Advertisement

Ochratoxin A and Epigenetics

Living reference work entry

Abstract

Ochratoxin A is a thermoresistant mycotoxin produced by ubiquitous molds of Aspergillus and Penicillium genera. It contaminates foodstuffs and feedstuffs worldwide and therefore is of human and animal concern.

Ochratoxin A induces oxidative stress, inflammation, and fibrosis, and is nephrotoxic, hepatotoxic, and neurotoxicin particularly in male subjects. Toxicity is mainly exerted through epigenetic mechanisms.

Nephrotoxicity is probably due to ochratoxin A-induced suppression of the collagen regulator mir-29b that results in an increase of translated collagen, fibrotic alteration, and nephropathy. Alternatively, ochratoxin A induces mir-132 upregulation that occurs in neurologic and psychiatric conditions as well as in oxidative stress. Undeniably, mir-132 acts in the reciprocal regulation of autism-related genes MeCP2 and PTEN decreasing the antioxidant Nrf2 that leads to the formation of high levels of reactive oxygen species. Reactive oxygen species, in turn, enhance the expression of mir-200c that impairs antioxidative mechanisms and synaptic plasticity through the reduction of HO-1 and NLGN4X. As for apoptosis, OTA exposure increases mir-122 that suppresses the anti-apoptotic genes Bcl-w and caspase-3 leading to cell death and hepatic damage.

Interestingly, both MECP2 and NLGN4X are involved in neurodevelopmental disorders, including autism, and are mapped on the X chromosome. As autism is a male predominant disorder, a possible contribution of ochratoxin A in its pathogenesis and in its strong male bias can be suggested.

Very few papers report about ochratoxin A-induced deacetylation:cells exposed to OTA underwent to a dramatic block of histone acetyltransferases leading to mitotic arrest and Nrf2 inhibition that, again, lead to reactive oxygen species formation.

Further studies are needed to obtain a complete picture of ochratoxin A-dependent epigenetic effects and to prevent or to counteract them.

Keywords

Ochratoxin A Epigenetics microRNA Phenylalanine hydroxylase Nephrotoxic Neurotoxic Hepatotoxic Fibrosis Oxidative stress Neurodegenerative diseases Autism Nrf2 MECP2 NLGN4X Sex-dependent 

List of Abbreviations

AREs

Antioxidant responsive elements

ASD

Autism spectrum disorder (ASD)

