Heptachlor alters expression and function of dopamine transporters
Miller, G.W.; Kirby, M.L.; Levey, A.I.; Bloomquist, J.R.
Neurotoxicology 20(4): 631-637
1999
ISSN/ISBN: 0161-813X PMID: 10499361 Document Number: 500309
Epidemiological data support a relationship between pesticide exposure and Parkinson's disease. In this paper, subchronic administration of heptachlor (0, 3, 6, 9 or 12 mg/kg given 3 times over a 2 week period) is reported to 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, transport studies in cell lines expressing the human forms of either DAT or VMAT2 were investigated. 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 micro M). 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. It is further proposed that altered dopamine transport by exposure to pesticides may provide a molecular basis for the increased incidence of Parkinson's disease.