Pyrethroid pesticide-induced alterations in dopamine transporter function

https://doi.org/10.1016/j.taap.2005.06.003Get rights and content

Abstract

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 DAT-mediated 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.

Section snippets

Materials

Analytical grade (purity ≥98%) deltamethrin and permethrin were 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 rat monoclonal antibody to DAT was purchased from Chemicon (Temecula, CA) and the monoclonal anti-mouse α-tubulin was purchased from Sigma (St. Louis, MO). The goat anti-rat secondary antibody was purchased from ICN (Costa Mesa, CA) and the goat anti-mouse

Results

No overt signs of toxicity, defined as tremor, choreoathetosis, and salivation, were observed following administration of either deltamethrin or permethrin. There were also no significant changes in weight in any of the treated animals (data not shown).

Based upon previous studies demonstrating increased dopamine uptake following deltamethrin or permethrin exposure (Kirby et al., 1999, Gillette and Bloomquist, 2003), we administered deltamethrin (3 mg/kg) or permethrin (0.8 mg/kg) three times

Discussion

Previous studies have demonstrated that repeated exposure of mice to the pyrethroid pesticides, deltamethrin and permethrin, results in increased synaptosomal dopamine uptake (Kirby et al., 1999, Karen et al., 2001, Gillette and Bloomquist, 2003). In this study, we confirm these observations and extend them by demonstrating that the functional up-regulation is accompanied by increases in DAT-binding sites. In addition, we demonstrate that permethrin and deltamethrin have no direct effect on DAT

Acknowledgments

This work was supported by the US Army Medical Research and Materiel Command under Award No. 00267036 (GWM), and in part by NIH U54 ES012068 (GWM) and F32 ES013457 (JRR), and an EPA STAR Fellowship (TSG). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army, NIH, or EPA.

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