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Of Pesticides and Men: a California Story of Genes and Environment in Parkinson’s Disease

  • Susceptibility Factors in Environmental Health (B Ritz, Section Editor)
  • Published:
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Abstract

At the start of the postgenomics era, most Parkinson’s disease (PD) etiology cannot be explained by our knowledge of genetic or environmental factors alone. For more than a decade, we have explored gene–environment (GxE) interactions possibly responsible for the heterogeneity of genetic as well as environmental results across populations. We developed three pesticide exposure measures (ambient due to agricultural applications, home and garden use, and occupational use) in a large population-based case–control study of incident PD in central California. Specifically, we assessed interactions with genes responsible for pesticide metabolism (PON1); transport across the blood–brain barrier (ABCB1); pesticides interfering with or depending on dopamine transporter activity (DAT/SLC6A3) and dopamine metabolism (ALDH2); impacting mitochondrial function via oxidative/nitrosative stress (NOS1) or proteasome inhibition (SKP1); and contributing to immune dysregulation (HLA-DR). These studies established some specificity for pesticides’ neurodegenerative actions, contributed biologic plausibility to epidemiologic findings, and identified genetically susceptible populations.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Caudle WM, Guillot TS, Lazo CR, et al. Industrial toxicants and Parkinson’s disease. Neurotoxicology. 2012;33:178–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lill CM, Roehr JT, McQueen MB, et al. Comprehensive research synopsis and systematic meta-analyses in Parkinson’s disease genetics: the PDGene database. PLoS Genet. 2012;8:e1002548. This study provides an exhaustive summary of the status of PD genetics on more than seven million polymorphisms originating from GWAS or smaller-scale PD association studies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Goldman SM. Environmental toxins and Parkinson’s disease. Annu Rev Pharmacol Toxicol. 2014;54:141–64.

    Article  CAS  PubMed  Google Scholar 

  4. Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46:989–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Langston JW, Ballard P, Tetrud JW, et al. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219:979–80. This study was the first to describe a specific toxicant as acting selectively on dopamine neurons.

    Article  CAS  PubMed  Google Scholar 

  6. Barbeau A, Dallaire L, Buu NT, et al. Comparative behavioral, biochemical and pigmentary effects of MPTP, MPP+ and paraquat in Rana pipiens. Life Sci. 1985;37:1529–38.

    Article  CAS  PubMed  Google Scholar 

  7. Brown TP, Rumsby PC, Capleton AC, et al. Pesticides and Parkinson’s disease—is there a link? Environ Health Perspect. 2006;114:156–64.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol. 2013;9:445–54.

    Article  CAS  PubMed  Google Scholar 

  9. Pihlstrøm L, Toft M. Parkinson’s disease: what remains of the ‘missing heritability’? Mov Disord. 2011;26:1971–3.

    Article  PubMed  Google Scholar 

  10. Quadri M, Yang X, Cossu G, et al. An exome study of Parkinson’s disease in Sardinia, a Mediterranean genetic isolate. Neurogenetics. 2015;16:55–64.

    Article  CAS  PubMed  Google Scholar 

  11. Goldberg DW, Wilson JP, Knoblock CA, et al. An effective and efficient approach for manually improving geocoded data. Int J Health Geogr. 2008;7:60.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Rull RP, Ritz B. Historical pesticide exposure in California using pesticide use reports and land-use surveys: an assessment of misclassification error and bias. Environ Health Perspect. 2003;111:1582–9.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ritz B, Costello S. Geographic model and biomarker-derived measures of pesticide exposure and Parkinson’s disease. Ann N Y Acad Sci. 2006;1076:378–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Narayan S, Liew Z, Paul K, et al. Household organophosphorus pesticide use and Parkinson’s disease. Int J Epidemiol. 2013;42:1476–85.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Liew Z, Wang A, Bronstein J, et al. Job exposure matrix (JEM)-derived estimates of lifetime occupational pesticide exposure and the risk of Parkinson’s disease. Arch Environ Occup Health. 2014;69:241–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Przedborski S, Ischiropoulos H. Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson’s disease. Antioxid Redox Signal. 2005;7:685–93.

