Pesticides that inhibit the ubiquitin–proteasome system: Effect measure modification by genetic variation in SKP1 in Parkinson׳s disease

Autor: Arthur G. Fitzmaurice, Janet S. Sinsheimer, Jeff M. Bronstein, Shannon L. Rhodes, Beate Ritz, Myles Cockburn
Rok vydání: 2013
Předmět:
Male
Secondary
Aging
Candidate gene
Parkinson's disease
Epidemiology
Parkinson′s disease
Rural Health
Neurodegenerative
Pharmacology
Toxicology
Biochemistry
chemistry.chemical_compound
80 and over
2.1 Biological and endogenous factors
Aetiology
S-Phase Kinase-Associated Proteins
General Environmental Science
Aged
80 and over
Genetics
education.field_of_study
Parkinson Disease
Middle Aged
Biological Sciences
Ubiquitin-proteasome system
Neurological
Female
Proteasome Inhibitors
Adult
Population
Biology
Article
Genetic variation
medicine
Humans
Climate-Related Exposures and Conditions
Parkinson Disease
Secondary
Pesticides
Gene–environment interaction
education
Aged
Ziram
Ubiquitin
Neurosciences
Genetic Variation
Environmental Exposure
Odds ratio
Pesticide
medicine.disease
Gene-environment interaction
Brain Disorders
Proteasome
chemistry
Case-Control Studies
Ubiquitin–proteasome system
Chemical Sciences
Environmental Sciences
Zdroj: Environmental Research. 126:1-8
ISSN: 0013-9351
Popis: 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.
Databáze: OpenAIRE
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