Selective Effects of Cyclodiene Insecticides on Dopamine Release in Mammalian Synaptosomes

Kirby, Michael; Barlow, Rebecca; Bloomquist, Jeffrey R.

doi:10.1006/taap.2002.9405

Cited by 28 publications

(14 citation statements)

References 19 publications

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“…Despite the widespread distribution of dieldrin throughout the fatty tissue of the brain, it appears that the nigrostriatal system is particularly susceptible to the effects of dieldrin exposure. Previous studies have shown the ability of dieldrin to preferentially cause dopamine release from syntaptosomes that is independent of its GABAergic inhibition (Kirby et al, 2002). In addition, in vitro studies from our lab show that physiologically-relevant concentrations of dieldrin do not directly inhibit DAT or the vesicular monoamine transporter 2 (VMAT2) -two key regulators or dopamine homeostasis (data not shown).…”

Section: Discussionmentioning

confidence: 64%

Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

Hatcher

Richardson

Guillot

et al. 2007

Experimental Neurology

135

107

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Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing Parkinson's disease (PD). Here, we provide evidence that the insecticide dieldrin causes specific oxidative damage in the nigrostriatal dopamine (DA) system. We report that exposure of mice to low levels of dieldrin for 30 days resulted in alterations in dopamine-handling as evidenced by a decrease in dopamine metabolites, DOPAC (31.7% decrease) and HVA (29.2% decrease) and significantly increased cysteinyl-catechol levels in the striatum. Furthermore, dieldrin resulted in a 53% decrease in total glutathione, an increase in the redox potential of glutathione, and a 90% increase in protein carbonyls. α-Synuclein protein expression was also significantly increased in the striatum (25% increase). Finally, dieldrin caused a significant decrease in striatal expression of the dopamine transporter as measured by 3 H-WIN 35,428 binding and 3 H-dopamine uptake. These alterations occurred in the absence of dopamine neuron loss in the substantia nigra pars compacta. These effects represent the ability of low doses of dieldrin to increase the vulnerability of nigrostriatal dopamine neurons by inducing oxidative stress and suggest that pesticide exposure may act as a promoter of PD. *Corresponding Author: Gary W. Miller, Ph.D., Emory University -Center for Neurodegenerative Disease, Whitehead Biomedical Research Building 505K, 615 Michael Street Atlanta, GA 30322, Phone: 404.712.8582, Fax: 404.727.3728, Email: gary.miller@emory.edu 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. Parkinson's disease (PD) is a chronic, progressive neurological disorder clinically characterized by resting tremor, bradykinesia, postural instability and rigidity (Marsden, 1984). Pathologically, PD presents as dopaminergic neuronal loss in the substantia nigra pars compacta (SNc), striatal depletion of the neurotransmitter dopamine (DA), the loss of neurochemical markers, such as the dopamine transporter (DAT), and the presence of Lewy bodies containing α-synuclein (Spillantini et al., 1997). Because only 5-10% of PD cases are thought to be primarily genetic in origin, investigation of the role of environmental factors in the pathogenesis of the disease is warranted (Dauer & Przedborski, 2003). NIH Public AccessNumerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing PD Le Couteur et al., 1999;Priyadarshi et al., 2000;Semchuk et al., 1991Semchuk et al., ,1992. In addition, a correlation between the presence of th...

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Section: Discussionmentioning

confidence: 64%

Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

Hatcher

Richardson

Guillot

et al. 2007

Experimental Neurology

135

107

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“…In this study, we found significant increases in DAT-binding sites as measured with 3 H-WIN 35,428 that mirrored the increase in DAT-mediated dopamine uptake. While no specific mechanism has been identified for the increase of DAT by these compounds, chemicals known to cause dopamine release, like amantidine and the organo-chlorine pesticide heptachlor, can increase DAT expression (Gordon et al, 1996;Miller et al, 1999aMiller et al, , 1999bPage et al, 2000;Kirby et al, 2002). If this were to be sustained over time, one would expect that the elevated extracellular dopamine would increase the expression of the dopamine transporter in an attempt to clear and recycle dopamine.…”

Section: Discussionmentioning

confidence: 99%

Pyrethroid pesticide-induced alterations in dopamine transporter function

Elwan

Richardson

Guillot

et al. 2006

Toxicology and Applied Pharmacology

104

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Parkinson's disease (PD) is a progressive neurodegenerative disease affecting the nigrostriatal dopaminergic pathway. Several epidemiological studies have demonstrated an association between pesticide exposure and the incidence of PD. Studies from our laboratory and others have demonstrated that certain pesticides increase levels of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for dopaminergic neurotoxins. Here, we report that repeated exposure (3 injections over 2 weeks) of mice to two commonly used pyrethroid pesticides, deltamethrin (3 mg/kg) and permethrin (0.8 mg/kg), increases DATmediated dopamine uptake by 31 and 28%, respectively. Using cells stably expressing DAT, we determined that exposure (10 min) to deltamethrin and permethrin (1 nM-100 μM) had no effect on DAT-mediated dopamine uptake. Extending exposures to both pesticides for 30 min (10 μM) or 24 h (1, 5, and 10 μM) resulted in significant decrease in dopamine uptake. This reduction was not the result of competitive inhibition, loss of DAT protein, or cytotoxicity. However, there was an increase in DNA fragmentation, an index of apoptosis, in cells exhibiting reduced uptake at 30 min and 24 h. These data suggest that up-regulation of DAT by in vivo pyrethroid exposure is an indirect effect and that longer-term exposure of cells results in apoptosis. Since DAT can greatly affect the vulnerability of dopamine neurons to neurotoxicants, up-regulation of DAT by deltamethrin and permethrin may increase the susceptibility of dopamine neurons to toxic insult, which may provide insight into the association between pesticide exposure and PD. KeywordsDeltamethrin; Permethrin; Pyrethroid; Dopamine transporter; Parkinson's disease Parkinson's disease (PD) is a disabling neurodegenerative disorder characterized by the loss of nigrostriatal dopamine neurons and the formation of intraneuronal inclusions termed Lewy bodies (Olanow and Tatton, 1999). Although the exact etiology of PD is unknown, both genetic and environmental factors are thought to contribute to the pathogenesis of PD. While there are rare instances of genetically-linked PD, data from a recent comprehensive

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“…Several studies in dopamine cell lines have demonstrated the ability of dieldrin to generate reactive oxygen species, induce ubiquitin-proteasome system dysfunction, promote α-synuclein aggregation, release and deplete intracellular dopamine, alter mitochondrial membrane potential and activate caspases [58,59]. In vitro dieldrin has been shown to promote fibrillization of α-synuclein [60] and cause synaptosomal release of dopamine by a mechanism independent of direct binding to the picrotoxin-binding site on the gamma-aminobutyric acid (GABA A ) receptor [61]. In mice dieldrin exposure has been shown to recapitulate many of the neuropathological changes seen in PD, such as increased α-synuclein expression, alterations in dopamine homeostasis and increased markers of oxidative stress including the formation of cysteinylcatechols [62].…”

Section: Organochlorinesmentioning

confidence: 99%

Parkinson's disease and pesticides: a toxicological perspective

Hatcher

Pennell

Miller

2008

Trends in Pharmacological Sciences

296

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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Selective Effects of Cyclodiene Insecticides on Dopamine Release in Mammalian Synaptosomes

Cited by 28 publications

References 19 publications

Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

Pyrethroid pesticide-induced alterations in dopamine transporter function

Parkinson's disease and pesticides: a toxicological perspective

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