1. How strong is the link between PD and exposure to pesticides Oct 21 Sarah Kim, Tanner Warren, Hyun Park, Khoi Nguyen

2. What is Parkinson’s Disease (PD)? Degenerative disorder of the CNS Affects nerve cells that produce dopamine Results from death of dopamine-generating cells in the substantia nigra (midbrain) Nerve cells in the substantia nigra release neurotransmitters that help control movement and coordination

3. Symptoms Muscle rigidity tremors Changes in speech Slowing of movement

4. What are pesticides? “A pesticide is any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any pest” Insecticides are frequently used synonymously with the term pesticides, however other pesticides include Fungicides Rodenticides Antimicrobials Herbicides Two largest classes are insecticides and herbicides

5. Pesticide Families Organochlorines Organophosphates Carbamates Pyrethroids DDT Malathion Permethrin

6. Benomyl Link between Parkinson’s disease and a Benomyl, a commonly used pesticide Benoyml is a pesticide that was banned by the US environmental protection agency in 2001 after being deemed a possible carcinogen Benomyl blocks the activity of an enzyme called aldehyde dehydrogenase (ALDH)

7. Mechanism of Action 1.ALDH converts DOPAL, a toxic metabolite of dopamine, to a less toxic substance 2.Benomyl blocks the activity of ALDH, preventing the breakdown of DOPAL 3.This results in buildup of DOPAL in the brain 4.Buildup kills dopaminergic neurons, which can lead to Parkinson’s Disease

8. Animal Studies Studies showing the effect of Benomyl on neurons was done using rat and zebrafish models. Zebrafish were used because scientists could observe their brain cells without harming them

9. Results of Animal Studies Benomyl prevented ALDH from breaking down toxic chemicals into their nontoxic forms. Among these toxic chemicals that remained toxic was DOPAL Exposure of Benomyl to zebrafish embryos caused 25% of dopaminergic neurons to die, other neurons were unaffected The treatment group that was exposed to Benomyl showed 50% decreased movement when compared to the control group. This suggests that the loss of dopaminergic neurons affected their behaviour

10. Relation to Humans Studies show that participants who possessed a genetic variant of the ALDH2 gene were more susceptible to ALDH blocking, and were 2-6 times more likely to develop PD compared to the individuals who were also exposed to pesticides, but did not have the genetic variant. However, individuals with the genetic variant who were not exposed to pesticides did not show increased risk of developing Parkinson’s Disease People exposed to Benomyl during their jobs, such as farmers, had an increased risk of developing PD Not every farm worker who has used Benomyl has developed PD, suggesting that other genetic or environmental factors may also be contributing to PD development People who lived near areas sprayed with Benomyl did not have an increased risk of PD Growing evidence, obtained from both laboratory experiments and studies of people with the disease, indicates that pesticide exposure may contribute to some, but not all, cases of sporadic PD

11. MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine MPTP is found in herbicide called paraquat Lipophilic, gets inside the brain (crosses blood brain barrier) The patients exposed to pesticides had a 70% higher incidence of Parkinson’s when the study ended; the risk was the same for exposed farmers and exposed non- farmers, hence some other farm-related factor wasn’t to blame MPTP induces acute and irreversible PD-like symptoms in monkeys

12. How? MPTP is toxic because it is converted into 1-methyl-4- phenylpyridinium ion (MPP+) It is converted to MPP+ by monoamine oxidase B (MAO- B) in astrocytes This is selectively imported into dopaminergic neurons by the plasma membrane dopamine transporter. MPP+ accumulates in mitochondria, where it inhibits complex I (also known as the NADH dehydrogenase complex), one of the enzymes involved in oxidative phosphorylation

13. How? This action is associated with reduced ATP formation, as well as with the formation of free radicals. Eventually, the mitochondrial permeability transition pore's electrochemical gradient is abolished and apoptosis (programmed cell death) is induced. MPP+'s action is blocked by MAO-B inhibitors (e.g., selegilene), nitric oxide synthase inhibitors (reducing the peroxynitrite radical), and by salicylates (inhibiting a variety of free radicals), suggesting the involvement of these biochemical pathways in the pathogenesis of cell death.

14. Summary Parkinson’s Disease (PD) is a degenerative disorder that affects nerve cells responsible for producing dopamine. Pesticides called Benomyl and MPTP are associated with Parkinson’s Disease symptoms 1. Benomyl Inhibits ALDH  leads to excess DOPAL which kills dopaminergic neurons ALDH2 gene mutation alone does not increase PD incidence Benomyl exposure doubles risk of PD ALDH2 + Benomyl  2-6x more likely to develop PD 2. MPTP Lipophilic; can enter the brain Forms free radicals, and induce apoptosis  Cause significant loss of dopaminergic neurons Conclusion: pesticide exposure may contribute to some but not all cases of PD

15. Reference “Parkinson’s disease: MPTP and drug induced Parkinson’s.” myDr. N.p., n.d. Web. 1 July. 2007. http://www.mydr.com.au/seniors-health/parkinson-s-disease-mptp-and- drug-induced-parkinson-s “Parkinson’s Disease and pesticides: what’s the connection?” scientific american N.p., n.d. Web 8 Apiril 2014 http://www.scientificamerican.com/article/parkinsons-disease-and- pesticides-whats-the-connection/ "Pesticides - General." Canadian Centre for Occupational Health and Safety. N.p., n.d. Web. 8 Oct. 2014. http://www.ccohs.ca/oshanswers/chemicals/pesticides/general.html http://www.ccohs.ca/oshanswers/chemicals/pesticides/general.html Gilbert, Steven. "Pesticides." Toxipedia. N.p., n.d. Web. 8 Oct. 2014. http://www.toxipedia.org/display/toxipedia/Pesticides http://www.toxipedia.org/display/toxipedia/Pesticides "Parkinson's Disease." Definition. N.p., n.d. Web. 18 Oct. 2014. http://www.medicalnewstoday.com/articles/272097.php http://articles.mercola.com/sites/articles/archive/2014/02/20/pesticide- exposure-parkinsons-disease.aspx http://www.pdf.org/en/science_news/release/pr_1363281762