    Article  CAS  PubMed  Google Scholar 

  17. Martinez TN, Greenamyre JT. Toxin models of mitochondrial dysfunction in Parkinson’s disease. Antioxid Redox Signal. 2012;16:920–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cannon JR, Greenamyre JT. Neurotoxic in vivo models of Parkinson’s disease recent advances. Prog Brain Res. 2010;184:17–33.

    Article  CAS  PubMed  Google Scholar 

  19. Wang X-F, Li S, Chou AP, et al. Inhibitory effects of pesticides on proteasome activity: implication in Parkinson’s disease. Neurobiol Dis. 2006;23:198–205.

    Article  PubMed  CAS  Google Scholar 

  20. Zhou Y, Shie F-S, Piccardo P, et al. Proteasomal inhibition induced by manganese ethylene-bis-dithiocarbamate: relevance to Parkinson’s disease. Neuroscience. 2004;128:281–91.

    Article  CAS  PubMed  Google Scholar 

  21. Fitzmaurice AG, Rhodes SL, Cockburn M, et al. Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. Neurology. 2014;82:419–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Roede JR, Jones DP. Thiol-reactivity of the fungicide maneb. Redox Biol. 2014;2:651–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Johnson ME, Bobrovskaya L. An update on the rotenone models of Parkinson’s disease: their ability to reproduce the features of clinical disease and model gene-environment interactions. Neurotoxicology. 2015;46:101–16.

    Article  CAS  PubMed  Google Scholar 

  24. Pan-Montojo F, Schwarz M, Winkler C, et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep. 2012;2:898.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Van der Mark M, Brouwer M, Kromhout H, et al. Is pesticide use related to Parkinson disease? Some clues to heterogeneity in study results. Environ Health Perspect. 2012;120:340–7. This is a comprehensive systematic review of PD and exposure to pesticides that investigates methodological differences between studies and heterogeneity in results.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Barr DB, Olsson AO, Wong L-Y, et al. Urinary concentrations of metabolites of pyrethroid insecticides in the general U.S. population: National Health and Nutrition Examination Survey 1999–2002. Environ Health Perspect. 2010;118:742–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Glotfelty DE, Seiber JN, Liljedahl LA. Pesticides in fog. Nature. 1987;325:602–5.

    Article  CAS  PubMed  Google Scholar 

  28. USGS. Pesticides in the atmosphere—distribution, trends and governing factors. Sacromento: U.S. Geological Survey; 1995. p. 94–506.

    Google Scholar 

  29. Tiefenbacher J. Mapping the pesticide driftscape: theoretical patterns of the drift hazard. Geogr Environ Model. 1998;2:83–102.

    Google Scholar 

  30. Camann DE, Geno PW, Harding HJ, et al. A pilot study of pesticides in indoor air in relation to agricultural applications. In: Indoor air’93: proceedings of 6th International Conference on Indoor Air Quality and Climate. Helsinki: Finnish Society of Indoor Air Quality and Climate; 1993. p. 207–12.

    Google Scholar 

  31. CPDR. Summary of pesticide use report data. Sacramento: California Department of Pesticide Regulation; 2000.

    Google Scholar 

  32. Teschke K, Chow Y, Bartlett K, et al. Spatial and temporal distribution of airborne Bacillus thuringiensis var. kurstaki during an aerial spray program for gypsy moth eradication. Environ Health Perspect. 2001;109:47–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Baker LW, Fitzell DL, Seiber JN, et al. Ambient air concentrations of pesticides in California. Environ Sci Technol. 1996;30:1365–8.

    Article  CAS  Google Scholar 

  34. Majewski MS, Foreman WT, Goolsby DA, et al. Airborne pesticide residues along the Mississippi River. Environ Sci Technol. 1998;32:3689–98.

