Can low level exposure to ochratoxin-A cause parkinsonism?

University of South Florida, Tampa, FL 33612, USA.
Journal of the Neurological Sciences (Impact Factor: 2.47). 12/2006; 249(1):68-75. DOI: 10.1016/j.jns.2006.06.006
Source: PubMed


Mycotoxins are fungal metabolites with pharmacological activities that have been utilized in the production of antibiotics, growth promoters, and other classes of drugs. Some mycotoxins have been developed as biological and chemical warfare agents. Bombs and ballistic missiles loaded with aflatoxin were stockpiled and may have been deployed by Iraq during the first Gulf War. In light of the excess incidence of amyotrophic lateral sclerosis (ALS) in veterans from Operation Desert Storm, the potential for delayed neurotoxic effects of low doses of mycotoxins should not be overlooked. Ochratoxin-A (OTA) is a common mycotoxin with complex mechanisms of action, similar to that of the aflatoxins. Acute administration of OTA at non-lethal doses (10% of the LD(50)) have been shown to increase oxidative DNA damage in brain up to 72 h, with peak effects noted at 24 h in midbrain (MB), caudate/putamen (CP) and hippocampus (HP). Levels of dopamine (DA) and its metabolites in the striatum (e.g., CP) were shown to be decreased in a dose-dependent manner. The present study focused on the effects of chronic low dose OTA exposure on regional brain oxidative stress and striatal DA metabolism. Continuous administration of low doses of OTA with implanted subcutaneous Alzet minipumps caused a small but significant decrease in striatal DA levels and an upregulation of anti-oxidative systems and DNA repair. It is possible that low dose exposure to OTA will result in an earlier onset of parkinsonism when normal age-dependent decline in striatal DA levels are superimposed on the mycotoxin-induced lesion.

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Available from: Juan Sanchez-Ramos, Feb 13, 2014
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    • "apoptosis in neurons (Yoon et al., 2009; Zhang et al., 2009) and upon acute exposure it evokes an oxidative stress response in murine brains (Sava et al., 2006a). Acute and chronic administration of OTA in mice causes loss of striatal dopaminergic neurons, but only acute OTA exposure evokes inhibition of oxidative DNA repair (Sava et al., 2006b). Previous studies in 3D aggregating rat brain cell cultures showed that repeated OTA exposure causes a development-dependent sensitivity of cholinergic and g-aminobutyric acid (GABAergic) neurons and decreases expression of an oligodendrocyte maturation marker (Monnet-Tschudi et al., 1997). "
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    ABSTRACT: Neurotoxic effects of the environmentally abundant mycotoxin Ochratoxin A (OTA) were studied in histotypic 3D rat brain cell cultures, comprising all brain cell types. Cultures were exposed to nanomolar OTA concentrations and samples were collected 48 h after a single exposure, or after 10 days of repeated administration. OTA-induced changes in gene- and protein expression, as well as alterations in cell morphology were assessed. Forty-eight-hour OTA exposure resulted in a disruption of the neuronal cytoskeleton and reduced expression of several oligodendrocyte-specific markers indicative of demyelination. Astrocyte disturbances were revealed by a decrease in two astrocytic proteins involved in regulation of inflammatory responses, metallothioneins I and II. Repeated OTA administration induced a neuroinflammatory response, as visualized by an increase of isolectin B4 labelled cells, increased expression of pro-inflammatory cytokines, and detection of macrophagic ED1/CD68 positive cells, as well as an upregulation of neurodegenerative M1 microglial phenotype markers. Partial recovery from OTA-induced deleterious effects on oligodendrocytes and astrocytes was achieved by co-treatment with sonic hedgehog (SHH). In addition, metallothionein I and II co-treatment partially restored OTA-induced effects on oligodendrocytes after 48 h, and modulated microglial reactivity after 10 days. These results suggest that OTA-exposure affects Shh-signalling, which in turn may influence both oligodendrocytes and astrocytes. Furthermore, the primarily astrocytic proteins MTI/MTII may affect microglial activation. Thus the neuroinflammatory response appears to be downstream of OTA-induced effects on demyelination, axonal instabilities and astrocytes disturbances. In conclusion, repeated OTA-exposure induced a secondary neuroinflammatory response characterized by neurodegenerative M1 microglial activation and pro-inflammatory response that could exacerbate the neurodegenerative process.
    NeuroToxicology 09/2014; 44. DOI:10.1016/j.neuro.2014.04.005 · 3.38 Impact Factor
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    • "Sava et al. [172] also examined the possibility that OTA can cause parkinsonism in male mice focusing on the effects of chronic low doses of OTA exposure on regional brain oxidative stress and striatal DA metabolism. They reported that continuous administration of low doses of OTA with implanted subcutaneous Alzet minipumps caused a small but significant decrease in striatal DA levels and an up-regulation of anti-oxidant systems and DNA repair. "
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    ABSTRACT: Among many mycotoxins, T-2 toxin, macrocyclic trichothecenes, fumonisin B(1) (FB(1)) and ochratochin A (OTA) are known to have the potential to induce neurotoxicity in rodent models. T-2 toxin induces neuronal cell apoptosis in the fetal and adult brain. Macrocyclic trichothecenes bring about neuronal cell apoptosis and inflammation in the olfactory epithelium and olfactory bulb. FB(1) induces neuronal degeneration in the cerebral cortex, concurrent with disruption of de novo ceramide synthesis. OTA causes acute depletion of striatal dopamine and its metabolites, accompanying evidence of neuronal cell apoptosis in the substantia nigra, striatum and hippocampus. This paper reviews the mechanisms of neurotoxicity induced by these mycotoxins especially from the viewpoint of oxidative stress-associated pathways.
    International Journal of Molecular Sciences 12/2011; 12(8):5213-37. DOI:10.3390/ijms12085213 · 2.86 Impact Factor
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    • "Swiss mice male I.p; infusion 2 weeks Acute 3.5 mg/kg; chronic 4, 8, 16 mg/kg Effect of chronic low dose OTA exposure on regional brain oxidative stress and stratial DA metabolism Low doses exposure caused global oxidative stress [111] F344 rats male diet 7 and 21 d; 4, 7 and 12 months 300 mg/kg bw OTA mechanism of action-microarrays study in liver and kidney Oxidative stress and metabolic response modulated involving mainly Nrf2 and HNF4α pathway disruption [47] "
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    ABSTRACT: The in vitro and in vivo evidence compatible with a role for oxidative stress in OTA carcinogenicity has been collected and described. Several potential oxido-reduction mechanisms have been identified in the past. More recently, the possibility of a reduction of cellular antioxidant defense has been raised as an indirect source of oxidative stress. Consequences resulting from the production of oxidative stress are observed at different levels. First, OTA exposure has been associated with increased levels of oxidative DNA, lipid, and protein damage. Second, various biological processes known to be mobilized under oxidative stress were shown to be altered by OTA. These effects have been observed in both in vitro and in vivo test systems. In vivo, active doses were often within doses documented to induce renal tumors in rats. In conclusion, the evidence for the induction of an oxidative stress response resulting from OTA exposure can be considered strong. Because the contribution of the oxidative stress response in the development of cancers is well established, a role in OTA carcinogenicity is plausible. Altogether, the data reviewed above support the application of a threshold-based approach to establish safe level of dietary human exposure to OTA.
    Journal of Toxicology 06/2011; 2011(2):645361. DOI:10.1155/2011/645361
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