Neurotoxic Insecticides Flashcards
Examples of natural pesticides used prior to 1940s?
inorganic metals and sulfur based products
mechanism of natural insecticides?
inhibited respiration via ATP
impaired heme synthesis
when were organochlorides first deployed?
during WW2 to combat typhus, malaria and dengue fever
Organochloride desired properties
persistent stimulation of the CNS
organochloride example
DDT
organophosphate example
Parathion and Malathion
organophosphate desired properties
irreversible/reversible stimulation of the CNS
degrade rapidly
Why were carbamates developed?
Wanted an insecticide with neuronal activity but with greater specificity and lower mammalian toxicity than organophosphates
carbamate properties
effects on neural system are reversible
degrade rapidly
Why is there a reduction in the use of insecticides?
Rise in GMOs and increased resistance
What is the half-life of DDT?
2-15 years
structure of organochlorides
chlorine substituted aliphatic or aromatic rings
What 2 properties make organochlorides so dangerous to the natural environment?
bio-accumulation and bio-magnification
How does DDT cause over-stimulation?
Keeps voltage gated sodium ion channels open causing them to fire spontaneously, leading to spasms and eventual death
highly processed alpha subunits associated with auxiliary beta subunits
prevents neuronal re-polarization
acts on pre-synaptic cell
Where do organochlorides bind?
open sodium channels
stabilize the open state and cause prolonged currents
sodium channel – resting state
polarized
electrical charge on the outside of the membrane is positive and contains excess sodium ions
sodium channel – action potential
sodium ions move inside the membrane
sodium channel – depolarized
threshold reached when chain of channel open sequentially
sodum channel sequence
resting potential > threshold > depolarization > repolarization > hyperpolarization
How does dieldrin work?
Causes overstimulation like DDT, but through GABA receptors
acts on post-synaptic cell
GABA receptor
ion-gated chlorine channel composed of 5 subunits
Role of GABA (neurotransmitter)
inhibit the activity of neurons
Action with GABA binding
channels open to Cl, this leads to hyperpolarization and inhibits the firing of new action potentials
Action of dieldrin
binds to the GABA receptor, blocking the GABA induced uptake of Cl ions and inhibiting hyperpolarization
What is the general structure of organophosphates?
O=P(OR)3
a central phosphate molecule with alkyl or aromatic substituents
Acetylcholinesterase
enzyme located in synaptic space that rapidly breaks down acetylcholine
Where do organochloride pesticides bind?
sodium ion channels
What are acetylcholine’s active sites?
anionic site and esteratic site
anionic site
electrostatic interaction with quaternary nitrogen in choline
esteratic site
serine residue that covalently binds to the ester carbonyl group
acetylcholine-acetylcholine esterase complex
forms an unstable tetrahedral intermediate which rapidly decomposes, liberating choline and leaving the enzyme covalently bound to esteric site
How is acetate removed from acetylcholinesterase?
water spontaneously hydrolyzes the bond in the esteric site, regenerating the free enzyme
How do organophosphates block acetylcholinesterase?
interact with the serine hydroxyl residue in the esteratic site to block enzyme regeneration
Organophosphate aging
chemical stabilization of phosphate bond to AChE occurs over time
R group leaves via hydrolysis strengthing the serine-phosphate bond
Two fates of OP-adducts
- spontaneously hydrolyze and restore enzyme activity
2. Irreversible process known as “aging”
How long until OPs are fully aged?
24-48 hours
What is used to treat OP poisoning?
pralidoxime (2-PAM)
prevents aging by bonding to organophosphate group
Feature of carbamates
carbamate-ester functional group
commonly used for agriculture, residential lawn, and garden applications
What do carbamates inhibit?
AChE
How do carbamates differ from OPs?
They don’t age
A draw back of carbamates?
tend to hydrolyze easily, resulting in low level persistence in soil and water
How long does it take AChE to be recovered after carbamate exposure?
24-48 hour window
How do insects develop resistance to insecticides?
- behavioral – avoid lethal dose
2. physiological
3 examples of physiological resistance (insects)
- reduced penetration
- target site insensitivity
- enhanced detoxification
What human neurological disease is associated with organochlorides?
Parkinson’s
What human neurological disease is associated with organophosphates and carbamates?
Parkinson’s
organophosphate-induced delayed neuropathy (OPIDN)
chronic organophosphate-induced neuropsychiatric disorder (COPIND)
What are some major challenges to chronic exposure?
- untangling acute vs. chronic
- multiple compound exposures
- many different endpoints beyond neuropathy
neurodegenerative disorders are considered an interaction between:
environmental factors and genetic predisposition
Motor manifestations of Parkinson’s disease are attributed to what?
progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc)
The misfolding of what protein is linked to Parkinson’s disease?
alpha-synuclein
Misfolding of alpha-synuclein leads to what?
Lewy bodies
Pesticides may play a role in parkinson’s by the production of what?
ROS
What neuron type are associated with Parkinson’s?
dopaminergic
ROS in dopaminergic neurons
oxidative metabolism of dopamine in the substantia nigra
ROS in resident macrophages
redox cycling initiates inflammatory cytokine production (NADPH oxidase)
Acute cholinergic syndrome
organophosphates
due to the inhibition of AChE activity
subsides within days
blood AChE activity used to monitor exposure
intermediate syndrome
organophosphates
usually starts 24-96 hours after the acute syndrome
respiratory paresis, weakness, depressed tendon reflexes without response to treatment
Organophosphate-induced delayed neuropathy (OPIDN)
weeks following an acute exposure
symmetric distal neuropathy
inhibition of the enzyme neuropathy-target esterase(NTE)
Example of OPIDN epidemic?
Ginger Jake from 1930s
product found to be contaminated with TOCP
Chronic Organophosphate induced neuropsychiatric disorder (COPIND)
mechanisms unclear but are not related to enzyme inhibition.
pesticide applicators
prolonged exposure to OPs