BACE1

β-Secretase-1 enzyme

BBB

Blood brain barrier

BDNF

Brain-derived neurotropic factor

BEN

Balkan endemic nephropathy

CASP3

Caspase3

CBP

CREB-binding protein

CNS

Central nervous system

DGCR8

DiGeorge syndrome critical region gene 8

FMRP

Fragile X mental retardation protein

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

HO-1

Heme oxygenase-1

MeCP2

Methyl-CpG-binding protein 2

NLGN4X

Neuroligin4x

OTA

Ochratoxin A

p300

Adenoviral E1A-associated protein

PAH

Phenylalanine hydroxylase

phe

Phenylalanine

PKU

Phenylketonuria

PTEN

Phosphatase and tensin homolog

TGFβ

Transforming-growth factor-beta

Nrf2

Nuclear factor erythroid 2-like 2

ROS

Reactive oxygen species

tyr

tyrosine

ZEB1

Zinc finger E-box binding homeobox 1

References

  1. Baieli S, Pavone L, Meli C et al (2003) Autism and phenylketonuria. J Autism Dev Disord 33(2):201–204CrossRefPubMedGoogle Scholar
  2. Baskerville TA, Douglas AJ (2010) Dopamine and oxytocin interactions underlying behaviors: potential contributions to behavioral disorders. CNS Neurosci Ther 16(3):e92–123. doi: 10.1111/j.1755-5949.2010.00154.x. Review. PubMed PMID: 20557568CrossRefPubMedGoogle Scholar
  3. Baudrimont I, Sostaric B, Yenot C, Betbeder AM, Dano-Djedje S, Sanni A, Steyn PS, Creppy EE (2001) Aspartame prevents the karyomegaly induced by ochratoxin A in rat kidney. Arch Toxicol 75(3):176–83CrossRefPubMedGoogle Scholar
  4. Bemben MA, Nguyen QA, Wang T et al (2015) Autism-associated mutation inhibits protein kinase C-mediated neuroligin-4X enhancement of excitatory synapses. Proc Natl Acad Sci U S A 112(8):2551–2556. doi: 10.1073/pnas.1500501112 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Beveridge NJ, Gardiner E, Carroll AP et al (2010) Schizophrenia is associated with an increase in cortical microRNA biogenesis. Mol Psychiatry 15(12):1176–1189. doi: 10.1038/mp.2009.84 CrossRefPubMedGoogle Scholar
  6. Bhat PV, Md P, Khanum F et al (2016) Cytotoxic effects of ochratoxin A in neuro-2a cells: role of oxidative stress evidenced by N-acetylcysteine. Front Microbiol 7:1142. doi: 10.3389/fmicb.2016.01142 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Boudra H, Le Bars P, Le Bars J (1995) Thermostability of ochratoxin A in wheat under two moisture conditions. Appl Environ Microbiol 61:1156–1158PubMedPubMedCentralGoogle Scholar
  8. Caccamo A, Maldonado MA, Bokov AF et al (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. doi: 10.1073/pnas.1012851108 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cai G, Edelmann L, Goldsmith JE et al (2008) Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT. BMC Med Genet 1:50. doi: 10.1186/1755-8794-1-50 Google Scholar
  10. Castegnaro M, Canadas D, Vrabcheva T et al (2006) Balkan endemic nephropathy: role of ochratoxins A through biomarkers. Mol Nutr Food Res 50(6):519–529CrossRefPubMedGoogle Scholar
  11. Cheng TL, Wang Z, Liao Q et al (2014) MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex. Dev Cell 28(5):547–560. doi: 10.1016/j.devcel.2014.01.032 CrossRefPubMedGoogle Scholar
  12. Chou C, Chang N, Shrestha S, Hsu S, Lin Y, Lee W et al (2015) miRTarBase 2016: updates to the experimentally validated miRNA-target interactions database. Nucleic Acids Res 44(D1):D239–D247CrossRefPubMedPubMedCentralGoogle Scholar
  13. Choudhary C, Kumar C, Gnad F et al (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325(5942):834–840. doi: 10.1126/science.1175371 CrossRefPubMedGoogle Scholar
  14. Clevers H (2006) Wnt/beta-catenin signaling in development and disease. Cell 127:469–480CrossRefPubMedGoogle Scholar
  15. Creppy EE, Chakor K, Fisher MJ et al (1990) The myocotoxin ochratoxin A is a substrate for phenylalanine hydroxylase in isolated rat hepatocytes and in vivo. Arch Toxicol 64(4):279–284CrossRefPubMedGoogle Scholar
  16. Cuadrado-Tejedor M, Vilariño M, Cabodevilla F et al (2011) Enhanced expression of the voltage-dependent anion channel 1 (VDAC1) in Alzheimer’s disease transgenic mice: an insight into the pathogenic effects of amyloid-β. J Alzheimers Dis 23(2):195–206. doi: 10.3233/JAD-2010-100966 PubMedGoogle Scholar
