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 pla sma membrane transport of dopamine and the expression of the plasma membran e dopamine transporter (DAT), as well as the vesicular monoamine transporte r (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 expressin g cell line, acute treatment with the putative toxic species of heptachlor, heptachlor epoxide, did not alter plasma membrane dopamine uptake. In a VM AT2 expressing cell line, heptachlor epoxide significantly inhibited vesicu lar uptake of dopamine (45% reduction at 10 mu M). Since DAT has been propo sed to be the molecular gateway for dopaminergic toxins, such as the parkin sonism-inducing neurotoxin MPP+, and VMAT2 has been proposed to protect cel ls from MPP+ and other toxins by sequestering the toxin into vesicles, the combined effects of heptachlor could increase the susceptibility of the nig rostriatal dopamine system to neurodegeneration. We further propose that al tered dopamine transport by exposure to pesticides may provide a molecular basis for the increased incidence of Parkinson's disease. (C)1999 Inter Pre ss, Inc.