Neurotoxicity in murine striatal dopaminergic pathways following long-term application of low doses of permethrin and MPTP

Abstract

The long-term effects of permethrin (PM) and its interaction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopaminergic pathways were investigated in C57BL/6 mice. In a 3-month exposure, technical PM (1.5 mg/kg) was administered once per week, with MPTP (20 mg/kg) given once on either the 7th week or 11th week. In a 6-month exposure, PM (0.8 mg/kg or 1.5 mg/kg) was administered once per week for 26 weeks, with MPTP (20 mg/kg) given once, on week 24. Alterations in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and α-synuclein proteins were analyzed 1 day after the last PM treatment using western blot assay. PM had no significant effect on striatal dopaminergic pathways by itself, whereas MPTP significantly reduced the expression of TH and DAT proteins. In both exposure paradigms, weekly 1.5 mg/kg PM treatments antagonized the toxic effect of MPTP on TH and DAT expression ( p < 0.05). There was no significant alteration of α-synuclein expression following any exposure to PM and/or MPTP. [ 3H]Tetrabenazine (TBZ) binding assay for expression of striatal vesicular monoamine transporter (VMAT) showed no effect of PM, but the reduction in this protein caused by MPTP was attenuated by PM, consistent with effects on other dopaminergic biomarkers. The overall findings demonstrate that long-term, low-dose exposure to PM alone did not cause signs of neurotoxicity to striatal dopaminergic neural terminals, or enhance the effects of MPTP. We conclude that under typical use conditions, PM poses little Parkinsonian hazard to humans, including when impregnated into clothing for control of biting flies.