title: Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolites.
abstract: Studies have shown that both in vivo and in vitro exposure to the herbicide atrazine (ATR) results in dopaminergic neurotoxicity manifested by decreased striatal dopamine (DA) levels. However, the mechanism behind this reduction is largely unknown. A decrease in striatal DA could be due to ATR exposure affecting vesicular and/or synaptosomal uptake resulting in disrupted vesicular storage and/or cellular uptake of DA. Hence, we investigated the effects of in vitro ATR exposure on DA uptake into isolated rat striatal synaptosomes and synaptic vesicles. In addition to ATR, effects of its major mammalian metabolites, didealkyl atrazine (DACT), desethyl atrazine (DE) and desiopropyl atrazine (DIP) were investigated. ATR (1-250 microM) inhibited DA uptake into synaptic vesicles in a dose-dependent manner. Of the three ATR metabolites tested, DACT did not affect vesicular DA uptake. DE and DIP, on the other hand, significantly decreased vesicular DA uptake with the effect of 100 microM DE/DIP being similar to the effect of the same concentration of ATR. Kinetic analysis of vesicular DA uptake indicated that ATR significantly decreased the V(max) while the K(m) value was not affected. Contrary to the inhibitory effects on vesicular DA uptake, synaptosomal DA uptake was marginally (6-13%) increased by ATR and DE, but not by DACT and DIP, at concentrations of <or=100 microM. As a result, ATR, DIP and DE increased the synaptosomal/vesicular (DAT/VMAT-2) uptake ratio. Collectively, results from this study suggest that ATR and two of its metabolites, DIP and DE, but not its major mammalian metabolite, DACT, decrease striatal DA levels, at least in part, by increasing cytosolic DA, which is prone to oxidative breakdown.
authors.affiliation: Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, MS 39762-6100, USA.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Hossain
authors.forename: Nikolay M
authors.initials: NM
authors.lastname: Filipov
mesh_terms: D000818:Animals; D001280:Atrazine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006540:Herbicides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology*
chemical_list: C445502:6-chloro-N-ethyl-1,3-5-triazine-2,4-diamine; D006540:Herbicides; D014227:Triazines; C405102:desethylatrazine; D001280:Atrazine; D004298:Dopamine