Ochratoxin A induces apoptosis in neuronal cells

The mycotoxin ochratoxin A (OTA), which is produced by Aspergillus and Penicillium subspecies, is a frequently present contaminant of food and feedstuffs. OTA exhibits a wide range of toxic activities including nephro- and hepatotoxicity. However, little is known regarding potential neurotoxic effects of OTA. In the present study primary neurons as well as SH-SY5Y neuronal cells were incubated with increasing concentrations of OTA (0.1–2.5 μmol/L). OTA treatment resulted in a dose-dependent increase in cytotoxicity in both neuronal cell types. Caspase-9 and caspase-3 were activated in response to OTA treatment. Furthermore, caspase inhibitors were effective in partly counteracting OTA induced neurocytotoxicity. OTA induced apoptosis was accompanied by a loss of mitochondria membrane potential. Overall, present data indicated that OTA is neurotoxic at relatively low concentrations. OTA induced neurotoxicity seems to be, at least party, mediated by apoptosis. OTA may contribute to the pathogenesis of neurodegenerative diseases (e.g. Alzheimer’s and Parkinson’s disease) in which apoptotic processes are centrally involved.

[1]  E. Creppy,et al.  Prevention of lipid peroxidation induced by ochratoxin A in Vero cells in culture by several agents. , 1997, Chemico-biological interactions.

[2]  J. Sanchez-Ramos,et al.  Can low level exposure to ochratoxin-A cause parkinsonism? , 2006, Journal of the Neurological Sciences.

[3]  C. Bortner,et al.  Glutathione Depletion and Disruption of Intracellular Ionic Homeostasis Regulate Lymphoid Cell Apoptosis* , 2008, Journal of Biological Chemistry.

[4]  K. Vähäkangas,et al.  Fumonisin B1-induced apoptosis in neuroblastoma, glioblastoma and hypothalamic cell lines. , 2006, Toxicology.

[5]  J. Schlatter,et al.  Ochratoxin A induces oxidative DNA damage in liver and kidney after oral dosing to rats. , 2005, Molecular nutrition & food research.

[6]  J. Schlatter,et al.  Ochratoxin A: induction of (oxidative) DNA damage, cytotoxicity and apoptosis in mammalian cell lines and primary cells. , 2005, Toxicology.

[7]  R. Harbison,et al.  Acute neurotoxic effects of the fungal metabolite ochratoxin-A. , 2006, Neurotoxicology.

[8]  Robert M Friedlander,et al.  Apoptosis and caspases in neurodegenerative diseases. , 2003, The New England journal of medicine.

[9]  R. Duval,et al.  Sensitive and reliable JC‐1 and TOTO‐3 double staining to assess mitochondrial transmembrane potential and plasma membrane integrity: Interest for cell death investigations , 2003, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[10]  A. Mally,et al.  Ochratoxin A as a potential etiologic factor in endemic nephropathy: lessons from toxicity studies in rats. , 2007, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[11]  T. Troxell,et al.  Identification and reduction of sources of dietary lead in the United States. , 1996, Food additives and contaminants.

[12]  T. Kuiper-Goodman Risk assessment of ochratoxin A: an update. , 1996, Food additives and contaminants.

[13]  J. Sanchez-Ramos,et al.  Adult hippocampal neural stem/progenitor cells in vitro are vulnerable to the mycotoxin ochratoxin-A. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  Ž. Ferenčić,et al.  Apoptosis and oxidative stress induced by ochratoxin A in rat kidney , 2003, Archives of Toxicology.

[15]  L. Pellerin,et al.  Unusual astrocyte reactivity caused by the food mycotoxin ochratoxin A in aggregating rat brain cell cultures , 2005, Neuroscience.

[16]  G. Rimbach,et al.  Effect of ochratoxin A on redox-regulated transcription factors, antioxidant enzymes and glutathione-S-transferase in cultured kidney tubulus cells. , 2008, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[17]  T. Vrabcheva,et al.  Balkan endemic nephropathy: role of ochratoxins A through biomarkers. , 2006, Molecular nutrition & food research.

[18]  Z. Islam,et al.  Neurotoxicity and inflammation in the nasal airways of mice exposed to the macrocyclic trichothecene mycotoxin roridin a: kinetics and potentiation by bacterial lipopolysaccharide coexposure. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[19]  Y. Schneider,et al.  Toxicokinetics and toxicodynamics of ochratoxin A, an update. , 2006, Chemico-biological interactions.

[20]  E. Petzinger,et al.  Ochratoxin A from a toxicological perspective. , 2000, Journal of veterinary pharmacology and therapeutics.

[21]  E. Creppy,et al.  Subchronic effects of ochratoxin A on young adult rat brain and partial prevention by aspartame, a sweetener , 1998, Human & experimental toxicology.

[22]  C. Lemaire,et al.  Different apoptotic pathways induced by zearalenone, T-2 toxin and ochratoxin A in human hepatoma cells. , 2008, Toxicology.

[23]  G. Rimbach,et al.  Ochratoxin A impairs Nrf2-dependent gene expression in porcine kidney tubulus cells. , 2009, Journal of animal physiology and animal nutrition.

[24]  G. Rimbach,et al.  Effect of vitamin E and polyphenols on ochratoxin A-induced cytotoxicity in liver (HepG2) cells. , 2005, Journal of plant physiology.

[25]  G. Brewer,et al.  Optimized survival of hippocampal neurons in B27‐supplemented neurobasal™, a new serum‐free medium combination , 1993, Journal of neuroscience research.

[26]  Junying Yuan,et al.  Apoptosis in the nervous system , 2000, Nature.

[27]  R. Manderville,et al.  Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans. , 2007, Molecular nutrition & food research.

[28]  J. Tillement,et al.  Effect of ethanol and red wine on ochratoxin a-induced experimental acute nephrotoxicity. , 2005, Journal of agricultural and food chemistry.

[29]  Y. Lou,et al.  Neuroprotective effects of icaritin against beta amyloid-induced neurotoxicity in primary cultured rat neuronal cells via estrogen-dependent pathway , 2007, Neuroscience.

[30]  T. Dingermann,et al.  A new approach to studying ochratoxin A (OTA)-induced nephrotoxicity: expression profiling in vivo and in vitro employing cDNA microarrays. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[31]  A. Huggett,et al.  Effects of the naturally occurring food mycotoxin ochratoxin A on brain cells in culture. , 1997, Neurotoxicology.

[32]  G. Schaaf,et al.  The role of oxidative stress in the ochratoxin A-mediated toxicity in proximal tubular cells. , 2002, Biochimica et biophysica acta.

[33]  C. Wolf,et al.  The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. , 2001, Cancer research.

[34]  E Borenfreund,et al.  Toxicity determined in vitro by morphological alterations and neutral red absorption. , 1985, Toxicology letters.