 

  • Liu J, Wang Y, Cui J et al (2012) Ochratoxin A induces oxidative DNA damage and G1 phase arrest in human peripheral blood mononuclear cells in vitro. Toxicol Lett 211(2):164–171

    CAS  Google Scholar 

  • Loboda A, Stachurska A, Podkalicka P et al (2017) Effect of heme oxygenase-1 on ochratoxin A-induced nephrotoxicity in mice. Int J Biochem Cell Biol 84:46–57

    CAS  Google Scholar 

  • Lühe A, Hildebrand H, Bach U, Dingermann T, Ahr HJ (2003) A new approach to studying ochratoxin A (OTA)-induced nephrotoxicity: expression profiling in vivo and in vitro employing cDNA microarrays. Toxicol Sci 73(2):315–328

    Google Scholar 

  • Luz C, Ferrer J, Mañes J, Meca G (2018) Toxicity reduction of ochratoxin A by lactic acid bacteria. Food Chem Toxicol 112:60–66

    CAS  Google Scholar 

  • Madhyastha M, Frohlich A, Marquardt R (1992) Effect of dietary cholestyramine on the elimination pattern of ochratoxin A in rats. Food Chem Toxicol 30(8):709–714

    CAS  Google Scholar 

  • Malekinejad H, Mirzakhani N, Razi M, Cheraghi H, Alizadeh A, Dardmeh F (2011) Protective effects of melatonin and Glycyrrhiza glabra extract on ochratoxin A--induced damages on testes in mature rats. Hum Exp Toxicol 30:110–123

    CAS  Google Scholar 

  • Malir F, Ostry V, Pfohl-Leszkowicz A, Novotna E (2013a) Ochratoxin A: developmental and reproductive toxicity-An overview. Birth Defects Res. B Dev Reprod Toxicol 98(6):493–502

    CAS  Google Scholar 

  • Malir F, Ostry V, Novotna E (2013b) Toxicity of the mycotoxin ochratoxin A in the light of recent data. Toxin Rev 32(2):19–33

    CAS  Google Scholar 

  • Malir F, Ostry V, Pfohl-Leszkowicz A, Malir J, Toman J (2016) Ochratoxin A: 50 years of research. Toxins 8(7):191

    Google Scholar 

  • Mally A (2012) Ochratoxin A and mitotic disruption: mode of action analysis of renal tumor formation by ochratoxin A. Toxicol Sci 127(2):315–330

    CAS  Google Scholar 

  • Mally A, Pepe G, Ravoori S et al (2005) Ochratoxin A causes DNA damage and cytogenetic effects but no DNA adducts in rats. Chem Res Toxicol 18(8):1253–1261

    CAS  Google Scholar 

  • Manderville R, Pfohl-Leszkowicz A (2008) Bioactivation and DNA adduction as a rationale for ochratoxin A carcinogenesis. World Mycotoxin J 1(3):357–367

    CAS  Google Scholar 

  • Mantle PG, Faucet-Marquis V, Manderville RA, Squillaci B, Pfohl-Leszkowicz A (2009) Structures of covalent adducts between DNA and ochratoxin A: a new factor in debate about genotoxicity and human risk assessment. Chem Res Toxicol 23(1):89–98

    Google Scholar 

  • Marin DE, Taranu I (2015) Ochratoxin A and its effects on immunity. Toxin Rev 34(1):11–20

    CAS  Google Scholar 

  • Marin DE, Braicu C, Gras MA et al (2017a) Low level of ochratoxin A affects genome-wide expression in kidney of pig. Toxicon 136:67–77

    CAS  Google Scholar 

  • Marin DE, Pistol GC, Gras MA, Palade ML, Taranu I (2017b) Comparative effect of ochratoxin A on inflammation and oxidative stress parameters in gut and kidney of piglets. Regul Toxicol Pharmacol 89:224–231

    CAS  Google Scholar 

  • Marin-Kuan M, Nestler S, Verguet C et al (2005) A toxicogenomics approach to identify new plausible epigenetic mechanisms of ochratoxin a carcinogenicity in rat. Toxicol Sci 89(1):120–134