    Article  CAS  Google Scholar 

  35. Harnly M, McLaughlin R, Bradman A, et al. Correlating agricultural use of organophosphates with outdoor air concentrations: a particular concern for children. Environ Health Perspect. 2005;113:1184–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wofford P, Segawa R, Schreider J, et al. Community air monitoring for pesticides. Part 3: using health-based screening levels to evaluate results collected for a year. Environ Monit Assess. 2014;186:1355–70.

    Article  CAS  PubMed  Google Scholar 

  37. Ward MH, Colt JS, Metayer C, et al. Residential exposure to polychlorinated biphenyls and organochlorine pesticides and risk of childhood leukemia. Environ Health Perspect. 2009;117:1007–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jones BC, Huang X, Mailman RB, et al. The perplexing paradox of paraquat: the case for host-based susceptibility and postulated neurodegenerative effects. J Biochem Mol Toxicol. 2014;28:191–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Costello S, Cockburn M, Bronstein J, et al. Parkinson’s disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol. 2009;169:919–26.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kelada SNP, Checkoway H, Kardia SLR, et al. 5′ and 3′ region variability in the dopamine transporter gene (SLC6A3), pesticide exposure and Parkinson’s disease risk: a hypothesis-generating study. Hum Mol Genet. 2006;15:3055–62. doi:10.1093/hmg/ddl247.

    Article  CAS  PubMed  Google Scholar 

  41. Kelada SN, Costa-Mallen P, Checkoway H, et al. Dopamine transporter (SLC6A3) 5′ region haplotypes significantly affect transcriptional activity in vitro but are not associated with Parkinson’s disease. Pharmacogenet Genomics. 2005;15:659–68.

    Article  CAS  PubMed  Google Scholar 

  42. Drgon T, Lin Z, Wang G-J, et al. Common human 5′ dopamine transporter (SLC6A3) haplotypes yield varying expression levels in vivo. Cell Mol Neurobiol. 2006;26:875–89.

    Article  CAS  PubMed  Google Scholar 

  43. Ritz BR, Manthripragada AD, Costello S, et al. Dopamine transporter genetic variants and pesticides in Parkinson’s disease. Environ Health Perspect. 2009;117:964–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Droździk M, Białecka M, Myśliwiec K, et al. Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson’s disease. Pharmacogenetics. 2003;13:259–63.

    Article  PubMed  Google Scholar 

  45. Zschiedrich K, König IR, Brüggemann N, et al. MDR1 variants and risk of Parkinson disease. Association with pesticide exposure? J Neurol. 2009;256:115–20.

    Article  PubMed  Google Scholar 

  46. Dutheil F, Beaune P, Tzourio C, et al. Interaction between ABCB1 and professional exposure to organochlorine insecticides in Parkinson disease. Arch Neurol. 2010;67:739–45.

    PubMed  Google Scholar 

  47. Narayan S, Sinsheimer JS, Paul KC, et al. Genetic variability in ABCB1, occupational pesticide exposure, and Parkinson’s disease. Environ Res. 2015. Accepted A.

  48. Lee P-C, Rhodes SL, Sinsheimer JS, et al. Functional paraoxonase 1 variants modify the risk of Parkinson’s disease due to organophosphate exposure. Environ Int. 2013;56:42–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hancock DB, Martin ER, Vance JM, et al. Nitric oxide synthase genes and their interactions with environmental factors in Parkinson’s disease. Neurogenetics. 2008;9:249–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Paul KC, Sinsheimer JS, Rhodes SL, et al. Organophosphate pesticide exposures, nitric oxide synthase gene variants, and gene-pesticide interactions in a case-control study of Parkinson’s Disease, California (USA). Environ Health Perspect. 2015. doi:10.1289/ehp.1408976. Published Online First.

    PubMed  Google Scholar 

  51. Rhodes SL, Fitzmaurice AG, Cockburn M, et al. Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson׳s disease. Environ Res. 2013;126:1–8.

    Article  CAS  PubMed  Google Scholar 

  52. Kannarkat GT, Cook DA, Lee J-K, et al. Common genetic variant association with altered HLA expression, synergy with pyrethroid exposure, and risk for Parkinson’s disease: an observational and case–control study. NPJ Park Dis. 2015;1:15002.

