Paraquat exposure induces Parkinsonism by altering lipid profile and evoking neuroinflammation in the midbrain. (November 2022)

• Record Type: Journal Article
• Authors: Tong, Tong; Duan, Weixia; Xu, Yudong; Hong, Huihui; Xu, Jia; Fu, Guanyan; Wang, Xue; Yang, Lingling; Deng, Ping; Zhang, Jingjing; He, Haotian; Mao, Gaofeng; Lu, Yuanqiang; Lin, Xiqin; Yu, Zhengping; Pi, Huifeng; Cheng, Yong; Xu, Shangcheng; Zhou, Zhou
• Is Part Of: Environment international. Volume 169(2022)
• Publication Date: 2022-11
• Subjects: Paraquat -- Parkinsonism -- Lipidome -- Inflammatory cytokines -- Neuroinflammation; AcCa Acyl carnitine -- AD Alzheimer's disease -- Cer Ceramides -- CerG3GNAc1 Simple Glc series -- ChE Cholesterol ester -- CL Cardiolipin -- CoA Coenzyme A -- DG Diglyceride -- GD1a/GD2 Gangliosides -- LCFA Long chain fatty acid -- LPC Lysophosphatidylcholine -- LPE Lysophosphatidylethanolamine -- LPG Lysophosphatidylglycerol -- LPI Lysophosphatidylinositol -- LPS Lysophosphatidylserine -- MGDG Monogalactosyldiacylglycerol -- MGMG Monogalactosylmonoacylglycerol -- MTBE Methyl tert-butyl ether -- OAHFA (O-acyl)-1-hydroxy fatty acid -- OPLS-DA Orthogonal partial least-squares-discriminant analysis -- PC Phosphatidylcholine -- PCA Principal component analysis -- PD Parkinson's disease -- PE Phosphatidylethanolamine -- PFA Paraformaldehyde -- PG Phosphatidylglycerol -- PhSM Phytosphingosine -- PI/PIP Phosphatidylinositol -- PLS-DA Partial least-squares-discriminant analysis -- PQ Paraquat -- PS Phosphatidylserine -- RF Radiofrequency -- RSD Relative standard deviation -- SM Sphingomyelin -- SPT Serine by serine palmitoyl transferase -- SNpc Substantia nigra pars compacta -- SQDG Sulfoquinovosyldiacylglycerol -- SQMG Sulfoquinovosylmonoacylglycerol -- TG Triglyceride -- TH Tyrosine hydroxylase -- UHPLC-HRMS Ultrahigh-performance liquid chromatography coupled with high-resolution mass spectrometry -- VLCFA very long chain fatty acid -- WE Wax esters; Environmental protection -- Periodicals; Environmental health -- Periodicals; Environmental monitoring -- Periodicals; Environmental Monitoring -- Periodicals; Environnement -- Protection -- Périodiques; Hygiène du milieu -- Périodiques; Environnement -- Surveillance -- Périodiques; Environmental health; Environmental monitoring; Environmental protection; Periodicals; 333.705
• DOI: 10.1016/j.envint.2022.107512
• Languages: English
• ISSNs: 0160-4120

Abstract

Highlights: PQ exposure perturbs lipid metabolism and elevates pro-inflammatory lipids in the midbrain; PQ exposure provokes neuroinflammation in the midbrain and induces an intense systemic inflammation in humans; Elevated pro-inflammatory lipids and cytokines correlate with motor deficits after PQ exposure. Abstract: Paraquat (PQ) is the most widely used herbicide in the world and a well-known potent neurotoxin for humans. PQ exposure has been linked to increase the risk of Parkinson's disease (PD). However, the mechanism underlying its neurotoxic effects in PD pathogenesis is unclear. In our present study, C57BL/6J mice treated with PQ manifested severe motor deficits indicated by the significant reductions in suspension score, latency to fall from rotarod, and grip strength at 8 weeks after PQ exposure. Pathological hallmarks of Parkinsonism in the midbrain such as dopaminergic neuron loss, increased α-synuclein protein, and dysregulated PD-related genes were observed. Non-targeted lipidome analysis demonstrated that PQ exposure alters lipid profile and abundance, increases pro-inflammatory lipids.27 significantly altered subclasses of lipids belonged to 6 different lipid categories. Glycerophospholipids, sphingolipids, and glycerides were the most abundant lipids. Abundance of pro-inflammatory lipids such as Cer, LPC, LPS, and LPI was significantly increased in the midbrain. mRNA expressions of genes regulating ceramide biosynthesis in the midbrain were markedly up-regulated. Moreover, PQ exposure increased serum pro-inflammatory cytokines and provoked neuroinflammation in the midbrain. Pro-inflammatory lipids and cytokines in the midbrain were positively correlated with motor deficits. PQ poisoning in humans significantly also elevated serum pro-inflammatory cytokines and induced an intense systemic inflammation. In summary, we presented initial investigations of PQ induced molecular events related to the PD pathogenesis, capturing aspects of disturbed lipid metabolism, neuroinflammation, impairment of dopaminergic neurons in the midbrain, and an intense systemic inflammation. These neurotoxic effects of PQ exposure may mechanistically contribute to the pathogenesis of PQ induced Parkinsonism. Results of this study also strongly support the hypothesis that ever-increasing prevalence of Parkinson's disease is etiologically linked to the health risk of exposure to neurotoxic environmental pollutants.