Background Parkinson’s disease (PD) has been associated with various workplace factors, but the evidence is inconsistent. Objective To estimate the risk of PD associated with various jobs and workplace exposures. Methods We conducted a population-based, case–control study of 404 incident PD cases and 526 age and sex-matched controls, collecting self-reported work histories including job titles and exposures to various industrial toxicants. Relative risks of PD from these exposures were estimated with odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. Results Risk was not significantly affected by farming work, by metal work, or by exposure to pesticides, metals, or solvents. Conclusions These findings do not provide support for the hypothesis that workplace factors affect the risk of PD.

Several pesticides such as organophosphates, carbamates and the organochlorine pesticides directly target nervous tissue as their mechanism of toxicity. In several others, such as the fumigants, the nervous system is affected by toxicological mechanisms that diffusely affect most or all tissues in the body. Both the central and peripheral nervous system are involved in the acute toxidromes of many pesticides resulting in acute short-term effects. There is strong human epidemiological evidence for persistent nervous system damage following acute intoxication with several important pesticide groups such as organophosphates and certain fumigants. However, whether persistent nervous system damage follows chronic low-level exposure to pesticides in adults (particularly organophosphpates), and whether in utero and/or early childhood exposure leads to persistent nervous system damage, is a subject of study at present. Parkinson's Disease, one of the most common chronic central nervous system diseases, has been linked to pesticide exposure in some studies, but other studies have failed to find an association. Several new pesticidal chemicals such as the neo-nicotinoids and fipronil have central nervous system effects, but only case reports are available to date on acute human intoxications with several of these. Little data are yet available on whether long-term effects result from these chemicals. Several ongoing or recently completed studies should add valuable insight into the effects of pesticides on the human nervous system particularly the effect of low-dose, chronic exposure both in adults and children.

Background: Pesticide exposures are suspected risk factors for Parkinson disease (PD), but epidemiological observations have been inconsistent. Objective: To investigate associations between pesticide exposures and idiopathic PD. Design: Population-based case-control study. Setting: Group Health Cooperative, a health care system in western Washington State, and the University of Washington. Participants: Two hundred fifty incident PD case patients and 388 healthy control subjects (age-and sexmatched). We assessed self-reported pesticide exposures using a structured interview. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined using logistic regression models, controlling for age, sex, and smoking. Results: Odds ratios for occupational exposures were not significant but suggested a gradient that paralleled occupational exposures (pesticide worker: OR, 2.07; 95% CI, 0.67-6.38; crop farmer: OR, 1.65; 95% CI, 0.84-3.27; animal and crop farmer: OR, 1.10; 95% CI, 0.60-2.00; and dairy farmer: OR, 0.88; 95% CI, 0.46-1.70). Odds ratios for organophosphates paralleled the World Health Organization hazard classifications, with parathion much higher than diazinon or malathion. We also found elevated ORs from herbicides (OR, 1.41; 95% CI, 0.51-3.88) and paraquat (OR, 1.67; 95% CI, 0.22-12.76). We found no evidence of risk from home-based pesticide exposures. We found significantly increased ORs from lifelong well water consumption (OR, 1.81; 95% CI, 1.02-3.21). Conclusions: The findings for occupational pesticide exposures are consistent with a growing body of information linking pesticide exposures with PD. However, the lack of significant associations, absence of associations with home-based exposures, and weak associations with rural exposures suggest that pesticides did not play a substantial etiologic role in this population.

The dopamine transporter gene (SLC6A3) is a candidate gene for Parkinson's disease (PD) on the basis of its critical role in dopaminergic neurotransmission. Previously, we identified 22 SNPs in the 5' region of SLC6A3, which segregate as eight haplotypes that differ in transcriptional activity when transfected in rat dopamine-producing cells. In the present work from a case-control study size of 293 cases and 395 controls, we employed a cladistic approach to examine gene-disease association. First, we found strong evidence of balancing selection in this region, as determined by a Tajima's D statistic of 2.97 (P<0.001). Second, we found that the eight haplotypes fit into two main clades and that diplotypes of these clades were marginally associated with PD. Then, after we classified cases and controls by the number of risk alleles, accounting for the well-known 3' region VNTR polymorphism, we found that having two or more risk alleles resulted in a modest but significant increase in PD risk [odds ratio=1.58; 95% confidence interval (CI): 1.03-2.40]. Finally, we detected a significant interaction between occupational pesticide exposure in men and the number of risk alleles. Among pesticide-exposed subjects, the odds ratio for having two or more risk alleles was 5.66 (95% CI: 1.73-18.53). Thus, allelic variants in SLC6A3, which affect gene expression, are associated with PD in this population and may interact with occupational pesticide exposure to increase PD risk.

The gamma 2 subunit of the GABA receptor (GABAA-R) is alternatively spliced. The long variant (gamma 2L) contains eight additional amino acids that possess a consensus sequence site for protein phosphorylation. Previous studies have demonstrated that a peptide or fusion protein containing these eight amino acids is a substrate for protein kinase C (PKC), but not cyclic AMP-dependent protein kinase A (PKA)-stimulated phosphorylation. We have examined the ability of PKA, PKC, and Ca2+/calmodulin-dependent protein kinase (CAM kinase II) to phosphorylate a synthetic peptide corresponding to residues 336-351 of the intracellular loop of the gamma 2L subunit and inclusive of the alternatively spliced phosphorylation consensus sequence site. PKC and CAM kinase II produced significant phosphorylation of this peptide, but PKA was ineffective. The Km values for PKC- and CAM kinase II-stimulated phosphorylation of this peptide were 102 and 35 microM, respectively. Maximal velocities of 678 and 278 nmol of phosphate/min/mg were achieved by PKC and CAM kinase II, respectively. The phosphorylation site in the eight-amino-acid insert of the gamma 2L subunit has been shown to be necessary for ethanol potentiation of the GABAA-R. Thus, our results suggest that PKC, CAM kinase II, or both may play a role in the effects of ethanol on GABAergic function.