Chronic cadmium exposure induces Parkinson-like syndrome by eliciting sphingolipid disturbance and neuroinflammation in the midbrain of C57BL/6J mice.

Cadmium (Cd) is known as a widespread environmental neurotoxic pollutant. Cd exposure is recently recognized as an etiological factor of Parkinson's disease (PD) in humans. However, the mechanism underlying Cd neurotoxicity in relation to Parkinsonism pathogenesis is unclear. In our present study, C57BL/6 J mice were exposed to 100 mg/L CdCl2 in drinking water for 8 weeks. It was found Cd exposure caused motor deficits, decreased DA neurons and induced neuropathological changes in the midbrain. Non-targeted lipidomic analysis uncovered that Cd exposure altered lipid profile, increased the content of proinflammatory sphingolipid ceramides (Cer), sphingomyelin (SM) and ganglioside (GM3) in the midbrain. In consistency with increased proinflammatory lipids, the mRNA levels of genes encoding sphingolipids biosynthesis in the midbrain were dysregulated by Cd exposure. Neuroinflammation in the midbrain was evinced by the up-regulation of proinflammatory cytokines at mRNA and protein levels. Blood Cd contents and lipid metabolites in Parkinsonism patients by ICP-MS and LC-MS/MS analyses demonstrated that elevated blood Cd concentration and proinflammatory lipid metabolites were positively associated with the score of Unified Parkinson's Disease Rating Scale (UPDRS). 3 ceramide metabolites in the blood showed good specificity as the candidate biomarkers to predict and monitor Parkinsonism and Cd neurotoxicity (AUC>0.7, p < 0.01). In summary, our present study uncovered that perturbed sphingomyelin lipid metabolism is related to the Parkinsonism pathogenesis and Cd neurotoxicity, partially compensated for the deficiency in particular metabolic biomarkers for Parkinsonism in relation to Cd exposure, and emphasized the necessity of reducing Cd exposure at population level.

Paraquat exposure induces Parkinsonism by altering lipid profile and evoking neuroinflammation in the midbrain.

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.