    Article  Google Scholar 

  53. Shimizu K, Matsubara K, Ohtaki K, et al. Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture. Neurosci Res. 2003;46:523–32.

    Article  CAS  PubMed  Google Scholar 

  54. Richardson JR, Quan Y, Sherer TB, et al. Paraquat neurotoxicity is distinct from that of MPTP and rotenone. Toxicol Sci. 2005;88:193–201.

    Article  CAS  PubMed  Google Scholar 

  55. Rappold PM, Cui M, Chesser AS, et al. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci U S A. 2011;108:20766–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Van de Giessen EM, de Win MML, Tanck MWT, et al. Striatal dopamine transporter availability associated with polymorphisms in the dopamine transporter gene SLC6A3. J Nucl Med. 2009;50:45–52.

    Article  PubMed  CAS  Google Scholar 

  57. Schinkel AH, Smit JJ, van Tellingen O, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77:491–502.

    Article  CAS  PubMed  Google Scholar 

  58. Bain LJ, McLachlan JB, LeBlanc GA. Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein. Environ Health Perspect. 1997;105:812–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lecoeur S, Videmann B, Mazallon M. Effect of organophosphate pesticide diazinon on expression and activity of intestinal P-glycoprotein. Toxicol Lett. 2006;161:200–9.

    Article  CAS  PubMed  Google Scholar 

  60. Sreeramulu K, Liu R, Sharom FJ. Interaction of insecticides with mammalian P-glycoprotein and their effect on its transport function. Biochim Biophys Acta. 2007;1768:1750–7.

    Article  CAS  PubMed  Google Scholar 

  61. Kimchi-Sarfaty C, Oh JM, Kim I-W, et al. A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:525–8.

    Article  CAS  PubMed  Google Scholar 

  62. Cascorbi I, Gerloff T, Johne A, et al. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001;69:169–74.

    Article  CAS  PubMed  Google Scholar 

  63. Hitzl M, Schaeffeler E, Hocher B, et al. Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1). Pharmacogenetics. 2004;14:309–18.

    Article  CAS  PubMed  Google Scholar 

  64. Wang A, Cockburn M, Ly TT, et al. The association between ambient exposure to organophosphates and Parkinson’s disease risk. Occup Environ Med. 2014;71:275–81. doi:10.1136/oemed-2013-101394.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Davies HG, Richter RJ, Keifer M, et al. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet. 1996;14:334–6.

    Article  CAS  PubMed  Google Scholar 

  66. Richter RJ, Jarvik GP, Furlong CE. Paraoxonase 1 (PON1) status and substrate hydrolysis. Toxicol Appl Pharmacol. 2009;235:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Costa LG, Cole TB, Furlong CE. Polymorphisms of paraoxonase (PON1) and their significance in clinical toxicology of organophosphates. J Toxicol Clin Toxicol. 2003;41:37–45.

    Article  CAS  PubMed  Google Scholar 

  68. O’Leary KA, Edwards RJ, Town MM, et al. Genetic and other sources of variation in the activity of serum paraoxonase/diazoxonase in humans: consequences for risk from exposure to diazinon. Pharmacogenet Genomics. 2005;15:51–60.

    Article  PubMed  Google Scholar 

  69. Liu Y-L, Yang J, Zheng J, et al. Paraoxonase 1 polymorphisms L55M and Q192R were not risk factors for Parkinson’s disease: a HuGE review and meta-analysis. Gene. 2012;501:188–92.

    Article  CAS  PubMed  Google Scholar 

  70. Taylor MC, Le Couteur DG, Mellick GD, et al. Paraoxonase polymorphisms, pesticide exposure and Parkinson’s disease in a Caucasian population. J Neural Transm. 2000;107:979–83.

    Article  CAS  PubMed  Google Scholar 

  71. Dick FD, De Palma G, Ahmadi A, et al. Gene-environment interactions in Parkinsonism and Parkinson’s disease: the Geoparkinson study. Occup Environ Med. 2007;64:673–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kavya R, Saluja R, Singh S, et al. Nitric oxide synthase regulation and diversity: implications in Parkinson’s disease. Nitric Oxide. 2006;15:280–94.

