Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease?

Thiruchelvam, Mona; Brockel, Becky; Richfield, Eric K.; Baggs, Raymond B.; Cory‐Slechta, Deborah A.

doi:10.1016/s0006-8993(00)02496-3

Cited by 288 publications

(231 citation statements)

References 56 publications

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“…Following cervical dislocation and rapid decapitation, frontal cortex and striatal blocks were dissected. High pressure liquid chromatography with electrochemical detection analysis was performed as described previously (33) and normalized to protein concentration as measured by the Bio-Rad DC protein assay (Bio-Rad). The concentrations of the neurotransmitters were expressed in units of ng/mg of protein.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of Superoxide Dismutase or Glutathione Peroxidase Protects against the Paraquat + Maneb-induced Parkinson Disease Phenotype

Thiruchelvam

Prokopenko²,

Cory‐Slechta

et al. 2005

Journal of Biological Chemistry

121

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Oxidative stress has been implicated in the pathogenesis of Parkinson disease based on its role in the cascade of biochemical changes that lead to dopaminergic neuronal death. This study analyzed the role of oxidative stress as a mechanism of the dopaminergic neurotoxicity produced by the combined paraquat and maneb model of the Parkinson disease phenotype. Transgenic mice overexpressing either Cu,Zn superoxide dismutase or intracellular glutathione peroxidase and non-transgenic mice were exposed to saline, paraquat, or the combination of paraquat ؉ maneb twice a week for 9 weeks. Non-transgenic mice chronically exposed to paraquat ؉ maneb exhibited significant reductions in locomotor activity, levels of striatal dopamine and metabolites, and dopaminergic neurons in the substantia nigra pars compacta. In contrast, no corresponding effects were observed in either Cu,Zn superoxide dismutase or glutathione peroxidase transgenic mice. Similarly, the increase in levels of lipid hydroperoxides in the midbrain and striatum of paraquat ؉ maneb-treated non-transgenic mice was not detected in either Cu,Zn superoxide dismutase or glutathione peroxidase transgenic mice. To begin to determine critical pathways of paraquat ؉ maneb neurotoxicity, the functions of cell death-inducing and protective mechanisms were analyzed. Even a single injection of paraquat ؉ maneb in the non-transgenic treated group modulated several key pro-and anti-apoptotic proteins, including Bax, Bad, Bcl-xL, and upstream stress-induced cascade. Collectively, these findings support the assertion that protective mechanisms against paraquat ؉ maneb-induced neurodegeneration could involve modulation of the level of reactive oxygen species and alterations of the functions of specific signaling cascades.Parkinson disease (PD) 1 is a neurodegenerative disorder resulting, in part, from the progressive loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc). A lack of evidence for heritability of the idiopathic form of PD has pointed to environmental risk factors as potential contributors to the disease etiology. In accord with that possibility, exposures to environmental agents have been linked repeatedly with the development of PD (1-9). Animal models, epidemiological studies, and clinical case reports have repeatedly identified exposure to the herbicide paraquat (PQ) and the fungicide maneb (MB) as potential risk factors for the PD phenotype (1, 9 -15). Our laboratories have demonstrated extensively that exposure to the combination of PQ ϩ MB produces a potentiated loss of dopaminergic neurons in the SNpc of mice compared with either compound alone (16). This model exemplifies the "multiple hit" hypothesis associated with PD. Furthermore, the neurotoxicity of PQ ϩ MB seems to be highly selective to the nigrostriatal dopaminergic system. Additionally, we have shown that exposure during critical periods of development and during advanced age as well as gender and genetic background all modify the susceptibility and response of dopaminergic...

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Section: Methodsmentioning

confidence: 99%

Overexpression of Superoxide Dismutase or Glutathione Peroxidase Protects against the Paraquat + Maneb-induced Parkinson Disease Phenotype

Thiruchelvam

Prokopenko²,

Cory‐Slechta

et al. 2005

Journal of Biological Chemistry

121

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“…It is possible that the parkinsonian symptoms are secondary to exposure to the manganese metal core and lead to symptoms similar to those seen in manganism [17]. Maneb has been shown to exacerbate toxicity of other agents in mouse models, such as paraquat (see below) [18]. Additionally, other dithiocarbamates have been shown to disrupt function of the ubiquitin proteasome system, a system thought to be involved in both genetic and idiopathic forms of PD [19].…”

Section: Fungicidesmentioning

confidence: 99%

“…One such combination is that of paraquat and the fungicide maneb. The overlap in geographic usage of these compounds was used as a rationale for animal studies that showed that coexposure caused decreased motor activity, altered striatal dopamine and dopamine metabolites, decreased striatal tyrosine hydroxylase and dopamine transporter (DAT) expression and increased accumulation of dopamine in synaptosomes [18,39,40]. However, the compounds are not used simultaneously [ATSDR -CERCLA Priority List of Hazardous Substances (http://www.atsdr.cdc.gov/cercla)] and, although paraquat does persist in the environment (Figure 4), due to its high affinity for soil it is not biologically available, making such simultaneous exposures unlikely in the human population.…”

Section: Paraquatmentioning

confidence: 99%

Parkinson's disease and pesticides: a toxicological perspective

Hatcher

Pennell

Miller

2008

Trends in Pharmacological Sciences

289

176

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Environmental factors have been shown to contribute to the incidence of Parkinson's disease (PD). Pesticides, which represent one of the primary classes of environmental agents associated with PD, share the common feature of being intentionally released into the environment to control or eliminate pests. Pesticides consist of multiple classes and subclasses of insecticides, herbicides, rodenticides, fungicides, fumigants and others and exhibit a vast array of chemically diverse structures. In this review we examine the evidence regarding the ability of each of the major pesticide subclasses to increase the incidence of PD. We propose that, from a toxicological perspective, it would be beneficial to identify specific subclasses, common structural features and the propensity for widespread human exposure when considering the potential role in PD, rather than using the overly broad term of 'pesticides' to describe this diverse group of chemicals. Furthermore, these chemicals and their environmentally relevant combinations should be evaluated for their ability to promote or accelerate PD and not merely for being singular causative agents.

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“…The neurotoxicity of paraquat (PQ), a bipyridial herbicide, mimics PD in experimental models and results in microglia activation and redox cycling via microglial NADPH oxidase (McCormack et al, 2002;Bonneh-Barkay et al, 2005). EBDCs, including MB, have enhanced the toxic effects of the prooxidants MPTP Bachurin et al, 1996) and PQ (Thiruchelvam et al, 2000a(Thiruchelvam et al, ,b, 2005 in rodent models, contributing to the PD-like phenotype.…”

Section: Introductionmentioning

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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Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease?

Cited by 288 publications

References 56 publications

Overexpression of Superoxide Dismutase or Glutathione Peroxidase Protects against the Paraquat + Maneb-induced Parkinson Disease Phenotype

Overexpression of Superoxide Dismutase or Glutathione Peroxidase Protects against the Paraquat + Maneb-induced Parkinson Disease Phenotype

Parkinson's disease and pesticides: a toxicological perspective

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

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