    Google Scholar 

  • Marin-Kuan M, Nestler S, Verguet C et al (2007) MAPK-ERK activation in kidney of male rats chronically fed ochratoxin A at a dose causing a significant incidence of renal carcinoma. Toxicol Appl Pharmacol 224(2):174–181

    CAS  Google Scholar 

  • Marin-Kuan M, Ehrlich V, Delatour T, Cavin C, Schilter B (2011) Evidence for a role of oxidative stress in the carcinogenicity of ochratoxin A. J Toxicol 645361

  • Milani J, Maleki G (2014) Effects of processing on mycotoxin stability in cereals. J Sci Food Agric 94:2372–2375

    CAS  Google Scholar 

  • Molnar O, Schatzmayr G, Fuchs E, Prillinger H (2004) Trichosporon mycotoxinivorans sp. nov., a new yeast species useful in biological detoxification of various mycotoxins. Syst Appl Microbiol 27:661–671

    CAS  Google Scholar 

  • Munoz L, Ammit AJ (2010) Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 58:561–568. https://doi.org/10.1016/j.neuropharm.2009

    Article  CAS  Google Scholar 

  • Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 63:71–124. https://doi.org/10.1016/S0301-0082(00)00014-9

    Article  CAS  Google Scholar 

  • Nabavi SF, Barber AJ, Spagnuolo C et al (2016) Nrf2 as molecular target for polyphenols: a novel therapeutic strategy in diabetic retinopathy. Crit Rev Clin Lab Sci 53(5):293–312

    CAS  Google Scholar 

  • Nehad E, Farag M, Kawther M, Abdel-Samed A, Naguib K (2005) Stability of ochratoxin A (OTA) during processing and decaffeination in commercial roasted coffee beans. Food Addit Contam 22:761–767

    CAS  Google Scholar 

  • Nephew KP, Huang THM (2003) Epigenetic gene silencing in cancer initiation and progression. Cancer Lett 190(2):125–133

    CAS  Google Scholar 

  • Ozcan G, Ozpolat B, Coleman RL, Sood AK, Lopez-Berestein G (2015) Preclinical and clinical development of siRNA-based therapeutics. Adv Drug Deliv Rev 87:108–119

    CAS  Google Scholar 

  • Ozden S, Kara NT, Sezerman OU, Durasi İM, Chen T, Demirel G, Alpertunga B, Chipman JK, Mally A (2015) Assessment of global and gene-specific DNA methylation in rat liver and kidney in response to non-genotoxic carcinogen exposure. Toxicol Appl Pharmacol 289(2):203–212

    CAS  Google Scholar 

  • Özpinar H, Bilal T, Abas I, Kutay C (2002) Degradation of ochratoxin A in rumen fluid in vitro. FU Med Biol 9:66–69

    Google Scholar 

  • Palabiyik S, Erkekoglu P, Zeybek N, Kızılgun M, Sahin G, Giray BK (2012) Ochratoxin A causes oxidative stress and cell death in rat liver. World Mycotoxin J 5(4):377–384

    CAS  Google Scholar 

  • Palabiyik SS, Erkekoglu P, Zeybek ND et al (2013) Protective effect of lycopene against ochratoxin A induced renal oxidative stress and apoptosis in rats. Exp Toxicol Pathol 65(6):853–861

    CAS  Google Scholar 

  • Palma N, Cinelli S, Sapora O, Wilson SH, Dogliotti E (2007) Ochratoxin A-induced mutagenesis in mammalian cells is consistent with the production of oxidative stress. Chem Res Toxicol 20(7):1031–1037

    CAS  Google Scholar 

  • Paradells S, Rocamonde B, Llinares C et al (2015) Neurotoxic effects of ochratoxin A on the subventricular zone of adult mouse brain. J Appl Toxicol 35(7):737–751

    CAS  Google Scholar 

  • Perez De Obanos A, Gonzalez-Penas E, Lopez de Cerain A (2005) Influence of roasting and brew preparation on the ochratoxin A content in coffee infusion. Food Addit Contam 22:463–471