    Article  CAS  PubMed  Google Scholar 

  73. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39:889–909.

    Article  CAS  PubMed  Google Scholar 

  74. Lukaszewicz-Hussain A. Role of oxidative stress in organophosphate insecticide toxicity—short review. Pestic Biochem Physiol. 2010;98:145–50.

    Article  CAS  Google Scholar 

  75. Licinio J, Prolo P, McCann SM, et al. Brain iNOS: current understanding and clinical implications. Mol Med Today. 1999;5:225–32.

    Article  CAS  PubMed  Google Scholar 

  76. Hague S, Peuralinna T, Eerola J, et al. Confirmation of the protective effect of iNOS in an independent cohort of Parkinson disease. Neurology. 2004;62:635–6.

    Article  CAS  PubMed  Google Scholar 

  77. Huerta C, Sánchez-Ferrero E, Coto E, et al. No association between Parkinson’s disease and three polymorphisms in the eNOS, nNOS, and iNOS genes. Neurosci Lett. 2007;413:202–5.

    Article  CAS  PubMed  Google Scholar 

  78. Levecque C, Elbaz A, Clavel J, et al. Association between Parkinson’s disease and polymorphisms in the nNOS and iNOS genes in a community-based case-control study. Hum Mol Genet. 2003;12:79–86.

    Article  CAS  PubMed  Google Scholar 

  79. Schulte C, Sharma M, Mueller JC, et al. Comprehensive association analysis of the NOS2A gene with Parkinson disease. Neurology. 2006;67:2080–2.

    Article  CAS  PubMed  Google Scholar 

  80. Przedborski S, Jackson-Lewis V, Yokoyama R, et al. Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci U S A. 1996;93:4565–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Liberatore GT, Jackson-Lewis V, Vukosavic S, et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med. 1999;5:1403–9.

    Article  CAS  PubMed  Google Scholar 

  82. Hunot S, Boissière F, Faucheux B, et al. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience. 1996;72:355–63.

    Article  CAS  PubMed  Google Scholar 

  83. Tsang AHK, Lee Y-I, Ko HS, et al. S-nitrosylation of XIAP compromises neuronal survival in Parkinson’s disease. Proc Natl Acad Sci U S A. 2009;106:4900–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Michel TM, Käsbauer L, Gsell W, et al. Aldehyde dehydrogenase 2 in sporadic Parkinson’s disease. Parkinsonism Relat Disord. 2014;20:S68–72.

    Article  PubMed  Google Scholar 

  85. Goldstein DS, Sullivan P, Cooney A, et al. Rotenone decreases intracellular aldehyde dehydrogenase activity: implications for the pathogenesis of Parkinson’s disease. J Neurochem. 2015;133:14–25.

    Article  CAS  PubMed  Google Scholar 

  86. Chiu C-C, Yeh T-H, Lai S-C, et al. Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. Exp Neurol. 2015;263:244–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Fitzmaurice AG, Rhodes SL, Lulla A, et al. Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease. Proc Natl Acad Sci U S A. 2013;110:636–41. doi:10.1073/pnas.1220399110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yoshii SR, Kishi C, Ishihara N, et al. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem. 2011;286:19630–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ebrahimi-Fakhari D, Wahlster L, McLean PJ. Protein degradation pathways in Parkinson’s disease: curse or blessing. Acta Neuropathol. 2012;124:153–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Licker V, Kövari E, Hochstrasser DF, et al. Proteomics in human Parkinson’s disease research. J Proteome. 2009;73:10–29.

    Article  CAS  Google Scholar 

  91. Wakabayashi K, Tanji K, Odagiri S, et al. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol Neurobiol. 2013;47:495–508.

    Article  CAS  PubMed  Google Scholar 

  92. Chen Q, Thorpe J, Keller JN. Alpha-synuclein alters proteasome function, protein synthesis, and stationary phase viability. J Biol Chem. 2005;280:30009–17.

