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.
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
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
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
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
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
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
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
Aiko V, Mehta A (2015) Occurrence, detection and detoxification of mycotoxins. J Biosci 40:943–954
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
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
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
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
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
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
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
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
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
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
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297
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
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
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
Becker PB, Workman JL (2013) Nucleosome remodeling and epigenetics. Cold Spring Harb Perspect Biol 5(9):a017905
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
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
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
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
Bhasin M, Reinherz EL, Reche PA (2006) Recognition and classification of histones using support vector machine. J Comput Biol 13(1):102–112
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Creppy EE, Schlegel M, Röschenthaler R, Dirheimer G (1980) Phenylalanine prevents acute poisoning by ochratoxin-a in mice. Toxicol Lett 6(2):77–80
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
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
Creppy EE, Baudrimont I, Marie A (1998) How aspartame prevents the toxicity of ochratoxin A. J Toxicol Sci 23:165–172
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
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
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
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
Dai J, Sullivan BA, Higgins JM (2006) Regulation of mitotic chromosome cohesion by Haspin and Aurora B. Dev Cell 11(5):741–750
Dai Q, Zhao J, Qi X et al (2014) MicroRNA profiling of rats with ochratoxin A nephrotoxicity. BMC Genomics 15(1):333
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
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
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
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
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
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
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
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
Dwivedi P, Burns RB (1984) Effect of ochratoxin A on immunoglobulins in broiler chicks. Res Vet Sci 36(1):117–121
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
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
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
Engelhardt G (2002) Degradation of ochratoxin a and b by the white rot funguspleurotus ostreatus. Mycotoxin Res 18:37–43
Essid E, Petzinger E (2011) Silibinin pretreatment protects against ochratoxin A-mediated apoptosis in primary rat hepatocytes. Mycotoxin Res 27(3):167–176
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
Ferguson-Smith AC (2011) Genomic imprinting: the emergence of an epigenetic paradigm. Nat Rev Genet 12(8):565
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
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
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
Friedlander RM (2003) Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348:1365–1375
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
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
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
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
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
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
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
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
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
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
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
Gazin C, Wajapeyee N, Gobeil S, Virbasius CM, Green MR (2007) An elaborate pathway required for Ras-mediated epigenetic silencing. Nature. 449:1073–1077
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
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
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
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
Ha TH (2015) Recent advances for the detection of ochratoxin A. Toxins 7(12):5276–5300
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Kőszegi T, Poór M (2016) Ochratoxin A: molecular interactions, mechanisms of toxicity and prevention at the molecular level. Toxins 8(4):111
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
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
Kumari D, Sinha S (1994) Effect of retinol on ochratoxin-produced genotoxicity in mice. Food Chem Toxicol 32(5):471–475
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
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
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
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
Liang R, Shen XL, Zhang B et al (2015) Apoptosis signal-regulating kinase 1 promotes ochratoxin A-induced renal cytotoxicity. Sci Report 5:8078
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
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
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
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
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
Luz C, Ferrer J, Mañes J, Meca G (2018) Toxicity reduction of ochratoxin A by lactic acid bacteria. Food Chem Toxicol 112:60–66
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
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
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
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
Malir F, Ostry V, Pfohl-Leszkowicz A, Malir J, Toman J (2016) Ochratoxin A: 50 years of research. Toxins 8(7):191
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
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
Manderville R, Pfohl-Leszkowicz A (2008) Bioactivation and DNA adduction as a rationale for ochratoxin A carcinogenesis. World Mycotoxin J 1(3):357–367
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
Marin DE, Taranu I (2015) Ochratoxin A and its effects on immunity. Toxin Rev 34(1):11–20
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
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
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
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
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
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
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
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
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
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
Nephew KP, Huang THM (2003) Epigenetic gene silencing in cancer initiation and progression. Cancer Lett 190(2):125–133
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
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
Özpinar H, Bilal T, Abas I, Kutay C (2002) Degradation of ochratoxin A in rumen fluid in vitro. FU Med Biol 9:66–69
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
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
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
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
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
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
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
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
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
Péteri Z, Téren J, Vágvölgyi C, Varga J (2007) Ochratoxin degradation and adsorption caused by astaxanthin-producing yeasts. Food Microbiol 24:205–210
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
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
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
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
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
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
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
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
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
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
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
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
Ramyaa P, Padma VV (2013) Ochratoxin-induced toxicity, oxidative stress and apoptosis ameliorated by quercetin–Modulation by Nrf2. Food Chem Toxicol 62:205–216
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
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
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
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
Ringot D, Chango A, Schneider YJ, Larondelle Y (2006) Toxicokinetics and toxicodynamics of ochratoxin A, an update. Chem Biol Interact 159(1):18–46
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
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
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
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
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
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
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
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
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
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
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
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
Scott P (1996) Effects of processing and detoxification treatments on ochratoxin A: introduction. Food Addit Contam 13:19
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
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
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
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
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
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
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
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
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
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
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
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
Tao Y, Xie S, Xu F et al (2018) Ochratoxin A: Toxicity, oxidative stress and metabolism. Food Chem Toxicol 112:320–331
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
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
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
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
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
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
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
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
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
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
Vettorazzi A, Van Delft J, De Cerain AL (2013) A review on ochratoxin A transcriptomic studies. Food Chem Toxicol 59:766–783
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
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
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
Wen J, Mu P, Deng Y (2016) Mycotoxins: cytotoxicity and biotransformation in animal cells. Toxicol Res 5(2):377–387
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
Wood AJ, Oakey RJ (2006) Genomic imprinting in mammals: emerging themes and established theories. PLoS Genet 2(11):e147
Wu BK, Brenner C (2014) Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation. Cell Rep 9:1827–1840
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
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
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
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
Yong S, Albassam M, Prior M (1987) Protective effects of sodium bicarbonate on murine ochratoxicosis. J Environ Sci Health B 22(4):455–470
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
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
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
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
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
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
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
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
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
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
Zhu L, Zhang B, Dai Y, Li H, Xu W (2017) A review: epigenetic mechanism in ochratoxin a toxicity studies. Toxins 9(4):113
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
Acknowledgments
The authors wish to thank and acknowledge their respective universities and institutes.
Author information
Authors and Affiliations
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
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
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-020-08991-y