Challenges for Epidemiological Research of Pesticide Exposure and Parkinson’s Disease
Challenges for Epidemiological Research of Pesticide Exposure and Parkinson’s Disease
Parkinson’s disease (PD), a neurodegenerative disease affecting at least one million individuals in the US, is characterized by a progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (inclusions composed of aggregated proteins) in the surviving neurons. Once approximately 70% of the dopaminergic neurons have been lost, the clinical signs of PD become apparent; these include resting tremor, muscular rigidity, and bradykinesia, among many other motor and non-motor manifestations. Increasing age is a major risk factor for PD, and as a consequence the disease prevalence and ensuing societal impact of the disease are expected to increase as the population ages in coming years. Despite this, the factors that trigger the pathological changes leading to PD remain unknown for the vast majority of cases.
A slow progressive loss of dopaminergic neurons accompanies normal aging, and exposure to harmful environmental factors may cause PD by accelerating the rate of neuronal depletion. Alternatively, environmental exposures in early life may reduce the number of dopaminergic neurons to levels below those needed to maintain function upon age-related neuronal depletion in later life. In either case, the environmental impact may not be immediately evident, and the disease may appear years later when dopamine levels drop below the threshold required for normal function.1 Investigators have long sought to identify harmful environmental factors leading to PD, particularly since the 1983 identification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a causal agent.2 MPTP contaminated a synthetic narcotic, leading to severe parkinsonism with features of classic PD in several young drug users. MPTP was later shown to act selectively on dopaminergic neurons in the substantia nigra. Since then, much epidemiological research has focused on the pathwaysleading to MPTP-induced parkinsonism.
Structural and functional similarities exist between the active metabolite of MPTP (MPP+) and some pesticide chemicals, particularly paraquat. Given this, pesticide exposure has been examined in many epidemiological studies as a risk factor for PD, but some uncertainty remains. A meta-analysis of case-control studies conducted prior to 2001 showed that individuals with PD were 85% more likely to report being directly exposed to pesticides compared with unaffected individuals.3 Lifestyle factors thought to correlate with pesticide exposure, including rural living, well-water consumption, and farming, have also been implicated in PD, adding support to the association between pesticide exposure and PD. However, rural living, well-water consumption, and farming are poorly defined, highly variable, and inter-related factors likely reflecting several environmental exposures, which may or may not include pesticide exposure. Furthermore, the lack of significant association between direct pesticide exposure and PD in several studies and the inconsistent reporting of specific pesticide chemicals as risk factors for PD have disputed the role of pesticide exposure in PD.4 In this article, we present the major challenges of examining the complex relationship between pesticide exposure and PD and suggest future directions for the research field.
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