    CAS  Google Scholar 

  • Periasamy R, Kalal IG, Krishnaswamy R, Viswanadha V (2016) Quercetin protects human peripheral blood mononuclear cells from OTA-induced oxidative stress, genotoxicity, and inflammation. Environ Toxicol 31(7):855–865

    CAS  Google Scholar 

  • Peromingo B, Núñez F, Rodríguez A, Alía A, Andrade MJ (2018) Potential of yeasts isolated from dry-cured ham to control ochratoxin A production in meat models. Int J Food Microbiol 268:73–80

    CAS  Google Scholar 

  • Perry JL, Goldsmith MR, Peterson MA et al (2004) Structure of the ochratoxin A binding site within human serum albumin. J Phys Chem B 108(43):16960–16964

    CAS  Google Scholar 

  • Petchkongkaew A, Taillandier P, Gasaluck P, Lebrihi A (2008) Isolation of Bacillus spp. from Thai fermented soybean (Thua-nao): screening for aflatoxin B1 and ochratoxin A detoxification. J Appl Microbiol 104:1495–1502

    CAS  Google Scholar 

  • Péteri Z, Téren J, Vágvölgyi C, Varga J (2007) Ochratoxin degradation and adsorption caused by astaxanthin-producing yeasts. Food Microbiol 24:205–210

    Google Scholar 

  • Petrik J, Žanić-Grubišić T, Barišić K et al (2003) Apoptosis and oxidative stress induced by ochratoxin A in rat kidney. Arch Toxicol 77(12):685–693

    CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • Pfohl-Leszkowicz A, Manderville RA (2011) An update on direct genotoxicity as a molecular mechanism of ochratoxin a carcinogenicity. Chem Res Toxicol 25(2):252–262

    Google Scholar 

  • Pfohl-Leszkowicz A, Bartsch H, Azémar B, Mohr U, Estève J, Castegnaro M (2002) MESNA protects rats against nephrotoxicity but not carcinogenicity induced by ochratoxin A, implicating two separate pathways. FU Med Biol 9:57–63

    Google Scholar 

  • Pfohl-Leszkowicz, A., & Manderville, R.A., 2012. An update on direct genotoxicity as molecular mechanism of ochratoxin A carcinogenicity. Chem. Res. Toxicol. 25, 252–262.Pfohl-Leszkowicz, A., Hadjeba-Medjdoub, K., Ballet, N., Schrickx, J., Fink-Gremmels, J., 2015. Assessment and characterisation of yeast-based products intended to mitigate ochratoxin exposure using in vitro and in vivo models. Food Addit Contam A 32(4), 604–616

  • Pinelli E, El Adlouni C, Pipy B, Quartulli F, Pfohl-Leszkowicz A (1999) Roles of cyclooxygenase and lipoxygenases in ochratoxin A genotoxicity in human epithelial lung cells. Environ Toxicol Pharmacol 7(2):95–107

    CAS  Google Scholar 

  • Piotrowska M, Żakowska Z (2000) The biodegradation of ochratoxin A in food products by lactic acid bacteria and baker’s yeast. Prog Biotechnol 307–310

  • Piva, A., Galvano, F., 1999. Nutritional approaches to reduce the impact of mycotoxins. Biotechnol. Feed Ind. 381–399

  • Pleadin J, Perši N, Kovačević D, Vulić A, Frece J, Markov K (2014) Ochratoxin A reduction in meat sausages using processing methods practiced in households. Food Addit Contam B 7(4):239–246

    CAS  Google Scholar 

  • Poór M, Kunsági-Máté S, Bencsik T, Petrik J, Vladimir-Knežević S, Kőszegi T (2012) Flavonoid aglycones can compete with Ochratoxin A for human serum albumin: A new possible mode of action. Int J Biol Macromol 51(3):279–283

    Google Scholar 

  • Poór M, Veres B, Jakus PB et al (2014) Flavonoid diosmetin increases ATP levels in kidney cells and relieves ATP depleting effect of ochratoxin A. J Photochem Photobiol B Biol 132:1–9

    Google Scholar 

  • Qi X, Yang X, Chen S et al (2014a) Ochratoxin A induced early hepatotoxicity: new mechanistic insights from microRNA, mRNA and proteomic profiling studies. Sci Report 4:5163

