title: Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson׳s disease.
abstract: Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin-proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. Our goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. We assessed 26S UPS activity in SK-N-MC(u) cells by fluorescence. We recruited idiopathic PD cases (n=360) and population-based controls (n=816) from three counties in California with considerable commercial agriculture. We determined ambient pesticide exposure by our validated GIS-based model utilizing residential and workplace address histories. We limited effect measure modification assessment to Caucasians (287 cases, 453 controls). Eleven of 28 pesticides we screened inhibited 26S UPS activity at 10 µM. Benomyl, cyanazine, dieldrin, endosulfan, metam, propargite, triflumizole, and ziram were associated with increased PD risk. We estimated an odds ratio of 2.14 (95% CI: 1.42, 3.22) for subjects with ambient exposure to any UPS-inhibiting pesticide at both residential and workplace addresses; this association was modified by genetic variation in the s-phase kinase-associated protein 1 gene (SKP1; interaction p-value=0.005). Our results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures.
authors.affiliation: Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, United States.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Rhodes
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Fitzmaurice
authors.forename: Myles
authors.initials: M
authors.lastname: Cockburn
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Bronstein
authors.forename: Janet S
authors.initials: JS
authors.lastname: Sinsheimer
authors.forename: Beate
authors.initials: B
authors.lastname: Ritz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D004781:Environmental Exposure / Q000009:adverse effects; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics*; D010575:Pesticides / Q000633:toxicity*; D061988:Proteasome Inhibitors / Q000633:toxicity*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics*; D025801:Ubiquitin / Q000037:antagonists & inhibitors
chemical_list: D010575:Pesticides; D061988:Proteasome Inhibitors; D044786:S-Phase Kinase-Associated Proteins; C097351:SKP1 protein, human; D025801:Ubiquitin
keywords: Epidemiology; Gene–environment interaction; Parkinson′s disease; Pesticides; Ubiquitin–proteasome system