In our newsblog on March 13, 2014, the etiology of Parkinson’s Disease (PD) was discussed. The etiology is believed to be multifactorial and consists of an interaction between environmental factors and genetic predisposition. Since then a lot of important new scientific papers have appeared.
A new French case-control study has now confirmed the association of Parkinson’s Disease to occupational pesticide exposure. There appeared to be a stronger association with intensity than duration of pesticide exposure based on separate models, as well as a synergistic interaction between duration and intensity. High-intensity pesticide exposures in farms that specialized in vineyards was significantly associated with tremor-dominant PD (OR = 2.56; 95% CI: 1.31, 4.98). There was, however, no information about the actual pesticide chemicals, workers were exposed to.
Widely used organophosphate (OP) pesticides can induce oxidative stress by interactions with nitric oxide synthase (NOS) enzymes produce nitric oxide (NO), a pro-oxidant that can damage neurons. Additionally, two single nucleotide polymorphisms (SNPs) from the paraoxonase 1 (PON1) gene influence the ability to metabolize organophosphate pesticides. A case-control study in California (USA) investigated the contributions of NOS genes and OP pesticides to PD risk, controlling for PON1 status. Organophosphate (OP) pesticides were more strongly associated with Parkinson’s Disease among participants with variant genotypes in NOS1, consistent with the importance of oxidative stress-inducing mechanisms. The study provided evidence for NOS1 modifying PD risk in OP exposed populations.
Some studies have suggested that variants in the ABCB1 gene encoding P-glycoprotein, a xenobiotic transporter, may increase susceptibility to pesticide exposures linked to Parkinson’s Disease (PD) risk. That knowledge was used in another population-based case control study study from California, showing that occupational exposures to organochlorine (OC) and organophosphorus (OP) pesticides and having variant ABCB1 genotypes at two polymorphic sites jointly increase risk of PD.
A descriptive study from Nebraska in the USA found for most Nebraska counties significant associations between PD incidence and exposure to different pesticides, such as alachlor and bromoxynil. However, the results also suggested that factors other than pesticide exposure may help further explain the risk of PD at the county level.
A study from USA examined the relationship between PD and pesticide levels in groundwater. The herbicides: atrazine, simazine, alachlor, and metolachlor were analysed in 286 well water samples. A logistic regression model with known Parkinson Disease (PD) risk factors was used to assess the association between residential groundwater pesticide levels and prevalent PD. It showed that for every 1.0 µg/L of pesticide in groundwater, the risk of PD increases by 3% (odds ratio = 1.03; 95% confidence interval: 1.02-1.04).
Mechanism of disease
Parkinson’s disease (PD) is characterized by the aggregation and misfolding of the α-synuclein (αS) protein. A French in vitro study showed that three pesticides (paraquat, rotenone and maneb), which have frequently been associated with PD, produced a dose-dependent increase in cellular αS levels, but also of αS released into the culture medium. Examining an additional series of 20 pesticides from different families and chemical structures, we found that beside some insecticides, including an organophosphate and three pyrethroids, a majority of the 12 studied fungicides were also producing an αS accumulation, three of them (thiophanate-methyl, fenhexamid and cyprodinil) having similar or more pronounced effects than paraquat. Thus, it was shown that a variety of pesticides could disrupt αS homeostasis in vitro.
Some American scientists report selective mitochondrial DNA (mtDNA) damage as a molecular marker of vulnerable nigral neurons in PD, and the persistence of abasic sites in mtDNA suggests an ineffective base excision repair response in PD. In this respect it should be mentioned that the Nobel Prize in Chemistry 2015 just have been awarded to three scientists (Aziz Sancar, Paul Modrich, and Tomas Lindahl) who discovered the mechanisms of DNA repair.