PHAR 303 Lecture Notes - Lecture 11: Arsenic Poisoning, Nicotinic Acetylcholine Receptor, Electronic Waste

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Lecture 11 (Feb 15th) Neurotoxicology 1 Nervous System, Animal & Plant Toxins
A lot of different things can affect the nervous system and that could kill you.
Socrates was given poison hemlock from spotted parsley & cowbane.
Big plant with white flowers.
Hemlock is a mixture of neutoxins poisons: nicotine, coniceine, methylconiine, coniine
All have a similar structure to nicotine so they can block the nicotinic receptor.
Stimulation, then block nicotinic receptors → bradycardia, ascending paralysis, coma.
Plant toxins kill by neurotoxicity or cardiotoxicity Galanthamine, Lycorine, taxine, scopolamine, ricin, atropine.
Animal poisons (scorpions) tend to usually be neurotoxic. There are other ways they could kill but the most common
way is to affect the nervous system.
People do not think about plants and animals when they think about toxins. They think more about synthetic poisons.
In fact, there are a lot of potential neurotoxins in electronic waste: lead, mercury, cadmium, chromium, PBDEs, PCBs
act by oxidative stress, interfering calcium signaling, neurotransmission (glutamatergic, dopaminergic),
neuroendocrine and hormone disruption, epigenetic control.
These lead to neurodevelopmental outcomes
Cognitive function Electronic waste goes into the environment and end up in
Attention agriculture & we are indirectly affected by them.
Executive & motor functions
Behavior
The priority list of hazardous substances do not change much: the most frequent are neurotoxins in the top 10 most
dangerous: Arsenic, Lead, Mercury, Vinyl chloride, Biphenyls, Benzene
Neurotoxicants
>80 000 of neurotoxins chemicals come from environment and unknown neurotoxic effects
Not easy to extrapolate from animal models so there’s been a continual attempt to try to come up with new models
for neurotoxicants in vitro.
Possible to grow neurons in wells & do high fast speed testing
Avoid animal testing by plate neurons in distinct parts of the chamber and see that they grow and make
connections with each other. Apply neurotoxin and see if it affects their ability to make connections and
communicate with each other.
Nerve outgrowth assays: stain neurons and measure how well they grown following neurotoxicants exposure.
Plate neurons on a surface that has electrodes that measure firing rates & test for different compounds to see if
they alter the firing rate of neurons.
o DMSO is a solvent that does not affect the firing (100%)
o Ibuprofen (NSAID) does not affect firing rate either
o Picrotoxin(250%) & Gabazine (200%) increase firing rate
o Domoic acid (0%) shut down completely the firing rate
In vivo: take rat brain and plate slice of hippocampus on petri dish connected to recording & stimulating
electrodes, microscopes..
Possible to take different parts from the nervous system (spine, nerves)
Have to look at impairment of developmental behavioral effects, fetal growth.
Have to look at Acute vs. Chronic Toxicity
o Acute toxicity can look in an isolated cell.
o Chronic toxicity need to keep cells alive for a long time (months) So need animal models.
Neurotoxic Effects
Cognitive & intellectual ability memory, learning, confusion, concentration impairment, speech impair, mental
slowing, reduced initiative, delirium
Motor skills weakness, fatigue, convulsion, paralysis (excitation or inhibition), tremors, reflex abnormalities,
lack of coordination
Sensory impairment vision, hearing, touch, balance, increased olfactory & auditory threshold, tinnitus,
equilibrium changes, dizziness, pain, tactile disorders, numbness, increased cold sensitivity
Mood & Personality sleep disturbances, depression, irritability, excitability, anxiety, delirium, hallucinations,
nervousness, loss sexual activity.
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General loss of appetite, anorexia, fatigue, headache, depression, thirst, drowsiness
Sometimes combination of a variety of things at the same time.
We still wonder whether neurotoxicants are involved in
o Parkinson’s disease in certain circumstances yes, it can be due to neurotoxicants
o Alzheimer’s disease – unknown, but we do know that environmental factors affect it bc twin studies
where one twin get it and another doesn’t. Neuron is shrunken, smaller
o Autism spectrum disorders
Special features of the Nervous System
Neuron very high energy requirement. Need as much energy all the time, as a skeletal muscle cell that would do
high exercise. Ion pumps take a lot of ATP.
If requirements not maintained & no continual supply of energy, they will die.
