Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system
Introduction
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 and Przedborski, 2003).
Numerous epidemiological studies have shown an association between pesticide exposure and an increased risk of developing PD (Kanthasamy et al., 2005, Le Couteur et al., 1999, Priyadarshi et al., 2000, Semchuk et al., 1991, Semchuk et al., 1992). In addition, a correlation between the presence of the organochlorine insecticide, dieldrin, in the brain and diagnosis of PD has been reported (Fleming et al., 1994). Similar observations have been reported in two small studies by Corrigan and coworkers, who observed elevated levels of dieldrin in post-mortem brains from PD patients living in the United Kingdom (Corrigan et al., 1998, Corrigan et al., 2000). However, the mechanism(s) by which pesticide exposure increases the risk of PD is still unknown.
Dieldrin is part of a class of synthetic organochlorine pesticides known as cyclodienes that were commonly used during the 1950s–1970s. Due to their low volatility, chemical stability, and lipophilic properties, these compounds have a strong tendency to bioaccumulate and biomagnify and are persistent in the environment (Jorgenson, 2001). The Agency for Toxic Substances and Disease Registry (ATSDR) lists dieldrin as the most hazardous cyclodiene pesticide based on its toxicity, widespread distribution, and potential for human exposure (ATSDR, 2005). Collectively, these factors result in continued concern over the toxicity of these compounds decades after their use was banned in the U.S.
Despite the potential link between dieldrin and PD, there have been few studies to investigate the biological impact of dieldrin on the nigrostriatal dopaminergic system in animals. Thiffault and colleagues report no effect on striatal DA levels in mice following a single high dose (40 or 80 mg/kg) injection of dieldrin (Thiffault et al., 2001), however they did not examine the overall state of the dopamine system. Our lab has previously reported that developmental exposure of mice to dieldrin leads to persistent alterations in the dopamine system and increases susceptibility to a dopaminergic toxin (Richardson et al., 2006). In this study, we hypothesized that exposure of adult mice to low levels of dieldrin over an extended period of time would lead to subtle alterations in the nigrostriatal dopamine system. We report dieldrin-induced cysteinyl-catechol formation, decreased striatal glutathione, and disruption of DA handling and DAT expression and function, all of which reflect an increase in oxidative stress. The effects reported here support the link between pesticide exposure and increased risk of developing PD.
Section snippets
Materials
Analytical grade (purity ≥ 98%) dieldrin was obtained from ChemService Inc. (West Chester, PA). 3H-dopamine (58 Ci/mmol) and 3H-WIN 35,428 (85 Ci/mmol) were purchased from Perkin-Elmer Life Sciences (Boston, MA). The source of immunochemical reagents is as follows: rat monoclonal antibody to DAT (cat #MAB369), rabbit polyclonal antibody to TH (cat #AB152), mouse monoclonal antibody to TH (cat #MAB318), rabbit polyclonal antibody to GAT-1 (cat #AB1570W), polyclonal guinea pig antibody to GLT (cat
Results
Previous studies have shown that dieldrin induces generation of reactive oxygen species (ROS) in a dopaminergic cell model (Kitazawa et al., 2001). Thus, we sought to examine the effects of direct application of dieldrin in a physiologically-relevant organotypic slice culture model of the rat midbrain to determine if the parent compound had an effect. Midbrain organotypic slices are advantageous because they maintain the cytoarchitecture of the region including glia and other supporting cells
Discussion
Exposure to pesticides has been consistently shown to be associated with increased risk of Parkinson's disease (Ascherio et al., 2006, Frigerio et al., 2006), but the specific compound(s) responsible for the association has not been determined. Previous studies have shown elevated levels of dieldrin in post-mortem brains of PD patients (Corrigan et al., 2000, Fleming et al., 1994) and we have recently generated data showing a similar association in a U.S. population (Hatcher and Miller,
Acknowledgments
This work was supported by the Emory Collaborative Center for Parkinson's Disease Environmental Research (CCPDER) U54ES012068 (GWM), Woodruff Health Sciences Center Fund (GWM), K25ES014659 (KDP), Georgia Tech Foundation (KDP) and other NIH grants F32ES013457 (JRR), F30ES014141 (JMH), R21ES013828 (JRR), ES10806 (DAD), ES12077 (DAD) and ES09047 (DPJ). We would like to thank the NIMH Chemical Repository for their generous donation of the cysteinyl-catechol standards.
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