    Article  CAS  PubMed  Google Scholar 

  93. Betarbet R, Sherer TB, Greenamyre JT. Ubiquitin-proteasome system and Parkinson’s diseases. Exp Neurol. 2005;191 Suppl 1:S17–27.

    Article  CAS  PubMed  Google Scholar 

  94. Chou AP, Li S, Fitzmaurice AG, et al. Mechanisms of rotenone-induced proteasome inhibition. Neurotoxicology. 2010;31:367–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chou AP, Maidment N, Klintenberg R, et al. Ziram causes dopaminergic cell damage by inhibiting E1 ligase of the proteasome. J Biol Chem. 2008;283:34696–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wills J, Credle J, Oaks AW, et al. Paraquat, but not maneb, induces synucleinopathy and tauopathy in striata of mice through inhibition of proteasomal and autophagic pathways. PLoS ONE. 2012;7:e30745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bai C, Sen P, Hofmann K, et al. SKP1 connects cell cycle regulators to the ubiquitin proteolysis machinery through a novel motif, the F-box. Cell. 1996;86:263–74.

    Article  CAS  PubMed  Google Scholar 

  98. Grünblatt E, Mandel S, Jacob-Hirsch J, et al. Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion/cellular matrix and vesicle trafficking genes. J Neural Transm. 2004;111:1543–73.

    Article  PubMed  CAS  Google Scholar 

  99. Fishman-Jacob T, Reznichenko L, Youdim MBH, et al. A sporadic Parkinson disease model via silencing of the ubiquitin-proteasome/E3 ligase component SKP1A. J Biol Chem. 2009;284:32835–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Esa AH, Warr GA, Newcombe DS. Immunotoxicity of organophosphorus compounds. Modulation of cell-mediated immune responses by inhibition of monocyte accessory functions. Clin Immunol Immunopathol. 1988;49:41–52.

    Article  CAS  PubMed  Google Scholar 

  101. Freire C, Koifman S. Pesticide exposure and Parkinson’s disease: epidemiological evidence of association. Neurotoxicology. 2012;33:947–71.

    Article  CAS  PubMed  Google Scholar 

  102. Dardiotis E, Xiromerisiou G, Hadjichristodoulou C, et al. The interplay between environmental and genetic factors in Parkinson’s disease susceptibility: the evidence for pesticides. Toxicology. 2013;307:17–23. doi:10.1016/j.tox.2012.12.016.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was funded in part by NIEHS Grants R01-ES010544, U54-ES012078, P01ES016732; the Michael J. Fox Foundation; The Parkinson Alliance, and the American Parkinson Disease Association. The funding organizations had no role in the design, conduct, interpretation, or publication of this work. Kim Paul also reports support from the Burroughs Wellcome Fund.

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Authors and Affiliations

  1. Department of Epidemiology, Fielding School of Public Health, UCLA, 650 Charles Young Dr South, Los Angeles, CA, 90095-1772, USA

    Beate R. Ritz & Kimberly C. Paul

  2. Center for Occupational and Environmental Health, UCLA, Los Angeles, CA, USA

    Beate R. Ritz

  3. Department of Neurology, Geffen School of Medicine, UCLA, 710 Westwood Plaza, Los Angeles, CA, 90095, USA

    Beate R. Ritz & Jeff M. Bronstein

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  1. Beate R. Ritz
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Correspondence to Beate R. Ritz.

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BR Ritz, KC Paul, and JM Bronstein declare that they have no conflict of interest.

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Written informed consent was obtained from all enrolled subjects. All procedures using animals were approved by the UCLA Human Subjects Committee.

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This article is part of the Topical Collection on Susceptibility Factors in Environmental Health

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Ritz, B.R., Paul, K.C. & Bronstein, J.M. Of Pesticides and Men: a California Story of Genes and Environment in Parkinson’s Disease. Curr Envir Health Rpt 3, 40–52 (2016). https://doi.org/10.1007/s40572-016-0083-2

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