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.

Selective effects of insecticides on nigrostriatal dopaminergic nerve pathways.

A degeneration of the nigrostriatal pathway is a primary component of Parkinson's disease (PD), and we have investigated the actions of insecticides on this pathway. For in vivo exposures, C57BL/6 mice were treated three times over a 2-week period with heptachlor, the pyrethroids deltamethrin and permethrin, or chlorpyrifos. One day after the last treatment, we observed that heptachlor and the pyrethroids increased maximal [3H]dopamine uptake in striatal synaptosomes from treated mice, with dose-dependent changes in Vmax displaying a bell-shaped curve. Western blot analysis confirmed increased levels of dopamine transporter (DAT) protein in the striatum of mice treated with heptachlor and permethrin. In contrast, we observed a small, but statistically significant decrease in dopamine uptake by 100 mg/kg chlorpyrifos. For heptachlor, doses that upregulated DAT expression had little or no effect on serotonin transport. Permethrin did cause an upregulation of serotonin transport, but required a 30-fold greater dose than that effective on dopamine uptake. Other evidence of specificity was found in transmitter release assays, where heptachlor and deltamethrin released dopamine from striatal terminals with greater potency than other transmitter types. These findings confirm that insecticides possess specificity for effects on striatal dopaminergic neurotransmission.