Differential up-regulation of striatal dopamine transporter and alpha-synuclein by the pyrethroid insecticide permethrin.
The effects of permethrin on striatal dopaminergic biomarkers were assessed in this study. Retired breeder male C57 B1/6 mice were given an ip dose of permethrin (0.1-200 mg/kg) at 7-day intervals, over a 2-week period (Days 0, 7, and 14). Animals were then sacrificed 1 day (t = 1), 14 days (t = 14), or 28 days after the last treatment (t = 28). Dopamine transporter (DAT) protein as assayed by Western blotting was increased to 115% in the 0.8 mg/kg group over that of control mice at t = 1 (P < 0.05). At t = 14, this value increased to 140% of control, and declined slightly to 133% of control at t = 28. The mice given the 1.5 mg/kg dose displayed a significant increase in DAT protein only at t = 28, to 145% of controls. Thus, upregulation of the DAT at low doses of PM is variable 24 h after treatment, and seems to stabilize by t = 28. The threshold dose for increasing DAT expression in Western blots by t = 28 was 0.2 mg/kg permethrin. [(3)H]GBR 12935, used to assay DAT binding, followed the same trend as that for the Western blotting data for 0.8 and 1.5 mg/kg doses of permethrin over the 4 weeks posttreatment. At 200 mg/kg permethrin, DAT protein was unchanged vs controls (t = 1), but had significantly increased by t = 14 and continued to increase at t = 28, suggesting that the reduced dopamine transport at this dose was due to nerve terminal stress and that recovery had occurred. The protein alpha-synuclein was also significantly induced at the 1.5 mg/kg dose at t = 1; however, unlike DAT up-regulation, this effect had declined to control values by t = 14. Maximal induction of alpha-synuclein protein occurred at a dose of 50 mg/kg permethrin. These data provide evidence that the pyrethroid class of insecticides can modulate the dopaminergic system at low doses, in a persistent manner, which may render neurons more vulnerable to toxicant injury.
Department of Entomology, Virginia Polytechnic and State University, Blacksburg, VA 24061-0319, USA.
Jeffrey S
JS
Gillette
Jeffrey R
JR
Bloomquist
D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D026023:Permethrin / Q000008:administration & dosage / Q000633:toxicity*; D010750:Phosphoproteins / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D051843:Synucleins; D015854:Up-Regulation; D051844:alpha-Synuclein
D050483:Dopamine Plasma Membrane Transport Proteins; D007306:Insecticides; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C493215:Slc6a3 protein, mouse; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D026023:Permethrin