Effects of the organochlorine pesticide methoxychlor on dopamine metabolites and transporters in the mouse brain.
Pesticide exposure has been suggested as a risk factor in developing Parkinson's disease (PD). While the molecular mechanism underlying this association is not clear, several studies have demonstrated a role for mitochondrial dysfunction and oxidative damage in PD. Although data on specific pesticides associated with PD are often lacking, several lines of evidence point to the potential involvement of the organochlorine class of pesticides. Previously, we have found that the organochlorine pesticide methoxychlor (mxc) causes mitochondrial dysfunction and oxidative stress in isolated mitochondria. Here, we sought to determine whether mxc-induced mitochondrial dysfunction results in oxidative damage and dysfunction of the dopamine system. Adult female CD1 mice were dosed with either vehicle (sesame oil) or mxc (16, 32, or 64 mg/kg/day) for 20 consecutive days. Following treatment, we observed a dose-related increase in protein carbonyl levels in non-synaptic mitochondria, indicating oxidative modification of mitochondrial proteins which may lead to mitochondrial dysfunction. Mxc exposure also caused a dose-related decrease in striatal levels of dopamine (16-31%), which were accompanied by decreased levels of the dopamine transporter (DAT; 35-48%) and the vesicular monoamine transporter 2 (VMAT2; 21-44%). Because mitochondrial dysfunction, oxidative damage, and decreased levels of DAT and VMAT2 are found in PD patients, our data suggest that mxc should be investigated as a possible candidate involved in the association of pesticides with increased risk for PD, particularly in highly exposed populations.
Schuh
Rosemary A
RA
Department of Anesthesiology and Trauma and Anesthesiology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA. rschu003@umaryland.edu
Richardson
Jason R
JR
Gupta
Rupesh K
RK
Flaws
Jodi A
JA
Fiskum
Gary
G
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006843:Hydrocarbons, Chlorinated / Q000633:toxicity*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008731:Methoxychlor / Q000633:toxicity*; D051379:Mice; D010575:Pesticides / Q000633:toxicity*
D006843:Hydrocarbons, Chlorinated; D026901:Membrane Transport Proteins; D010575:Pesticides; D008731:Methoxychlor; D004298:Dopamine