Transcript How strong is the link between PD and exposure to pesticides

How strong is the link
between PD and
exposure to pesticides
Oct 21
Sarah Kim, Tanner Warren, Hyun Park, Khoi Nguyen
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
Symptoms
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Muscle rigidity
tremors
Changes in speech
Slowing of movement
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
Pesticide Families
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Organochlorines
Organophosphates
Carbamates
Pyrethroids
DDT
Malathion
Permethrin
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)
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
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
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
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
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 nonfarmers, hence some other farm-related factor wasn’t to
blame
• MPTP induces acute and irreversible PD-like symptoms in
monkeys
How?
• MPTP is toxic because it is converted into 1-methyl-4phenylpyridinium ion (MPP+)
• It is converted to MPP+ by monoamine oxidase B (MAOB) 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
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.
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
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-anddrug-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-andpesticides-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
Gilbert, Steven. "Pesticides." Toxipedia. N.p., n.d. Web. 8 Oct. 2014.
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/pesticideexposure-parkinsons-disease.aspx
http://www.pdf.org/en/science_news/release/pr_1363281762