Dangers of your Grandparents Shed

lecture 4

odds ratio of pesticide exposure and PD

• use retrospective study → odds of those who had previously been exposed to pesticides

  • large chance of PD if exposed to pesticides → OR of 1.94

    • PD patients 2x more likely to have been exposed to pesticides

• prospective study → 1.7 fold increased relarive risk of PD with pesticide use

Parkinsons disease

• progressive neurological condition

• symptoms → tremor, slow movement, muscle stiffness

• risk → increased age, 1.5x more in males, genetics, environmental (head injury, pesticide and herbicide exposure and chlorinated solvents)

• pathology → loss of DA neurones in substantia nigra pars compacta in midbrain → nigrostriatal pathway is impaired (motor feedback control)

Rotenone

• netural product → in tropical and subtropical plants, especially gena Derris

• lipophilic → LogP = 3.3, so can cross BBB

• potent → IC50 is 1-10nm

• imhibits complex 1 of mitochondrial electron transport chain

• used in pesticides → insects eg. weevils, beetles and flies

• used to clear lakes of invasive fish (piscicide)

• environmental half life of days

• associated and causal agent of PD

mechanism of rotenone

• complexes of electron transport chain pump H+ across the membtane to power the priduction of ATP

• rotenone blocks the transfer of electrons in complex 1 → cannot produce ptoton gradient so no ATP is produced

• generates reactive oxygen species (ROS) which activate apoptosis by geberation of caspase 3

• can cross BBB

• apoptosis of cells in substantia nigra and decreased ATP of these cells

• kills dopaminergic cells → parkinsonism

• rotenone is selective for the substantia nigra → unknown why, dopamine metabolism?

effect of rotanone on DA metabolism

• decreases ATP, so decreased VMAT DA uptake → increased cytosolic DA

• MAO oxidises DA to DOPAL → increase cystolic DOPAL

• increased ROS decreases ALDH enzyme activity so decreases DOPAC production → build up of cytosolic DOPAL

• DOPAL fixes the cell and causes apoptosis → specific to substantia nigra neurones

casscade of intrinsic apoptosis

• ROS are generated

• causes mitochondrial damage

• opens mitochondrial permeability transition pore → hole in the mitochondrial membrane

• collapse of mitochondrial membrane potential, loss of membrane and matrix proteins

• release of cytochrome C into cytosol → activates Apaf 1 (apoptotic protease activating factor 1)

• apoptosome forms

• caspase enzyme activation → procaspase 9 activates executioner caspases (3, 6 and 7)

• execution phase → DNA fragmentation, degredation of cytoskeleton proteins and formation of apoptotic bodies

  

interventions regarding rotenone

• evidence for association with PD and mechanistic cause of neurodegeneration

• banned in 2009 in UK

• banned in USA, EU and switzerland

• environmental half life of days → photodegredation

  • permitted for some things → piscicide

paraquat use

• man made oxidant

• herbicide

  • 1950s

  • cheap

  • increased food productivity and weed control

  • used on 100s of crop types, mostly plantation crops → maize, organges, tea, coffee, palm oil, sugar cane

  • USA use troppled 1992-2018

paraquat toxicity

• only associated with PD, not causal → no causal mechanism

• strong comercial interests and is still exported worldwide

• is a systemic poison

• half life → >7 years

• contaminates soil and water

• no antidote to poisoning

LogP of paraquat

• LogP = -6.7

• hydrophilic → cannot cross BBB

• acts like rotenone on isolated mitochondria but cannot enter brain its self

• could enter damaged BBB or be metabolised to something which can

paraquat and PD

• odds ratios from meta analyses

• OR of 1.64

• correlational, not causal

forrest plots

• use in meta analysis

• plot means and weights of odds ratios

• calculate mean OR

confounders in the link between PD and paraquat

• exposure to other pesicides

• male

• smoke

• farmers

• farm animal exposure

• living on a farm

• drinking well water

• living in rural area

legistaltion surrounding paraquat

• banned in 68 countries

• banned in UK in 2007

trichloroethylene (TCE)

• solvent

• volatile colourless liquid

• logP = 2.2 → lipophilic

• used to extract fat soluble compounds

• uses:

  • paint remover

  • degreaser

  • decaffinating coffee

  • dry cleaning

  • carpet cleaning

  • anaesthetics → trilene, banned 1977

• persists in environment → halogenated forever chemical

• found in water, food, fat and breast milk

• associated with PD

studys on solvent (TCE) exposure

• cohort study of US army vererans

  • increased PD incidence in one camp over another (OR was 1.70)

  • this camp has TCE contamination in the water supply → from water runnoff from decreasing and cleaning machinery

  • ingested in food, water and bathing water

  • associated with PD and no other neurological condition

• twin studies

  • one had PD and one didnt

  • interviewed on pervious work

  • increased PD development of worked with degreaser

  • association not causation

TCE animal study

• rat models → replicate in weeks what takes years in a man

• high dose of TCE oraly dosed for 6 weeks

• measured mitochondrial bioenergetics

  • use mitochondria from substantia nigra and compared to striatum and liver as controls

• changes in bioenergetics seen only in substantia nigra

• selectively inhibited complex 1

TCE mechanism

• inhibits complex 1 to blovk the electron transport chain, oxygen consumption and ATP production

• like rotenone

nigrostriatal DA histochemistry after TCE

• loss of tyrosine hydroxylase in neurones in substantia nigra pars compacta after TCE treatment (A control vs B TCE)

• loss of retrograde labelled fluorogold dopaminergic neurones in substantia nigra pars compacta (C control vs D TCE)

TCE mechanism in relation to parkinsons

• has candidate toxic metabolites → DCVC, TaClo and TACH (inhibits ALDH)

current use of TCE

• degreasing

• chemocal feedstock

• textiles

• dry cleaning

• military (reduced)

• no longer used in:

  • anaesthetic

  • decaffination

  • animal feed processing

• enters environment via industrial processes leaching into water supply

TCE in in human breastmilk

• women with lower BMI have highest breastmilk TCE concentration

• fat is protective → leeches TCE

• not replicated and small sample

TCE legislation

• regulated

  • america → centre for disease control

  • europe → european chemical agency

• still advertised

• ban on domestic use in EU

• organic alternatives available