Neurotoxicity and behavioral toxicology Flashcards
What is neurotoxicology?
The study of chemical agents that cause adverse structural or functional effects on the nervous system.
What is included in the CNS vs PNS?
The central nervous system (CNS) includes the brain and spinal cord.
The peripheral nervous system (PNS) include
The autonomic:
- sympathetic (arousing)
- parasympathetic (calming)
And the somatic:
- motor output
- sensory input.
The brain can be divided into three parts, which?
Forebrain
-Telencephalon: cerebrum
-Diencephalon: thalamus, hypothalamus
Midbrain
-Colliculi, tegmentum, cerebral peduncles
-Substantia nigra
Hindbrain
-Pons/medulla oblongata
-Cerebellum
There’s very big diversity in function in different parts, and all can be subject to toxic insult, both chronic and acute, which can have detrimental effects!
Explain in short how the PNS and CNS are connected.
- The PNS received sensory input via receptors (photo, mechano, and chemical) to detect changes in the environment
- Action potentials are propagated via afferent neurons to reach the CNS
- The action potential is propagated to the central nervous system (brain/spinal chord)
- The signal is relayed through interneurons (CNS) to efferent neurons (PNS)
(the number of interneurons connecting an afferent and efferent neurons depends on the complexity of response, and for each afferent neuron there are about 200 000 interneurons and 10 efferent neurons)
- Efferent neurons connect to effector cells (muscle, other neuron, tissues) and produce motor output.
What features makes nerve cells so vulnerable to toxic insult?
- Length: Some neurons can be up to a meter in length! One break anywhere on it can have detrimental effects.
- Metabolism: Nerve cells rely heavily on ATP to maintain ion gradients needed to relay signals, toxic effects on mitochondria can be very bad.
- Excitability: It’s important to remember that all signals in the NS are electric, if anything happens with excitability the effects an be severe.
Explain neurotransmission in the brain in short.
- Sodium-potassium pumps generates a resting potential (net positive on the outside, 3 Na+ out for every K- in, ATP driven).
- Upon stimulation, sodium channels open which cause a influx of Na+ into the cell and rapid depolarization of the membrane.
- The action potential generates a local current which cause voltage gated Na+ channels to open along the axon (once opened they have a locked conformation a short while to ensure that signal is unidirectional) = saltatory conduction (very fast because of insulating myelin sheaths, signal “jumps” between nodes of Ranvier)
- When the action potential reaches the pre-synapse, it depolarizes the membrane and voltage gated calcium channels open, causing an influx of Ca2+ that causes vesicles filled with NTs to fuse with membrane and be released into the synaptic cleft.
- The NTs can have different effects on the postsynaps, like depolarization, biochemical cascades or expressional changes.
(6.) The NTs are either enzymatically degraded, actively transported back into pre-synapse or surrounding glial cells for recycling or diffuse away to stop the signal transmission.
ANY of these steps can be affected by toxicant, so there are many toxicants that target the central nervous system.
Axonal breakage (axotomy) have many consequences, not only can signals not be relayed, but it affects transport too, how?
Everything the nerve cell needs is synthesized in the cell body, but things that are needed in other parts of the cell needs to get it somehow and that’s where axonal transport comes in. There is fast, intermediate and slow axonal transport:
Fast: transport of proteins that relies on transport proteins driven by microtubule associated ATPase:
- Kinesin – anterograde transport
- Dynein – retrograde transport
Vesicles can be transported 40 cm/day!
Intermediate: Transport of organelles (mitochondria). 50 mm/day
Slow: Transport of cytoskeleton (neurofilaments, actin and microtubules), “stop and go” (stops a lot on the way). 1-4 mm/day.
Toxicants doesn’t need to affect the neurons to have toxic effects on the CNS, they can also affect supporting cells. Which kinds of supporting cells are there and what is their function?
Oligodendrocytes – myelin sheet around axon
– Equivalent in PNS: Schwann cells
Astrocytes –BBB, regulates composition of extracellular fluids (K
and neurotransmitters in synaptic cleft), sustains metabolism, sequestration and processing of toxins, physical barrier.
Microglia – macrophage like cells which perform immune functions.
Which four anatomical and physiological features are important for the BBB?
- Endothelial cells are tightly joined (tight junctions), leaving no or very small pores in between.
- Endothelial cells contain multi-drug- resistant proteins (mdr) that exude chemicals back into the blood.