Neurons depend on aerobic glycolysis need continual supply of O2 and glucose.Vulnerable to anything that
would impair the O2 capability to be transported in blood& glucose transported to brain, or impaired blood flow.
Neurons have few enzymes to metabolize xenobiotics do have a small nb of P450s but not a lot of enzymatic
capacity. Compounds are not metabolized in the brain. Often need to be washed out through CSF before getting
rid out.
NS has a high lipid contend (50% myelin). Lipid soluble compounds that can enter the brain could accumulate a
long time in fat.
Neurons are the largest cells in the body high energy requirement bc a lot of ion pumps, long,big size and other
special features: has to transport things from brain cell body to nerve terminals down the toes
Axonal transport along microtubules: anterograde & retrograde transport that requires a specialized system that
requires energy & that’s vulnerable to specific toxicants that interfere with it.
Block axonal transport → neuron die
Normal neuron myelin sheet and synapse
Neuronopathy (MPTP solvent) neuron is dead & degraded
Axonopathy (Hexane) axon is chemically destroyed (by a solvent). The cell body doesn’t die & could regrow an
axon. Could recover sometimes if the axonal damage wasn’t too extensive.
Myelinopathy (Pb) toxican will destroy some myelin possible to remyelinate the neuron axon.
Stopping transmission (Botulinum) & interfere ability of cell to communicate with other cells, depending where
the block in transmission occurs, it could be lethal. If you paralyze the muscle for respiration because no inhition,
then you can’t breathe.
Neurons cannot regenerate. If you damage the axon you can regrow but can’t regrow cell body.
Even if a small area in the brain is damaged, depending on what it controls, it could be fatal.
Problems extrapolating between species: may be able to detect motor damage in rat but more difficult to detect
intellectual changes that can occur following toxicant exposure.
Neuronal plasticity & networking may mask toxicity for years
o Neurons are designed to be flexible, cope with what happens constantly change synaptic connections &
potential magnitude of what they’re going to release to synapses → Learning
o It can protect us. We can relearn things & this can protect us from neural toxicity but at the same time, it can
hide neural toxicity. We can be chronically exposed to something that is dangerous/damaging to us, but bc of
the neuroplasticity compensating for it, we may not be aware of this until the damage gets to a point where
it’s irreversible – We should detect neural changes & toxicity at earlier stages.
Fetal exposure “non reversible tolerance, chemical imprinting fetal exposure can be obvious or more subtle
changes (people personalities are different)
Anatomical Features
CNS - Brain, spinal cord, PNS, ANS (vital in controlling all coordination)
Brain and spinal cord are covered by skull & vertebras.
Meninges protect the brain against injuries.
Each part of CNS is vulnerable to different types of neurotoxicsnts & effects are different depending on area that
is affected.
Some neurotoxicants have much more generalized effects, not specifi Chronic alcohol makes the brain smaller
Specific effects on spinal cord or neurofibers going in (sensory) or out ( motor) of spinal cord.
Toxicants can affect sensory neurons in periphery, dorsal root ganglia, could lose sensation of touch.
Everything is connected, NS is changing physiology
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Document Summary

Lecture 11 (feb 15th) neurotoxicology 1 nervous system, animal & plant toxins. A lot of different things can affect the nervous system and that could kill you. Socrates was given poison hemlock from spotted parsley & cowbane. Hemlock is a mixture of neutoxins poisons: nicotine, coniceine, methylconiine, coniine . All have a similar structure to nicotine so they can block the nicotinic receptor. Stimulation, then block nicotinic receptors bradycardia, ascending paralysis, coma. Plant toxins kill by neurotoxicity or cardiotoxicity galanthamine, lycorine, taxine, scopolamine, ricin, atropine. Animal poisons (scorpions) tend to usually be neurotoxic. There are other ways they could kill but the most common way is to affect the nervous system. People do not think about plants and animals when they think about toxins. In fact, there are a lot of potential neurotoxins in electronic waste: lead, mercury, cadmium, chromium, pbdes, pcbs act by oxidative stress, interfering calcium signaling, neurotransmission (glutamatergic, dopaminergic), neuroendocrine and hormone disruption, epigenetic control.

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