    CAS  Google Scholar 

  • Qi X, Yu T, Zhu L et al (2014b) Ochratoxin A induces rat renal carcinogenicity with limited induction of oxidative stress responses. Toxicol Appl Pharmacol 280(3):543–549

    CAS  Google Scholar 

  • Rached E, Pfeiffer E, Dekant W, Mally A (2006) Ochratoxin A: apoptosis and aberrant exit from mitosis due to perturbation of microtubule dynamics? Toxicol Sci 92(1):78–86

    CAS  Google Scholar 

  • Rahimtula A, Béréziat JC, Bussacchini-Griot V, Bartsch H (1988) Lipid peroxidation as a possible cause of ochratoxin A toxicity. Biochem Pharmacol 37(23):4469–4477

    CAS  Google Scholar 

  • Ramyaa P, Padma VV (2013) Ochratoxin-induced toxicity, oxidative stress and apoptosis ameliorated by quercetin–Modulation by Nrf2. Food Chem Toxicol 62:205–216

    CAS  Google Scholar 

  • Ramyaa P, Padma VV (2014) Quercetin modulates OTA-induced oxidative stress and redox signalling in HepG2 cells—up regulation of Nrf2 expression and down regulation of NF-κB and COX-2. Biochim Biophys Acta Gen Subj 1840(1):681–692

    CAS  Google Scholar 

  • Rašić D, Mladinić M, Želježić D et al (2018) Effects of combined treatment with ochratoxin A and citrinin on oxidative damage in kidneys and liver of rats. Toxicon. 1646:99–105

    Google Scholar 

  • Renzulli C, Galvano F, Pierdomenico L, Speroni E, Guerra M (2004) Effects of rosmarinic acid against aflatoxin B1 and ochratoxin-A-induced cell damage in a human hepatoma cell line (Hep G2). J Appl Toxicol 24(4):289–296

    CAS  Google Scholar 

  • Reverberi M, Gazzetti K, Punelli F et al (2012) Aoyap1 regulates OTA synthesis by controlling cell redox balance in Aspergillus ochraceus. Appl Microbiol Biotechnol 95(5):1293–1304

    CAS  Google Scholar 

  • Ringot D, Chango A, Schneider YJ, Larondelle Y (2006) Toxicokinetics and toxicodynamics of ochratoxin A, an update. Chem Biol Interact 159(1):18–46

    CAS  Google Scholar 

  • Romani S, Pinnavaia GG, Dalla Rosa M (2003) Influence of roasting levels on ochratoxin A content in coffee. J Agric Food Chem 51:5168–5171

    CAS  Google Scholar 

  • Rossiello MR, Rotunno C, Coluccia A, Carratù MR, Di Santo A, Evangelista V, Semeraro N, Colucci M (2008) Ochratoxin A inhibits the production of tissue factor and plasminogen activator inhibitor-2 by human blood mononuclear cells: Another potential mechanism of immune-suppression. Toxicol Appl Pharmacol 229(2):227–231

    CAS  Google Scholar 

  • Rudeš, K., 2006. The effect of ochratoxin A on the concentration of protein carbonyls in rats. Farmaceutsko-biokemijski fakultet, Sveučilište u Zagrebu

  • Russo A, La Fauci L, Acquaviva R et al (2005) Ochratoxin A-induced DNA damage in human fibroblast: protective effect of cyanidin 3-O-β-D-glucoside. J Nutr Biochem 16(1):31–37

    CAS  Google Scholar 

  • Sava V, Reunova O, Velasquez A, Harbison R, Sanchez-Ramos J (2006a) Acute neurotoxic effects of the fungal metabolite ochratoxin-A. Neurotoxicology. 27(1):82–92

    CAS  Google Scholar 

  • Sava V, Reunova O, Velasquez A, Sanchez-Ramos J (2006b) Can low level exposure to ochratoxin-A cause parkinsonism? J Neurol Sci 249(1):68–75

