Parkinson’s disease risk from ambient exposure to pesticides

Abstract

Due to the heavy and expanding agricultural use of neurotoxic pesticides suspected to affect dopaminergic neurons, it is imperative to closely examine the role of pesticides in the development of Parkinson’s disease (PD). We focus our investigation on pesticide use in California’s heavily agricultural central valley by utilizing a unique pesticide use reporting system. From 2001 to 2007, we enrolled 362 incident PD cases and 341 controls living in the Central Valley of California. Employing our geographic information system model, we estimated ambient exposures to the pesticides ziram, maneb, and paraquat at work places and residences from 1974 to 1999. At workplaces, combined exposure to ziram, maneb, and paraquat increased risk of PD three-fold (OR: 3.09; 95% CI: 1.69, 5.64) and combined exposure to ziram and paraquat, excluding maneb exposure, was associated with a 80% increase in risk (OR:1.82; 95% CI: 1.03, 3.21). Risk estimates for ambient workplace exposure were greater than for exposures at residences and were especially high for younger onset PD patients and when exposed in both locations. Our study is the first to implicate ziram in PD etiology. Combined ambient exposure to ziram and paraquat as well as combined ambient exposure to maneb and paraquat at both workplaces and residences increased PD risk substantially. Those exposed to ziram, maneb, and paraquat together experienced the greatest increase in PD risk. Our results suggest that pesticides affecting different mechanisms that contribute to dopaminergic neuron death may act together to increase the risk of PD considerably.

Pesticides and Parkinson’s Disease: is It in Your genes?

“…We studied two groups of pesticides; pesticides that had previously been implicated in PD and a second group that we found to alter a biological pathway believed to be involved in the pathogenesis of PD (e.g., ubiquitin proteasome system [UPS]). Using this approach, we confirmed the association of paraquat with PD (especially if co-exposed to maneb or ziram) and identified previously unrecognized pesticides that increase the risk of PD [11][12][13][14][15]. For example, ziram, a dithiocarbamate fungicide, was found to inhibit E1 ligase of the UPS and selectively injure dopaminergic neurons in primary cultures and in mice [16].…”

“…For example, ziram, a dithiocarbamate fungicide, was found to inhibit E1 ligase of the UPS and selectively injure dopaminergic neurons in primary cultures and in mice [16]. Exposure to ziram in our PEG study subjects led to a 300% increase (odds ratio: 3) in risk of developing PD [12]. As a reference for effect size, the cumulative genetic risk for those with all the bad polymorphisms identified in multiple GWAS adds up to an odds ratio of only 2.51 [5].…”

Aldehyde dehydrogenase inhibition as a pathogenic mechanism in Parkinson disease

“…Subject recruitment methods and case definition criteria have been described in detail (42). Pesticide exposure assessments were performed using a geographic information system-based computer model incorporating Pesticide Use Reporting forms that have been mandated by the California Department of Pesticide Regulation since 1974 and provide information on the location, date, and amount of pesticide in each commercial application (43,(48)(49)(50). Geocoded lifetime occupational and residential addresses were considered separately.…”

“…Notably, this model only estimates relative ambient exposures and does not take into account other routes of exposures such as occupational handling of pesticides and drinking well water, both associated with increased risk of PD, which could exacerbate the estimated risk even further (39)(40)(41). We have used this method to report positive associations between PD onset and exposures to ziram, maneb, and paraquat (42,43). In a logistic regression model that includes our benomyl variable and a variable for the combination of ziram, maneb, and paraquat, the benomyl association remains robust and the confidence interval excludes the null.…”

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

“…A new zebra fish study [147] used the fungicide ziram (zinc bis(dithiocarbamate)), an inhibitor of ubiquitin E1 ligase of the UPS [148][149][150], which is linked to increased risk of PD [151]. Inhibition of E1 ligase has been shown to damage dopaminergic neurons preferentially and to increase α-synuclein levels and synaptic currents [150,152].…”