  17. 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. doi: 10.1093/toxsci/kfr110 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dai Q, Zhao J, Qi X et al (2014) MicroRNA profiling of rats with ochratoxin A nephrotoxicity. BMC Genomics 15:333. doi: 10.1186/1471-2164-15-333 CrossRefPubMedPubMedCentralGoogle Scholar
  19. De Santis B, Brera C, Mezzelani A et al (2017a) Role of mycotoxins in the pathobiology of autism: a first evidence. Nutr Neurosci 1–13. doi: 10.1080/1028415X.2017.1357793
  20. De Santis B, Raggi ME, Moretti G et al (2017b) Study on the association among mycotoxins and other variables in children with autism. Toxins 29;9(7). pii: E203. doi: 10.3390/toxins9070203
  21. Deepmala, Slattery J, Kumar N et al (2015) Clinical trials of N-acetylcysteine in psychiatry and neurology: a systematic review. Neurosci Biobehav Rev 55:294–321. doi: 10.1016/j.neubiorev.2015.04.015 CrossRefPubMedGoogle Scholar
  22. Denli M, Perez JF (2010) Ochratoxins in feed, a risk for animal and human health: control strategies. Toxins (Basel) 2(5):1065–1077. doi: 10.3390/toxins2051065 CrossRefGoogle Scholar
  23. Eden S, Hashimshony T, Keshet I et al (1998) DNA methylation models histone acetylation. Nature 394(6696):842CrossRefPubMedGoogle Scholar
  24. EFSA, European Food Safety Authority (2006) EFSA Opinion of the scientific panel on contaminants in the food chain on a request from the commission related to ochratoxin A (OTA) in food Quest. N° EFSA-Q-2005-154. EFSA J 365(2006):1–56. doi: 10.2903/j.efsa.2006.365 Google Scholar
  25. Fardmanesh H, Shekari M, Movafagh A et al (2016) Upregulation of the double-stranded RNA binding protein DGCR8 in invasive ductal breast carcinoma. Gene 581(2):146–151. doi: 10.1016/j.gene.2016.01.033 CrossRefPubMedGoogle Scholar
  26. Faustman EM, Silbernagel SM, Fenske RA, Burbacher TM, Ponce RA (2000) Mechanisms underlying Children’s susceptibility to environmental toxicants. Environ Health Perspect 108(Suppl 1):13–21CrossRefPubMedPubMedCentralGoogle Scholar
  27. Gayathri L, Dhivya R, Dhanasekaran D et al (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. doi: 10.1016/j.fct.2015.06.009 CrossRefPubMedGoogle Scholar
  28. Guo M, Huang K, Chen S, Qi X, He X, Cheng WH, Luo Y, Xia K, Xu W (2014) Combination of metagenomics and culture-based methods to study the interaction between ochratoxin a and gut microbiota. Toxicol Sci 141(1):314–323. doi: 10.1093/toxsci/kfu128 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Hagelberg S, Hult K, Fuchs R (1989) Toxicokinetics of ochratoxin A in several species and its plasma-binding properties. J Appl Toxicol 9(2):91–96Google Scholar
  30. Hennemeier I, Humpf HU, Gekle M et al (2014) Role of microRNA-29b in the ochratoxin A-induced enhanced collagen formation in human kidney cells. Toxicology 3(324):116–122. doi: 10.1016/j.tox.2014.07.012 CrossRefGoogle Scholar
  31. Hope JH, Hope BE (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 2012:835059. doi: 10.1155/2012/835059 CrossRefPubMedGoogle Scholar
  32. Jafari N, Dogaheh HP, Bohlooli S et al. (2013) Expression levels of microRNA machinery components Drosha, Dicer and DGCR8 in human (AGS, HepG2, and KEYSE-30) cancer cell lines. Int J Clin Exp Med 6(4):269–274Google Scholar
  33. 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 ratinvivo model. Arch Toxicol 86:571–589CrossRefPubMedGoogle Scholar
  34. Jennings P, Limonciel A, Felice L, Leonard MO (2013) An overview of transcriptional regulation in response to toxicological insult. Arch Toxicol 87:49–72CrossRefPubMedGoogle Scholar
  35. Jin J, Cheng Y, Zhang Y et al (2012) Interrogation of brain miRNA and mRNA expression profiles reveals a molecular regulatory network that is perturbed by mutant huntingtin. J Neurochem 123(4):477–490. doi: 10.1111/j.1471-4159.2012.07925.x CrossRefPubMedPubMedCentralGoogle Scholar