    CAS  Google Scholar 

  • Sava V, Velasquez A, Song S, Sanchez-Ramos J (2007) Adult hippocampal neural stem/progenitor cells in vitro are vulnerable to the mycotoxin ochratoxin-A. Toxicol Sci 98(1):187–197

    CAS  Google Scholar 

  • Schaaf G, Nijmeijer S, Maas R, Roestenberg P, De Groene E, Fink-Gremmels J (2002) The role of oxidative stress in the ochratoxin A-mediated toxicity in proximal tubular cells. Biochim Biophys Acta Mol basis Dis 1588(2):149–158

    CAS  Google Scholar 

  • Schatzmayr G, Heidler D, Fuchs E, Binder E, Loibner A, Braun R (2002) Evidence of ochratoxin A-detoxification activity of rumen fluid, intestinal fluid and soil samples as well as isolation of relevant microorganisms from these environments. Mycotoxin Res 18:183–187

    Google Scholar 

  • Schatzmayr G, Heidler D, Fuchs E, Nitsch S, Mohnl M, Täubel M, Loibner A, Braun R, Binder E (2003) Investigation of different yeast strains for the detoxification of ochratoxin A. Mycotoxin Res 19:124

    CAS  Google Scholar 

  • Schatzmayr G, Zehner F, Täubel M, Schatzmayr D, Klimitsch A, Loibner AP, Binder EM (2006) Microbiologicals for deactivating mycotoxins. Mol Nutr Food Res 50:543–551

    CAS  Google Scholar 

  • Schatzmayr, G., Heidler, D., Fuchs, E., Binder, E.M., 2012. Microorganism for biological detoxification of mycotoxins, namely ochratoxins and/or zearalenons, as well as method and use thereof. Google Patents

  • Schmidt-Heydt M, Stoll D, Schütz P, Geisen R (2015) Oxidative stress induces the biosynthesis of citrinin by Penicillium verrucosum at the expense of ochratoxin. Int J Food Microbiol 192:1–6

    CAS  Google Scholar 

  • Schulz MC, Schumann L, Rottkord U, Humpf HU, Gekle M, Schwerdt G (2018) Synergistic action of the nephrotoxic mycotoxins ochratoxin A and citrinin at nanomolar concentrations in human proximal tubule-derived cells. Toxicol Lett 291:149–157

    CAS  Google Scholar 

  • Scott P (1996) Effects of processing and detoxification treatments on ochratoxin A: introduction. Food Addit Contam 13:19

    CAS  Google Scholar 

  • Sepúlveda L, Ascacio A, Rodríguez-Herrera R, Aguilera-Carbó A, Aguilar CN (2011) Ellagic acid: biological properties and biotechnological development for production processes. Afr J Biotechnol 10(22):4518–4523

    Google Scholar 

  • Serra RW, Fang M, Park SM, Hutchinson L, Green MR (2014) A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype. eLife. 3:e02313

    Google Scholar 

  • Son WC, Kamino K, Lee YS, Kang KS (2003) Lack of effects of sodium 2-mercaptoethane sulfonate (mesna) on ochratoxin A induced renal tumorigenicity following life-time oral administration of Ochratoxin A in DA and Lewis rats. Toxicol Lett 142(1):19–27

    CAS  Google Scholar 

  • Songsermsakul P, Razzazi-Fazeli E, Böhm J, Zentek J (2007) Occurrence of deoxynivalenol (DON) and ochratoxin A (OTA) in dog foods. Mycotoxin Res 23(2):65–67

    CAS  Google Scholar 

  • Sorrenti V, Di Giacomo C, Acquaviva R et al (2012) Dimethylarginine dimethylaminohydrolase/nitric oxide synthase pathway in liver and kidney: protective effect of cyanidin 3-O-β-D-glucoside on ochratoxin-A toxicity. Toxins 4(5):353–363

    CAS  Google Scholar 

  • Sorrenti V, Di Giacomo C, Acquaviva R, Barbagallo I, Bognanno M, Galvano F (2013) Toxicity of ochratoxin a and its modulation by antioxidants: a review. Toxins 5(10):1742–1766

    Google Scholar 

  • Spoendlin M, Moch H, Brunner F et al (1995) Karyomegalic interstitial nephritis: further support for a distinct entity and evidence for a genetic defect. Am J Kidney Dis 25(2):242–252

