Research On The Role And Underlying Mechanism Of Pesticides Composition In Parkinson's Disease

Objective: Parkinson's disease(PD)is one of the most common neurodegenerative diseases.The pathogenesis of PD has not yet been completely elucidated.Evidence suggested that environmental and genetic factors contributed to the onset and progression of PD.Pesticides are a class of environmental toxins,which were reported to be associated with increased risk of PD.However,the identification of the specific pesticides associated with PD in Chinese population and the underlying mechanism are lacking.Methods: A total of 90 patients with PD and their healthy spouses from urban and rural areas were included in this case-control study.Serum samples were collected.The level of serum pesticides(16 organochlorine pesticide and 3organophosphorus pesticide)was detected by Gas Chromatography-Mass Spectrometer(GC-MS)method.The difference of serum level of pesticides was investigated between PD patients and controls.The specific pesticides associated with risk of PD were also identified.We also analyzed the association between pesticides and clinical features of PD patients.In addition,several single nucleotide polymorphisms(SNP)were detected and the pesticide-gene interaction was also analyzed.Based on the previous study,we further investigated the underlying mechanism of pesticides asscociated with increased risk of PD.Cell viability of neuronal SH-SY5 Y cells induced by the pesticides were tested using CCK-8(cell counting kit-8)method.The production of reactive oxygen species(ROS)in neuronal cells induced by different concentrations of pesticides was detected with CM-H2 DCFDA probe.Changes of mitochondrial membrane potential in neuronal cells upon the pesticides stimulation were detected with JC-10 probe.Moreover,western blot analysis was used to investigate whether the pesticides were able to induce ?-synuclein aggregation in neuronal cells.Results: In this cross-sectional research,we found that serum levels of organochlorine pesticides,such as ?-hexachlorocyclohexane(?-HCH),?-hexachlorocyclohexane(?-HCH),?-hexachlorocyclohexane(?-HCH),propanil,heptachlor,dieldrin and p,p?-Dichlorodiphenyltrichloroethane(p,p?-DDE)were higher in patients with PD compared with their spouse controls.?-HCH and propanil were found to be associated with increased risk of PD.Serum levels of dieldrin were associated with HAMD scores in PD patients.Moreover,our data suggested the distribution of genotypes and alleles were not significantly different between PD patients and controls.Serum levels of some pesticides may differ in people carrying different genotypes,for example,genotypes in MAPT rs16940758 and ABCB1 rs1045642.Moreover,the interaction between ?-HCH and SNCA rs11931074,as well as the interaction between ?-HCH and MAPT rs16940758 significantly increased the risk of PD.We further investigated the underlying mechanism of ?-HCH and propanil which were associated with increased risk of PD.Cell viability of neuronal SH-SY5 Y cells was decreased upon ?-HCH and propanil stimulation in a dosedependent manner.The effective concentration of ?-HCH and propanil to induce about 25% and 50% decrease in cell viability of SH-SY5 Y cells was calculated to be about 700 ?M and 1000 ?M in ?-HCH and about 100 ?M and200 ?M in propanil respectively.Exposure to ?-HCH and propanil increased the level of oxidative stress in neuronal cells in a dose-dependent manner.The mitochondrial membrane potential of neuronal cells was also decreased upon?-HCH and propanil stimulation.Moreover,the aggregation of ?-synuclein of SH-SY5 Y cells was induced by propanil stimulation,whereas ?-HCH had no significant effect on ?-synuclein aggregation.Conclusions: These data suggested that organochlorine pesticides and the interaction between organochlorine pesticides and genes were associated with increased risk of PD.Organochlorine pesticides ?-HCH and propanil induced the decrease of cell viability and mitochondrial membrane potential,as well as the increase of oxidative stress in SH-SY5 Y cells.The aggregation of ?-synuclein of SH-SY5 Y cells was also induced by propanil,rather than ?-HCH.This study may provide insights into understanding the role of organochlorine pesticides and gene interaction in PD and the underlying mechanism,and provide some clues for the prevention of Parkinson's disease and the rational use of pesticides in China.