- Capillaries are surrounded by astrocytes (glial cells).
- The protein concentration in the interstitial fluid (CSF) is much lower than in the rest of the body.
Name five charachteristics that makes the CNS so vulnerable to toxic insult.
- Lipid-rich environment
- Repair mechanisms are limited (post mitotic)
- High dependence on oxygen (loss = cell death)
- Dependence on glucose (loss = cell death)
- Receives lots of blood flow (~15%)
- High metabolic rate
- Many inhaled substances go straight to the brain
- Neurotoxic injury may result in multiple outcomes
such as:
− Sensory disorders
− Movement disorders
− Learning disorders
− Memory disorders
There are four main types of damage that happen from toxic insult to the CNS, which?
- Neuronopathy
– Cell death, irreversible
– MPTP, trimethyltin - Axonopathy
– Degeneration of axon (may be reversible)
– Hexane, acrylamide, trauma - Myelinopathy
– Damage to myelin (e.g. schwann cells)
– Lead, hexachlorophene - Transmission toxicity
– Disruption of neurotransmission
– Heavy metals, OP pesticides, DDT
There are naturally occurring, anthropogenic and endogenous sources of neurotoxicants. Name one of each.
Natural:
Tetrodotoxin
- Produced by algae, accumulates in symbionts
- Puffer fish, heat stable so not removed by cooking
- Blocks ion channels (e.g. Na channels)
-Loss of sensation, paralysis, respiratory arrest, death
Domoic acid
− Produced by algae, then bioaccumulates e.g. in Shellfish
− Excitatory amino acid receptor agonist
− Causes seizures and cell death in limbic regions (hippocampus)
BMAA (B-N-methylamino-L-alanine)
− Excitatory amino acid receptor agonist (e.g. glutamate)
− Produced by cyanobacteria and present in symbionts / aquatic organisms (shark fin..)
− Believed to be associated with numerous neurodegenerative disorders
Anthropogenic:
- Heavy metals: lead, manganese, cadmium
- Solvents: carbon disulfide, n-hexane, etc.
- Pesticides, fungicides, and insecticides: chlorpyrifos, rotenone, organophos-phates, carbamates, etc.
- Drugs of abuse: cocaine, methamphetamine, LSD, MDMA (ecstasy)
Endogenous:
− Glutamate (naturally-occurring excitatory amino acid) can increase dramatically following hypoxia, hypoglycemia, and stroke—and produce excitotoxic cell death.
− Tryptophan metabolites, such quinolinic acid and 3- hydroxykynurenine, have been demonstrated to produce cell death and may be linked to some neurodegenerative conditions.
What is neuronopathy?
Neuronopathy is the loss of cell body (target) and all processes without possibility for regeneration (irreversible).
Name two chemicals that can cause neuronopathy.
Methyl mercury (MeHg), MPTP, Paraquat (herbicide) and Maned (fungicide).
Explain in short how methyl mercury cause neuronopathy.
Methyl mercury is an environmental pollutant from waste sites that can accumulate in aquatic organisms exposure via inhalation and GI-tract.
When absorbed, it sneaks through the BBB by hijacking existing transport ways, and well inside it wreaks havoc because of it’s high affinity and binding properties. Inside the cells it can impair glycolysis, affects nucleic acid biosynthesis, aerobic respiration, protein synthesis, cause oxidative stress, DNA damage, alter calcium homeostasis and neurotransmitter release to name a few and with so many processes disturbed it leads to cell death (apoptosis/necrosis).
It has very severe symptoms:
– Adults: neurons in visual cortex, granular cells in cerebellar cortex. Blindness and ataxia
– Children: cognitive effects, mental retardation, developmental disabilities (underdeveloped BBB gives access to higher levels of MeHg)
How does MPTP cause neuronopathy in short?
The metabolite MPP+ can enter dopaminergic neurons of the substantia nigra which leads to selective loss of dopaminergic neurons due to inhibition of mitochondrial complex I (ROS generation).
– High dose exposures result in idiopathic Parkinsonism
– Moderate (sublethal) doses alters susceptibility of the dopaminergic system -> more vulnerable
– Toxic manifestations resemble those of Parkinson’s disease: difficulty initiating and terminating movement, tremors, rigidity
What is axonopathy?
Axonopathy is the chemical transection of the axon, so the axon is the primary target site of toxicity, and the cell body is still intact.