    CAS  Google Scholar 

  • Stachurska A, Ciesla M, Kozakowska M et al (2013) Cross-talk between microRNAs, nuclear factor E2-related factor 2, and heme oxygenase-1 in ochratoxin A-induced toxic effects in renal proximal tubular epithelial cells. Mol Nutr Food Res 57(3):504–515

    CAS  Google Scholar 

  • Stemmer K, Ellinger-Ziegelbauer H, Ahr HJ, Dietrich DR (2007) Carcinogen-specific gene expression profiles in short-term treated Eker and wild-type rats indicative of pathways involved in renal tumorigenesis. Cancer Res 67(9):4052–4068

    CAS  Google Scholar 

  • Streit E, Schatzmayr G, Tassis P et al (2012) Current situation of mycotoxin contamination and co-occurrence in animal feed—Focus on Europe. Toxins 4(10):788–809

    CAS  Google Scholar 

  • Sutken E, Aral E, Ozdemir F, Uslu S, Alatas O, Colak O (2007) Protective role of melatonin and coenzyme Q10 in ochratoxin A toxicity in rat liver and kidney. Int J Toxicol 26(1):81–87

    CAS  Google Scholar 

  • Taniai E, Yafune A, Nakajima M et al (2014) Ochratoxin A induces karyomegaly and cell cycle aberrations in renal tubular cells without relation to induction of oxidative stress responses in rats. Toxicol Lett 224(1):64–72

    CAS  Google Scholar 

  • Tao Y, Xie S, Xu F et al (2018) Ochratoxin A: Toxicity, oxidative stress and metabolism. Food Chem Toxicol 112:320–331

    CAS  Google Scholar 

  • Thomas B, Ogunkanmi L, Iwalokun B, Agu G (2018) Transcriptional factor influence on OTA production and the quelling attribute of Sirna on the OTA producing strains of Aspergillus section Nigri. Afr J Clin Exp Microbiol 18(4):210–217

    Google Scholar 

  • Torack RM, Morris JC (1992) Tyrosine hydroxylase-like (TH) immunoreactivity in Parkinson’s disease and Alzheimer’s disease. J Neural Transm Park Dis Dement Sect 4:165–171. https://doi.org/10.1007/BF02251479

    Article  CAS  Google Scholar 

  • Tozlovanu M, Faucet-Marquis V, Pfohl-Leszkowicz A, Manderville RA (2006) Genotoxicity of the hydroquinone metabolite of ochratoxin A: structure-activity relationships for covalent DNA adduction. Chem Res Toxicol 19(9):1241–1247

    CAS  Google Scholar 

  • Tozlovanu M, Canadas D, Pfohl-Leszkowicz A, Frenette C, Paugh RJ, Manderville RA (2012) Glutathione conjugates of ochratoxin a as biomarkers of exposure/Glutationski Konjugati Okratoksina A Kao Biomarkeri Izloženosti. Arch Hig Rada Toksikol 63(4):417–427

    CAS  Google Scholar 

  • Trailović J, Stefanović S, Trailović S (2013) In vitro and in vivo protective effects of three mycotoxin adsorbents against ochratoxin A in broiler chickens. Br Poult Sci 54(4):515–523

    Google Scholar 

  • Van De Walle J, Sergent T, Piront N, Toussaint O, Schneider YJ, Larondelle Y (2010) Deoxynivalenol affects in vitro intestinal epithelial cell barrier integrity through inhibition of protein synthesis. Toxicol Appl Pharmacol 245(3):291–298

    Google Scholar 

  • Van Der Merwe KJ, Steyn PS, Fourie L, Scott DB, Theron JJ (1965) Ochratoxin A, a toxic metabolite produced by Aspergillus ochraceus Wilh. Nature 205(4976):1112–1113

    Google Scholar 

  • Van Der Stegen GH, Essens PJ, Van der Lijn J (2001) Effect of roasting conditions on reduction of ochratoxin A in coffee. J Agric Food Chem 49:4713–4715

