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

详细信息    查看全文

• 作者：Shannon L. Rhodes ; Arthur G. Fitzmaurice ; Myles Cockburn ; Jeff M. Bronstein ; Janet S. Sinsheimer ; Beate Ritz
• 关键词：Epidemiology ; Gene&ndash ; environment interaction ; Parkinson&prime ; s disease ; Pesticides ; Ubiquitin&ndash ; proteasome system
• 刊名：Environmental Research
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：126
• 期：Complete
• 页码：1-8
• 全文大小：426 K

文摘

Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson¡äs 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 ¦ÌM. 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.