Disruption of dopamine transport by DDT and its metabolites.
Epidemiological studies suggest a link between pesticide exposure and an increased risk of developing Parkinson's disease (PD). Although studies have been unable to clearly identify specific pesticides that contribute to PD, a few human studies have reported higher levels of the organochlorine pesticides dieldrin and DDE (a metabolite of DDT) in post-mortem PD brains. Previously, we found that exposure of mice to dieldrin caused perturbations in the nigrostriatal dopamine system consistent with those seen in PD. Given the concern over the environmental persistence and reintroduction of DDT for the control of malaria-carrying mosquitoes and other pests, we sought to determine whether DDT and its two major metabolites, DDD and DDE, could damage the dopamine system. In vitro analyses in mouse synaptosomes and vesicles demonstrated that DDT and its metabolites inhibit the plasma membrane dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2). However, exposure of mice to either DDT or DDE failed to show evidence of nigrostriatal damage or behavioral abnormalities in any of the measures examined. Thus, we report that in vitro effects of DDT and its metabolites on components of the dopamine system do not translate into neurotoxicological outcomes in orally exposed mice and DDT appears to have less dopamine toxicity when compared to dieldrin. These data suggest elevated DDE levels in PD patients may represent a measure of general pesticide exposure and that other pesticides may be responsible for the association between pesticide exposure and PD.
Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, United States.
Jaime M
JM
Hatcher
Kristin C
KC
Delea
Jason R
JR
Richardson
Kurt D
KD
Pennell
Gary W
GW
Miller
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003634:DDT / Q000378:metabolism* / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009447:Neuroblastoma; D010575:Pesticides / Q000494:pharmacology*; D050050:Protein Carbonylation / Q000187:drug effects; D014316:Tritium / Q000378:metabolism
D050483:Dopamine Plasma Membrane Transport Proteins; D005452:Fluoresceins; D010575:Pesticides; D014316:Tritium; C065013:2',7'-dichlorodihydrofluorescein; D003634:DDT; D004298:Dopamine