    Google Scholar 

  • Varga J, Péteri Z, Tábori K, Téren J, Vágvölgyi C (2005) Degradation of ochratoxin A and other mycotoxins by Rhizopus isolates. Int J Food Microbiol 99:321–328

    CAS  Google Scholar 

  • Varga J, Kocsubé S, Péteri Z, Vágvölgyi C, Tóth B (2010) Chemical, physical and biological approaches to prevent ochratoxin induced toxicoses in humans and animals. Toxins 2:1718–1750

    CAS  Google Scholar 

  • Vettorazzi A, Van Delft J, De Cerain AL (2013) A review on ochratoxin A transcriptomic studies. Food Chem Toxicol 59:766–783

    CAS  Google Scholar 

  • Wajapeyee N, Malonia SK, Palakurthy RK, Green MR (2013) Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors. Genes Dev 27:2221–2226

    CAS  Google Scholar 

  • Wang Y, Liu J, Cui J et al (2012) ERK and p38 MAPK signaling pathways are involved in ochratoxin A-induced G2 phase arrest in human gastric epithelium cells. Toxicol Lett 209(2):186–192

    CAS  Google Scholar 

  • Wang S, Zhang C, Sheng X, Zhang X, Wang B, Zhang G (2014) Peripheral expression of MAPK pathways in Alzheimer’s and Parkinson’s diseases. J Clin Neurosci 21:810–814. https://doi.org/10.1016/j.jocn.2013.08.017

    Article  CAS  Google Scholar 

  • Wen J, Mu P, Deng Y (2016) Mycotoxins: cytotoxicity and biotransformation in animal cells. Toxicol Res 5(2):377–387

    CAS  Google Scholar 

  • Whitlow, L.W., 2006. Evaluation of mycotoxin binders. In: Proceedings 4th Mid-Atlantic Nutr. Conf. 132–143

  • Wielogórska E, MacDonald S, Elliott C (2016) A review of the efficacy of mycotoxin detoxifying agents used in feed in light of changing global environment and legislation. World Mycotoxin J 9(3):419–433

    Google Scholar 

  • Wood AJ, Oakey RJ (2006) Genomic imprinting in mammals: emerging themes and established theories. PLoS Genet 2(11):e147

    Google Scholar 

  • Wu BK, Brenner C (2014) Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation. Cell Rep 9:1827–1840

    CAS  Google Scholar 

  • Wu TS, Yang JJ, Wang YW, Yu FY, Liu BH (2016) Mycotoxin ochratoxin A disrupts renal development via a miR-731/prolactin receptor axis in zebrafish. Toxicol Res 5(2):519–529

    CAS  Google Scholar 

  • Yang Q, He X, Li X et al (2014a) DNA damage and S phase arrest induced by Ochratoxin A in human embryonic kidney cells (HEK 293). Mutat Res Fundam Mol Mech Mutagen 765:22–31

    CAS  Google Scholar 

  • Yang Q, Shi L, Huang K, Xu W (2014b) Protective effect of N-acetylcysteine against DNA damage and S-phase arrest induced by ochratoxin A in human embryonic kidney cells (HEK-293). Food Chem Toxicol 70:40–47

    CAS  Google Scholar 

  • Yang X, Liu S, Huang C, Wang H, Luo Y, Xu W, Huang K (2017) Ochratoxin A induced premature senescence in human renal proximal tubular cells. Toxicology 382:75–83

    CAS  Google Scholar 

  • Yong S, Albassam M, Prior M (1987) Protective effects of sodium bicarbonate on murine ochratoxicosis. J Environ Sci Health B 22(4):455–470

    CAS  Google Scholar 

  • Zanicgrubisic T, Zrinski R, Čepelak I, Petrik J, Radić B, Pepeljnjak S (2000) Studies of ochratoxin A-induced inhibition of phenylalanine hydroxylase and its reversal by phenylalanine. Toxicol Appl Pharmacol 167(2):132–139

    CAS  Google Scholar 

  • Zeljezic D, Domijan AM, Peraica M (2006) DNA damage by ochratoxin A in rat kidney assessed by the alkaline comet assay. Br J Med Biol Res 39(12):1563–1568

