Heptachlor alters expression and function of dopamine transporters.
Epidemiological data support a relationship between pesticide exposure and Parkinson's disease; however, no experimental evidence has been provided to support this association. Here we report that subchronic administration of the organochlorine insecticide heptachlor (0, 3, 6, 9, or 12 mg/kg given 3 times over a 2 week period) leads to a pronounced increase in both the plasma membrane transport of dopamine and the expression of the plasma membrane dopamine transporter (DAT), as well as the vesicular monoamine transporter (VMAT2) in the striatum of C57BL mice. To address possible mechanisms of increased DAT and VMAT2 expression, we performed transport studies in cell lines expressing the human forms of either DAT or VMAT2. In a DAT expressing cell line, acute treatment with the putative toxic species of heptachlor, heptachlor epoxide, did not alter plasma membrane dopamine uptake. In a VMAT2 expressing cell line, heptachlor epoxide significantly inhibited vesicular uptake of dopamine (45% reduction at 10 microM). Since DAT has been proposed to be the molecular gateway for dopaminergic toxins, such as the parkinsonism-inducing neurotoxin MPP, and VMAT2 has been proposed to protect cells from MPP and other toxins by sequestering the toxin into vesicles, the combined effects of heptachlor could increase the susceptibility of the nigrostriatal dopamine system to neurodegeneration. We further propose that altered dopamine transport by exposure to pesticides may provide a molecular basis for the increased incidence of Parkinson's disease.
Miller
G W
GW
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA. gwmiller@mail.utexas.edu
Kirby
M L
ML
Levey
A I
AI
Bloomquist
J R
JR
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D006533:Heptachlor / Q000008:administration & dosage / Q000633:toxicity*; D006534:Heptachlor Epoxide / Q000633:toxicity; D006801:Humans; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D014793:Visual Cortex / Q000378:metabolism*
D007306:Insecticides; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; C493452:SLC18A2 protein, human; C493453:Slc18a2 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D006534:Heptachlor Epoxide; D006533:Heptachlor; D004298:Dopamine