  36. Kim B, Lee JH, Park JW et al (2014) An essential microRNA maturing microprocessor complex component DGCR8 is up-regulated in colorectal carcinomas. Clin Exp Med 14(3):331–336. doi: 10.1007/s10238-013-0243-8 CrossRefPubMedGoogle Scholar
  37. Kriegel AJ, Liu Y, Fang Y et al (2012) The miR-29 family: genomics, cell biology, and relevance to renal and cardiovascular injury. Physiol Genomics 44:237–244CrossRefPubMedPubMedCentralGoogle Scholar
  38. Kumar MS, Lu J, Mercer KL et al (2007) Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nature Genet 39:673–677CrossRefPubMedGoogle Scholar
  39. Limonciel A, Jennings P (2014) A review of the evidence that ochratoxin A is an Nrf2 inhibitor: implications for nephrotoxicity and renal carcinogenicity. Toxins (Basel) 6(1):371–379. doi: 10.3390/toxins6010371 CrossRefGoogle Scholar
  40. Loboda A, Damulewicz M, Pyza E et al (2016) Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci 73(17):3221–3247. doi: 10.1007/s00018-016-2223-0 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Lu J, Clark AG (2012) Impact of microRNA regulation on variation in human gene expression. Genome Res 22(7):1243–1254CrossRefPubMedPubMedCentralGoogle Scholar
  42. Lugli G, Torvik VI, Larson J, Smalheiser NR (2008) Expression of microRNAs and their precursors in synaptic fractions of adult mouse forebrain. J Neurochem 106(2):650–661. doi: 10.1111/j.1471-4159.2008.05413.x CrossRefPubMedPubMedCentralGoogle Scholar
  43. Lyu JW, Yuan B, Cheng TL et al (2016) Reciprocal regulation of autism-related genes MeCP2 and PTEN via microRNAs. Sci Rep 6:20392. doi: 10.1038/srep20392 CrossRefPubMedPubMedCentralGoogle Scholar
  44. MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26. doi: 10.1016/j.devcel.2009.06.016 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Magenta A, Cencioni C, Fasanaro P et al (2011) MC. miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ 18(10):1628–1639. doi: 10.1038/cdd.2011.42 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Malir F, Ostry V, Pfohl-Leszkowicz A et al (2016) Ochratoxin A: 50 years of research. Toxins (Basel) 8(7):191. doi: 10.3390/toxins8070191 CrossRefGoogle Scholar
  47. 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. PubMed PMID: 16097798CrossRefPubMedGoogle Scholar
  48. Manners MT, Tian Y, Zhou Z, Ajit SK (2015) MicroRNAs downregulated in neuropathic pain regulate MeCP2 and BDNF related to pain sensitivity. FEBS Open Bio 5:733–740CrossRefPubMedPubMedCentralGoogle Scholar
  49. 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):174–181CrossRefPubMedGoogle Scholar
  50. McLaughlin J, Padfield PJ, Burt JP, O’Neill CA (2004) Ochratoxin A increases permeability through tight junctions by removal of specific claudin isoforms. Am J Physiol Cell Physiol 287(5):C1412–C1417CrossRefPubMedGoogle Scholar
  51. McMasters DR, Angelo Vedani A (1999) Ochratoxin Binding to Phenylalanyl-tRNA Synthetase:   Computational Approach to the Mechanism of Ochratoxicosis and Its Antagonism. Journal of Medicinal Chemistry 42(16):3075–3086Google Scholar
  52. Mellios N, Sur M (2012) The emerging role of microRNAs in schizophrenia and autism spectrum disorders. Front Psych 3:39. doi: 10.3389/fpsyt.2012.00039 Google Scholar
  53. Mor F, Kilic MA, Ozmen O et al (2014) The effects of orchidectomy on toxicological responses to dietary ochratoxin A in Wistar rats. Exp Toxicol Pathol 66(5-6):267–275. doi: 10.1016/j.etp.2014.04.002 CrossRefPubMedGoogle Scholar
  54. 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. doi: 10.1016/S0301-0082(00)00014-9 CrossRefPubMedGoogle Scholar
  55. Oba S, Kumano S, Suzuki E et al (2010) miR-200b precursor can ameliorate renal tubulointerstitial fibrosis. PLoS One 5(10):e13614. doi: 10.1371/journal.pone.0013614 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Pastor L, Vettorazzi A, Campión J, Cordero P, López de Cerain A (2016) Gene expression kinetics of renal transporters induced by ochratoxin A in male and female F344 rats. Food Chem Toxicol 98(Pt B):169–178. doi: 10.1016/j.fct.2016.10.019 CrossRefPubMedGoogle Scholar
