Genetic modification of the association of paraquat and Parkinson's disease

The Parkinson's Institute, Sunnyvale, California, USA. .
Movement Disorders (Impact Factor: 5.68). 11/2012; 27(13). DOI: 10.1002/mds.25216
Source: PubMed


Paraquat is one of the most widely used herbicides worldwide. It produces a Parkinson's disease (PD) model in rodents through redox cycling and oxidative stress (OS) and is associated with PD risk in humans. Glutathione transferases provide cellular protection against OS and could potentially modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione S-transferase M1 (GSTM1) or T1 (GSTT1). Eighty-seven PD subjects and 343 matched controls were recruited from the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. PD was confirmed by in-person examination. Paraquat use and covariates were determined by interview. We genotyped subjects for homozygous deletions of GSTM1 (GSTM1*0) and GSTT1 (GSTT1*0) and tested interaction between paraquat use and genotype using logistic regression. Two hundred and twenty-three (52%) subjects had GSTM1*0, 95 (22%) had GSTT1*0, and 73 (17%; all men) used paraquat. After adjustment for potential confounders, there was no interaction with GSTM1. In contrast, GSTT1 genotype significantly modified the association between paraquat and PD. In men with functional GSTT1, the odds ratio (OR) for association of PD with paraquat use was 1.5 (95% confidence interval [CI]: 0.6-3.6); in men with GSTT1*0, the OR was 11.1 (95% CI: 3.0-44.6; P interaction: 0.027). Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. GSTT1*0 is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat. © 2012 Movement Disorder Society.

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Available from: Aaron Blair, Mar 31, 2015
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    • "Because of the absence of non-cancer disease registries in the United States, many of the health outcomes for which adverse effects have been linked to agricultural exposures could not have been studied using another design. For example, pesticides have been associated with retinal degeneration [Kamel et al., 2000], non-malignant respiratory disease [Hoppin et al., 2006; Hoppin et al., 2014], thyroid disease [Goldner et al., 2010], depression [Beseler et al., 2006], diabetes [Montgomery et al., 2008; Starling et al., 2014], Parkinson's disease [Tanner et al., 2011; Goldman et al., 2012], and amyotrophic lateral sclerosis [Kamel et al., 2012]. Exposure to solvents was also studied in relation to fertility [Sallmén et al., 2006]. "
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    • "Both variants confer lack of enzyme activity. Goldman et al. (2012) showed that individuals homozygous for GSTT1 * 0 and exposed to paraquat had an odds ratio for PD risk of 11.1 compared to people with GSTT1 and exposed to paraquat with an OR of 1.5. No additional risk for GSTM1 or GSTM1 * 0 and exposure to PQ was reported in the study. "
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    Full-text · Article · Sep 2014 · Frontiers in Genetics
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    • "A second possibility is that some mutated ( Goldman et al . , 2012 ) or experimentally knocked down gene ( s ) may confer resistance to DAergic neurons against PQ - driven OS , thereby increasing life span and locomotor activity . Our data support the latter hypothesis . In fact , Dmp53 , bas - ket and drICE RNAi described herein in an in vivo system appears to mirror the pharmacological inhibition of "
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    ABSTRACT: Understanding the mechanism(s) by which dopaminergic (DAergic) neurons are eroded in Parkinson's disease (PD) is critical for effective therapeutic strategies. By using the binary tyrosine hydroxylase (TH)-Gal4/UAS-X RNAi Drosophila melanogaster system, we report that Dmp53, basket and drICE gene knockdown in dopaminergic neurons prolong life span (p < 0.05; log-rank test) and locomotor activity (p < 0.05; χ(2) test) in D. melanogaster lines chronically exposed to (1 mM) paraquat (PQ, oxidative stress (OS) generator) compared to untreated transgenic fly lines. Likewise, knockdown flies displayed higher climbing performance than control flies. Amazingly, gallic acid (GA) significantly protected DAergic neurons, ameliorated life span, and climbing abilities in knockdown fly lines treated with PQ compared to flies treated with PQ only. Therefore, silencing specific gene(s) involved in neuronal death might constitute an excellent tool to study the response of DAergic neurons to OS stimuli. We propose that a therapy with antioxidants and selectively "switching off" death genes in DAergic neurons could provide a means for pre-clinical PD individuals to significantly ameliorate their disease condition.
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