Effect of manganese exposure on MPTP neurotoxicities.
ABSTRACT We used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model to evaluate whether manganese (Mn) exposure can affect MPTP-induced neurotoxicity. We randomly assigned adult male C57BL/6 mice (n=5-7 per group) the following treatments: SO, Mn(-) x MPTP(-); MO, Mn(+) x MPTP(-); SM, Mn(-) x MPTP(+); MM, Mn(+) x MPTP(+). Mn (MnCl(2).4H(2)O) was administered intraperitoneally at a dose of 2 mg/kg daily for 3 weeks. MPTP was then administered intraperitoneally at a dose of 30 mg/kg daily for 5 days in the SM and MM groups. Seven days after the last MPTP injection, the animals were sacrificed. Blood Mn levels were elevated in the Mn-exposed groups. Striatal Mn levels were not influenced by Mn treatment alone, however, they were decreased following MPTP. Tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in the substantia nigra pars compacta (SNpc) were decreased significantly in the MPTP-exposed groups. Densities of TH- and dopamine transporter (DAT)-ir axon terminals in the caudate-putamen (CPU) were also decreased in the MPTP-treated groups. Furthermore, glial fibrillary acidic protein (GFAP)-ir astrocytes increased in the CPU with MPTP treatment. However, no effects were observed with Mn exposure. Concentrations of dopamine (DA), 3,4-dihydrophenyl acetic acid (DOPAC) and homovanillic acid (HVA) in the corpus striatum were also decreased significantly with MPTP treatment alone, but Mn had no effect. Thus, decreased dopaminergic activities with MPTP led to decreased DA and its metabolites. Significant hypertrophies of GFAP-ir astrocytes in the globus pallidus (GP) were observed in Mn-exposed groups, especially in the MM group. MPTP targeted dopaminergic systems whereas Mn neurotoxicities occurred in the GP. In conclusion, our data suggest that Mn does not potentiate the neurotoxicity of MPTP.
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ABSTRACT: The aim of the present work is the assessment of metal toxicity in runoff, in their contaminated soils and in the groundwater sampled from two mining areas in the region of Marrakech using a microbial bioassay MetPLATE. This bioassay is based on the specific inhibition of the beta-galactosidase enzyme of a mutant strain of Escherichia coli, by the metallic pollutants. The stream waters from all sampling stations in the two mines were all very toxic and displayed percent enzyme inhibition exceeding 87% except SWA4 and SWB1 stations in mine C. Their high concentrations of copper (Cu) and zinc (Zn) confirm the acute toxicity shown by MetPLATE. The pH of stream waters from mine B and C varied between 2.1 and 6.2 and was probably responsible for metal mobilization, suggesting a problem of acid mine drainage in these mining areas. The bioassay MetPLATE was also applied to mine tailings and to soils contaminated by the acidic waters. The results show that the high toxicity of these soils and tailings was mainly due to the relatively concentration of soluble Zn and Cu. The use of MetPLATE in groundwater toxicity testing shows that, most of the samples exhibited low metal toxicity (2.7-45.5% inhibition) except GW3 of the mine B (95.3% inhibition during the wet season and 82.9% inhibition during the dry season). This high toxicity is attributed to the higher than usual concentrations of Cu (189 microg Cu l(-1)) and Zn (1505 microg Zn l(-1)). These results show the potential risk of the contamination of different ecosystems situated to the vicinity of these two metalliferous sites. The general trend observed was an increase in metal toxicity measured by the MetPLATE with increasing total and mobile metal concentrations in the studied matrices. Therefore, the MetPLATE bioassay is a reliable and fast bioassay to estimate the metals toxicity in the aquatic and solids samples.Environmental Monitoring and Assessment 02/2008; 136(1-3):147-60. · 1.68 Impact Factor
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ABSTRACT: Iron deficiency is a risk factor for manganese (Mn) accumulation. Excess Mn promotes neurotoxicity but the mechanisms involved and whether iron depletion might affect these pathways is unknown. To study Mn intoxication in vivo, iron deficient and control rats were intranasally instilled with 60mg MnCl2/kg over 3 weeks. TUNEL staining of olfactory tissue revealed that Mn exposure induced apoptosis and that iron deficiency potentiated this effect. In vitro studies using the dopaminergic SH-SY5Y cell line confirmed that Mn-induced apoptosis was enhanced by iron depletion using the iron chelator desferrioxamine. Mn has been reported to induce apoptosis through endoplasmic reticulum stress. In SH-SY5Y cells, Mn exposure induced the ER stress genes glucose regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP). Increased phosphorylation of the eukaryotic translation initiation factor 2α (phospho-eIF2α) was also observed. These effects were accompanied by the activation of ER resident enzyme caspase-12, and the downstream apoptotic effector caspase-3 was also activated. All of the Mn-induced responses were enhanced by DFO treatment. Inhibitors of ER stress and caspases significantly blocked Mn-induced apoptosis and its potentiation by DFO, indicating that ER stress and subsequent caspase activation underlie cell death. Taken together, these data reveal that Mn induces neuronal cell death through ER stress and the UPR response pathway and that this apoptotic effect is potentiated by iron deficiency most likely through upregulation of DMT1.NeuroToxicology 06/2013; · 2.65 Impact Factor