Dieldrin exposure induces oxidative damage in the mouse nigrostriatal dopamine system

Abstract

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...

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…In another study, combined intraperitoneal administration of paraquat and maneb in mice, but not either alone, lead to degeneration of nigral dopaminergic neurons, loss of striatal dopamine and reduced motor activity [369]. In vitro, dieldrin (an organochlorine) caused increased α-Synuclein fibril formation [370] and in mice, dieldrin exposure lead to increased α-Synuclein expression and alterations in the dopaminergic system [371]. Although experimental evidence indicates that several pesticides can exert a neurotoxic effect to dopaminergic neurons, doses and routes of administration were not comparable to the conditions present in pesticide users, making it difficult to generalize the results to humans.…”

Disruption of dopamine transport by DDT and its metabolites

“…These findings are supported by numerous animal studies that have identified potential mechanistic links between pesticides and PD pathogenesis (Betarbet et al, 2000;Bloomquist et al, 2002;Caudle et al, 2005;Hatcher et al, 2007;Kitazawa et al, 2001Kitazawa et al, , 2003McCormack et al, 2005;Miller et al, 1999;Purkerson-Parker et al, 2001;Richardson et al, 2006;Thiruchelvam et al, 2003). Additionally, higher levels of pesticides have been identified in post-mortem PD brains versus age-matched controls (Corrigan et al, 1998(Corrigan et al, , 2000Fleming et al, 1994;Pennell et al, 2006).…”

“…The tissue extraction procedure was based on methods of Corrigan et al (2000) and Grandjean et al (2001) and performed as previously described (Hatcher et al, 2007). Frozen frontal cortex mouse tissue (~150 mg) was added to 5 ml of a 1:1 mixture of hexane and acetone in an amber vial.…”

“…Control mice were orally gavaged with vehicle (methoxytriglycol; n = 12) and treated mice were orally gavaged with p,p′-DDT (1 or 3 mg/kg in methoxytriglycol) or p,p′-DDE (1, 3, or 6 mg/kg in methoxytriglycol) every 3 days for 30 days. These doses were chosen based on previous experiments examining exposure to the organochlorine dieldrin (Hatcher et al, 2007) in order to achieve similar mouse brain pesticide concentrations. Three days following the last treatment, mice were sacrificed by live decapitation and brains removed for further analysis.…”

“…Based on the analysis of pesticides levels in human tissue samples, we first examined dieldrin with exposure studies in mice and reported several changes in the nigrostriatal dopamine system that are consistent with changes seen in PD, including increased oxidative damage, decreased dopamine transporter (DAT) expression and function, and increased alpha-synuclein expression in the striatum (Hatcher et al, 2007). In light of these findings and the persistence of DDT and its metabolites, we sought to perform similar studies looking to assess effects of DDT compounds on the nigrostriatal dopamine system and dopamine homeostasis.…”