1. Academic Validation
  2. Bifenthrin Caused Parkinson's-Like Symptoms Via Mitochondrial Autophagy and Ferroptosis Pathway Stereoselectively in Parkin-/- Mice and C57BL/6 Mice

Bifenthrin Caused Parkinson's-Like Symptoms Via Mitochondrial Autophagy and Ferroptosis Pathway Stereoselectively in Parkin-/- Mice and C57BL/6 Mice

  • Mol Neurobiol. 2024 May 1. doi: 10.1007/s12035-024-04140-5.
Ying Zhang 1 Baorong Zhang 2
Affiliations

Affiliations

  • 1 Neuroscience Care Unit, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 2 Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. brzhang@zju.edu.cn.
Abstract

It has been proposed that pyrethroid exposure contributes to the increasing prevalence of neurodegenerative diseases. However, the potential mechanisms remain unclear. The current study aimed to investigate the effects of the widely used pyrethroid bifenthrin on Parkinson's disease (PD) risk. Bifenthrin (1S-cis-bifenthrin, 1R-cis-bifenthrin, raceme) was administered to male Parkin-/- mice and C57BL/6 mice by oral gavage at a dose of 10 mg/kg bw/day for 28 days. Bifenthrin exposure significantly increased the time of pole climbing and decreased the period of rotarod running, indicating that bifenthrin decreased motor coordination in Parkin-/- mice, which was more evident by 1S-cis-bifenthrin. Furthermore, administration of bifenthrin induced obvious decreases in tyrosine hydroxylase (TH)+ cell count and the protein expression of TH. Increased protein of mitochondrial Autophagy LC3B and p62 was observed after exposure to bifenthrin. Increased iron deposition and protein expression of iron transport transferrin (Tf) and Transferrin Receptor 2 (TfR2) was detected. 1S-cis-bifenthrin bound with Tf, TfR2, and GPX4 with lower binding energies than 1R-cis-bifenthrin, resulting in stronger interactions with these proteins. These results show structure-dependent PD-like effects of bifenthrin on motor activity and coordination associated with the disturbed mitochondrial Autophagy and ferroptosis-related pathway. These data demonstrate that pyrethroid exposure increases the potential of Parkinson's-like symptoms via the Ferroptosis pathway in Parkin-/- mice that is more pronounced than in C57BL/6 mice, providing a prospective enantioselective toxic effect of environmental neurotoxins on PD risk.

Keywords

Bifenthrin; Ferroptosis; Mitochondrial autophagy; Parkinson; Parkin−/− mice.

Figures
Products