  57. Preissner SC, Hoffmann MF, Preissner R, Dunkel M, Gewiess A, Preissner S (2013) Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy. PLoS One 8(12):e82562. doi: 10.1371/journal.pone.0082562 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Ringot D, Chango A, Schneider YJ, Larondelle Y (2006) Toxicokinetics and toxicodynamics of ochratoxin A, an update. Chem Biol Interact 159(1):18–46CrossRefPubMedGoogle Scholar
  59. Roshan R, Shridhar S, Sarangdhar MA et al (2014) Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice. RNA 20(8):1287–1297. doi: 10.1261/rna.044008.113 CrossRefPubMedPubMedCentralGoogle Scholar
  60. San Román MS, Holgado MJ (2015) Intercalation of phenylalanine, isocoumarin and ochratoxin A (OTA) into LDH’s. Open Journal of Inorganic Chemistry 5:52–62. doi: 10.4236/ojic.2015.53007 CrossRefGoogle Scholar
  61. Sand M, Skrygan M, Georgas D, Arenz C, Gambichler T, Sand D, Altmeyer P, Bechara FG (2012) Expression levels of the microRNA maturing microprocessor complex component DGCR8 and the RNA-induced silencing complex (RISC) components argonaute-1, argonaute-2, PACT, TARBP1, and TARBP2 in epithelial skin cancer. Mol Carcinog 51(11):916–922. doi: 10.1002/mc.20861 CrossRefPubMedGoogle Scholar
  62. Sava V, Reunova O, Velasquez A, Harbison R, Sanchez-Ramos J (2006) (2006a). Acute neurotoxic effects of the fungal metabolite ochratoxin-A. Neurotoxicology 27:82–92. doi: 10.1016/j.neuro.2005.07.004 CrossRefPubMedGoogle Scholar
  63. Schilter B, Marin-Kuan M, Delatour T et al (2005) Ochratoxin A: potential epigenetic mechanisms of toxicity and carcinogenicity. Food Addit Contam 22(Suppl 1):88–93CrossRefPubMedGoogle Scholar
  64. 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. doi: 10.1002/mnfr.201200456 CrossRefPubMedGoogle Scholar
  65. Sun Z, Chin YE, Zhang DD (2009) Acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 during the antioxidant response. Mol Cell Biol 29(10):2658–2672. doi: 10.1128/MCB.01639-08 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Ueta E, Kodama M, Sumino Y et al (2010) Gender-dependent differences in the incidence of ochratoxin A-induced neural tube defects in the Pdn/Pdn mouse. CongenitAnom (Kyoto) 50(1):29–39. doi: 10.1111/j.1741-4520.2009.00255.x. PubMed PMID: 20201966CrossRefGoogle Scholar
  67. Waxman DJ, Holloway MG (2009) Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 76(2):215–228. doi: 10.1124/mol.109.056705 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Woodmansey EJ (2007) Intestinal bacteria and ageing. Appl Microbiol 102(5):1178–1186CrossRefGoogle Scholar
  69. Wu Q, Dohnal V, Huang L et al (2011) Metabolic pathways of ochratoxin A. Curr Drug Metab 12(1):1–10CrossRefPubMedGoogle Scholar
  70. Xu J, Zhu X, Wu L et al (2012) MicroRNA-122 suppresses cell proliferation and induces cell apoptosis in hepatocellular carcinoma by directly targeting Wnt/β-catenin pathway. Liver Int 32(5):752–760. doi: 10.1111/j.1478-3231.2011.02750.x CrossRefPubMedGoogle Scholar
  71. Xue ZQ, He ZW, Yu JJ et al (2015) Non-neuronal and neuronal BACE1 elevation in association with angiopathic and leptomeningeal β-amyloid deposition in the human brain. BMC Neurol 15:71. doi: 10.1186/s12883-015-0327-z CrossRefPubMedPubMedCentralGoogle Scholar
  72. Zanic-Grubisić T, Zrinski R, Cepelak 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):132–139CrossRefPubMedGoogle Scholar
  73. 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):41–48. doi: 10.1007/s12263-008-0109-y CrossRefPubMedPubMedCentralGoogle Scholar
  74. Zhu L, Yu T, Qi X, Yang B, Shi L, Luo H, He X, Huang K, Xu W (2016) miR-122 plays an important role in ochratoxin A-induced hepatocyte apoptosis in vitro and in vivo. Toxicol Res 5:160–167CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.National Research Council, Institute of Biomedical Technologies (CNR-ITB)Segrate (MI)Italy

Personalised recommendations