Modulation of Antioxidant Defense Systems by the Environmental Pesticide Maneb in Dopaminergic Cells

Barlow, Brian K.; Lee, Donna W.; Cory‐Slechta, Deborah A.; Opanashuk, Lisa A.

doi:10.1016/j.neuro.2004.07.004

Cited by 96 publications

(51 citation statements)

References 63 publications

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“…Consistent with previous observations made by us and others, Mn-EBDC and MPP ϩ produced significant DAergic selective neurotoxicity in primary mesencephalic culture as well as in immortalized MES cells (15,(32)(33)(34). More importantly, Mn-EBDC-and MPP ϩ -mediated neurotoxicity was enhanced by the addition of microglia to the cultures, concurring with the hypothesis that microglial activation initiated either directly by offending factors or secondary to neuronal cell death could contribute to further neurodegeneration.…”

Section: Discussionsupporting

confidence: 92%

Microglial Activation Induced by Neurodegeneration

Zhou

Wang

Kovacs

et al. 2005

Molecular & Cellular Proteomics

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Section: Discussionsupporting

confidence: 92%

Microglial Activation Induced by Neurodegeneration

Zhou

Wang

Kovacs

et al. 2005

Molecular & Cellular Proteomics

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“…Fitsanakis et al (2002) found that Mn-EBDCs catalyze a one electron transfer from dopamine or norepinephrine to molecular oxygen, resulting in ROS products like superoxide and semiquinone species. Barlow et al (2005) reported that MB, a Mn-EBDC very similar to MZ, at doses not affecting cell viability induced significant changes in the GSH antioxidant system in PC12 cells (catecholaminergic cell line) and in mesencephalic cells. More specifically, low doses (0.0376-3.76 uM) of MB diminished GSH levels and prevented the recovery of GSH levels in cell culture systems.…”

Section: Discussionmentioning

confidence: 99%

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

Domico

Cooper

Bernard³

et al. 2007

NeuroToxicology

122

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Previous in vitro studies in our laboratory have shown that mancozeb (MZ) and maneb (MB), both widely used EBDC fungicides, are equipotent neurotoxicants that produce cell loss in mesencephalic dopaminergic and GABAergic cells after an acute 24 h exposure. Mitochondrial uncoupling and inhibition were associated with fungicide exposure. Inhibition of mitochondrial respiration is known to increase free radical production. Here the mechanism(s) of neuronal damage associated with MZ exposure was further explored by determining the role that reactive oxygen species (ROS) played in toxicity. Damage to mesencephalic dopamine and GABA cell populations were significantly attenuated when carried out in the presence of ascorbate or SOD indicative of a free radical mediated contribution to toxicity. ROS generation monitored by H 2 O 2 production using Amplex Red increased in a dose-dependent manner in response to MZ. Inhibition of intracellular catalase with aminotriazole had little effect on H 2 O 2 generation, whereas exogenously added catalase significantly reduced H 2 O 2 production demonstrating a large extracellular contribution to ROS generation. Conversely, cells preloaded with the ROS indicator dye DCF showed significant MZ-induced ROS production, demonstrating an increase in intracellular ROS. Both the organic backbone of MZ as well as its associated Mn ion, but not Zn ion were responsible and required for H 2 O 2 generation. The functionally diverse NADPH oxidase inhibitors, diphenylene iodonium chloride, apocynin, and 4-(2-aminoethyl)benzene-sulfonyl fluoride hydrochloride significantly attenuated H 2 O 2 production by MZ. In growth medium lacking cells, MZ produced little H 2 O 2 , but enhanced H 2 O 2 generation when added with xanthine plus xanthine oxidase whereas, in cultured cells, allopurinol partially attenuated H 2 O 2 production by MZ. Minocycline, an inhibitor of microglial activation, modestly reduced H 2 O 2 formation in mesencephalic cells. In contrast, neuronal enriched cultures or cultures treated with MAC-1-SAP to kill microglia, did not show an attenuation of ROS production. These findings demonstrate that Mn-containing EBDC fungicides such as MZ and MB can produce robust ROS generation that likely occurs via redox cycling with extracellular and intracellular oxidases. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurotoxicology. Author manuscript; available in PMC 2008 November 1. The findings further show that microglia may contribute to but are not required for ROS production by MZ.

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“…Furthermore, MB inhibits proteosomal activity and induces presynaptic protein, a-synuclein aggregation in dopaminergic mammals cell cultures (Domico et al 2006(Domico et al , 2007. Besides, oxidative stress plays a critical role in MB-induced toxicities (Barlow et al 2005;Patel et al 2006;Domico et al 2007). In fact, MB induces oxidative stress via the inhibition of mitochondria complex III, catecholamines auto-oxidation, and antioxidant level attenuation in mesencephalic neuronal cultures (Zhang et al 2003; Barlow et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Maneb disturbs expression of superoxide dismutase and glutathione peroxidase, increases reactive oxygen species production, and induces genotoxicity in liver of adult mice

Amara

Saad

Hamdaoui

et al. 2015

Environ Sci Pollut Res

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Maneb (MB), a fungicide largely used in agriculture throughout the world including Tunisia, protects many vegetables, fruits and field crops against a wide spectrum of fungal diseases. However there is a lack of informations regarding the risks arising from MB exposure on non target organisms, especially mammals. The aim of this study was to investigate the morphological, biochemical and molecular aspects of liver injury after exposure of mice to MB. Four doses of MB corresponding to 1/8 (group D1), 1/6 (group D2), 1/4 (group D3), and 1/2 (group D4) of lethal dose (DL50 = 1500 mg/kg body weight) were administered to adult mice. Oxidative stress parameters were also objectified by molecular and histological endpoints in the liver. Maneb caused hepatotoxicity as characterized by the significant increase in the levels of malondialdehyde and protein oxidation marker, advanced oxidation protein products (AOPP). The activities of catalase, glutathione peroxidase, superoxide dismutase and the levels of glutathione decreased significantly in all treated mice, while vitamin C levels decreased only in group D4. We also noted a significant decrease in gene expression of superoxide dismutase and glutathione peroxidase enzymes. Maneb caused nucleic acids degradation testifying its genotoxicity. Yet, biochemical markers in plasma showed a decrease in total protein and an increase in aspartate, alanine amino transferases and bilirubin levels in all treatment groups. Moreover, plasma levels of cholesterol, triglycerides and low density lipoprotein-cholesterol significantly increased, while those of high density lipoprotein-cholesterol decreased. These biochemical alterations were correlated with significantly histological changes. Our data showed, for the first time, that intraperitoneal injection of very high non environmentally relevant MB concentrations to adult mice resulted in oxidative stress leading to hepatotoxicity and the impairment of defense systems, confirming the pro-oxidant and genotoxic effects of this fungicide.

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Modulation of Antioxidant Defense Systems by the Environmental Pesticide Maneb in Dopaminergic Cells

Cited by 96 publications

References 63 publications

Microglial Activation Induced by Neurodegeneration

Microglial Activation Induced by Neurodegeneration

Reactive oxygen species generation by the ethylene-bis-dithiocarbamate (EBDC) fungicide mancozeb and its contribution to neuronal toxicity in mesencephalic cells

Maneb disturbs expression of superoxide dismutase and glutathione peroxidase, increases reactive oxygen species production, and induces genotoxicity in liver of adult mice

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