    CAS  Google Scholar 

  • Zhang X, Boesch-Saadatmandi C, Lou Y, Wolffram S, Huebbe P, Rimbach G (2009) Ochratoxin A induces apoptosis in neuronal cells. Genes Nutr 4(1):41

    Google Scholar 

  • Zhang B, Shen XL, Liang R et al (2014) Protective role of the mitochondrial Lon protease 1 in ochratoxin A-induced cytotoxicity in HEK293 cells. J Proteome 101:154–168

    CAS  Google Scholar 

  • Zhang H, Apaliya MT, Mahunu GK, Chen L, Li W (2016) Control of ochratoxin A-producing fungi in grape berry by microbial antagonists: a review. Trends Food Sci Technol 51:88–97

    CAS  Google Scholar 

  • Zhang H, Wang Y, Zhao C, Wang J, Zhang X (2017) Biodegradation of ochratoxin A by Alcaligenes faecalis isolated from soil. J Appl Microbiol 123:661–668

    CAS  Google Scholar 

  • Zhang TY, Wu RY, Zhao Y et al (2018) Ochratoxin A exposure decreased sperm motility via the AMPK and PTEN signaling pathways. Toxicol Appl Pharmacol 340:49–57

    CAS  Google Scholar 

  • Zhao J, Qi X, Dai Q et al (2017) Toxicity study of Ochratoxin A using HEK293 and HepG2 cell lines based on microRNA profiling. Hum Exp Toxicol 36(1):8–22

    CAS  Google Scholar 

  • Zheng J, Zhang Y, Xu W et al (2013) Zinc protects HepG2 cells against the oxidative damage and DNA damage induced by ochratoxin A. Toxicol Appl Pharmacol 268(2):123–131

    CAS  Google Scholar 

  • Zhu L, Yu T, Qi X et al (2016) miR-122 plays an important role in ochratoxin A-induced hepatocyte apoptosis in vitro and in vivo. Toxicol Res 5(1):160–167

    CAS  Google Scholar 

  • Zhu L, Zhang B, Dai Y, Li H, Xu W (2017) A review: epigenetic mechanism in ochratoxin a toxicity studies. Toxins 9(4):113

    Google Scholar 

  • Zlokovic BR (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci 12(12):723–738

  • Zurich MG, Lengacher S, Braissant O, Monnet-Tschudi F, Pellerin L, Honegger P (2005) Unusual astrocyte reactivity caused by the food mycotoxin ochratoxin A in aggregating rat brain cell cultures. Neuroscience 134(3):771–782

    CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank and acknowledge their respective universities and institutes.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Bio-Sciences, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63100, Pakistan

    Kamal Niaz

  2. Department of Pathology, Faculty of Veterinary Science, Cholistan University of Veterinary and Animal Sciences, Bahawalpur, 63100, Pakistan

    Syed Zahid Ali Shah

  3. The Institute of Pharmaceutical Sciences (TIPS), School of Pharmacy, International Campus, Tehran University of Medical Sciences (IC-TUMS), Tehran, 1417614411, Iran

    Fazlullah Khan

  4. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, 1417614411, Iran

    Fazlullah Khan

  5. Department of Pharmacy, College of Medicine and Health Sciences, Ambo University, Ambo, Oromia, Ethiopia

    Mohammed Bule

Authors
  1. Kamal Niaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Syed Zahid Ali Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fazlullah Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammed Bule
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KN gave the idea and prepared the outlines and draft of the manuscript. SA, SZAS, FK, and MB designed the figures along with comprehensive tables along with critical editing and reviewing of the whole manuscript. All the authors have read and approved the final version.

Corresponding author

Correspondence to Kamal Niaz.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Responsible Editor: Mohamed M. Abdel-Daim

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Niaz, K., Shah, S.Z.A., Khan, F. et al. Ochratoxin A–induced genotoxic and epigenetic mechanisms lead to Alzheimer disease: its modulation with strategies. Environ Sci Pollut Res 27, 44673–44700 (2020). https://doi.org/10.1007/s11356-020-08991-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-020-08991-y

Keywords

Search

Navigation