Neurotoxicology Flashcards
final exam
major poison in hemlock
coniine
mechanism/effect of coniine
- first stimulates then blocks nicotinic receptors
- so, leads to bradycardia (slowing of heart rate), ascending paralysis (b/c blocking nicotinic in periphery), coma (extension to paralysis, but everywhere), and death.
many plant poisons are a variant of _____
nicotine
most toxins found in living creatures are __________
neurotoxins
why where neurotoxins developed in living creatures (e.g. plants)?
- self-protection: other organisms don’t eat them since recognized as toxic
- attack mechanism: neurotoxins can paralyze/harm others, allowing the plant to consume it.
top 6 hazardous substances
- arsenic
- lead
- mercury
- vinyl chloride
- polychlorinated bisphenols
- benzene
what are advantages and disadvantages of animal/rat studies for neurotoxicology?
advantage: can help assess developmental/behavioral neurotoxicity, harder to do in vitro
disadvantage: difficult to extrapolate from for more subtle neurotoxic effects (e.g. mood and intellect)
major advantage of using human induced pluripotent cells (iPSCs)
- can be induced to differentiate into any type of neuron, so can analyze how different neural cells types will react with the neurotoxin.
- can also observe synapse formation process, which can give insight on neurodevelopmental toxicity.
what do nerve growth assays tell us?
help visualize the effect of a toxin on neuron growth
what do automated testing systems help us do?
identify neurotoxins based on neuronal growth
Acute vs chronic toxicity testing (showing causation)
acute: easier to establish and show causation – can be studies in rat models
chronic: harder to establish causation since looking at subtle things over a long period of time – rats can be used, but imaging in people is preferred since there aren’t any confounding factors.
what are whole animal endpoints that can be studied?
- cognitive function (memory, learning, confusion)
- motor function (weakness, convulsion, paralysis)
- sensory function (vision, hearing, touch, balance)
- mood and personality
- general effects (loss of appetite, overall fatigue)
what is a major difficult when studying whole animal enpoints?
neural plasticity and extra neurons may mask the toxicity for years (so hard to properly identify risks in epidemiology studies)
what other non-whole organism endpoints can be used to study neurotoxicity?
- structure of the neuron
- dendritic branching
- specific structures in the brain
what different pathologies of the neuron can be seen?
neuropath, axonopathy, myelopathy, transmission
neuropathy
the entire neuron is destroyed and cannot be replaced (loss of the cell body is final)
axonopathy
only the axon is injured; peripheral Schwann cells can mediate axonal growth
myelopathy
only the myelin is injured; if the axon is still intact, the sheath can grow back
transmission neuron pathology
blocking the transmission (from blocking of Na channels, so Na-induced depolarization is stopped); with time, repairs can take place
how is dendritic branching affected in various pathologies?
decreased
branches of the nervous system
- peripheral nervous system (PNS)
- autonomic nervous system (ANS)
- central nervous system (CNS) – brain and spinal cord
how is the CNS protected?
- brain: by BBB, skull, meninges
- spinal cord: vertebrae
properties of the BBB and how toxicants can affect it/interact with it
- has tight junction between endothelial cells
- capillary has foot processes of the astrocytes surrounding it, adding transportation control
- toxicants can either interfere with the permeability or can make use of transportation pathways to get in.
role of the CSF
cushions the CNS from harsh impacts
role of the cerebrospinal fluid barrier
protect against various toxins from getting into the CNS
what is the CSF/what is it made up of?
made by choroid plexus, which has a barrier, of ventricles, flows through the brain and is drained by arachnoid villi (and returned to venous side of circulation)
cells of the nervous system
- neurons
- small blood vessels
- astrocytes
- glial cells: microglia and oligodendrocytes
- endothelial cells
role of astrocytes
housekeeping and nurturing cells – control the microenvironment around the neuron
role of glial cells (generally)
- maintenance of the structure of the nervous system
role of microglia
- patrol the neuronal environment for foreign substances (like phagocytes)
- have pattern recognition receptors, which can recognize many PAMPs
- release free radicals and trigger inflammation
role of oligodendrocytes
mediate production of myelin (can myelinate several different CNS axons)
role of endothelial cells in the NS
keep foreign substances out of the brain
effect/mechanism of carbon monoxide
interferes with aerobic metabolism:
- blocks ability of Hb to transport oxygen
- brain cannot supply itself with enough energy, leading to cell death
- neuronal cells die very quickly due to high energy demand
effect/mechanism of manganese
interferes with protein folding:
- cause protein misfolding
- other effects such as receptor dysfunction and inflammation
what is MPTP
a by-product of attempts to synthesize a psychoactive opioid compound
effect/mechanism of MPTP
interferes with intermediate metabolism:
- taken up by astrocytes, where MAOs in the cell convert it to MPP+
- MPP+ taken up by dopamine transporters (especially in substantia nigra)
- can interact with and destroy mitochondria
- ATP production stopped so leads to neuronal death
where does tetrodotoxin come from?
pufferfish
tetrodotoxin effect/mechanism
alter electrical transmission along the cell membrane:
- block voltage-gated sodium channels
- blocks propagation of AP
- leads to paralysis and death
sodium channel blockers (toxins)
- tetrodotoxin (pufferfish)
- conotoxin (cone shell)
- scorpion venom
- batrachotoxin (poison dart frogs + insects)
effect/mechanism of vinca alkaloids
interfere with axonal transport:
- prevent tubulin formation by binding tubulin monomers
- prevent microtubule formation, blocking effective axonal transport
where was hexachlorophene found?
disinfectants in hospitals (not anymore)
effect/mechanism of hexachlorophene
damage to myelin sheath:
- cause demyelination and myelin edema via damage to Schwann cells and oligodendrocytes
- slows transmission of AP, but can also harm health axon
where was hexane found?
used as solvent in glue (children would breath it in to get high)
effect of hexane
a diketone metabolite in hexane disrupts the crosslinks in the axonal cytoskeleton, causing axonopathy (in periphery first then goes central)
where can arsenic be found/how was it used?
- can be found naturally in ground and water
- was used to treat wood, so was found in playgrounds.
effect of arsenic
induce peripheral neuropathy, so symptoms follow a stocking-glove pattern since start at outer extremities before leading to death
where is methanol found
part of rubbing alcohol and commonly used as a chemical solvent
effect of methanol
- converted by ADH to formaldehyde then to formic acid by ALDH
- formic acid can damage nervous system (cerebral cortex, cerebellum, retina (blindness))
what to do when someone ingests methanol? why?
give ethanol since will compete for site on ADH and ALDH so will reduce amount of metabolite
ways that toxins can interfere with synaptic transmission (pre and postsynaptic)
presynaptic:
- direct: increase or decrease transmitter release
- indirect: synaptic modulation
postsynaptic:
- prevent neurotransmitter inactivation or reuptake
- act as direct agonist or antagonist for postsynaptic receptors
discarded plastics degrade into ______ and ________
microplastics (<5um) and nano-plastics (<1um)
characteristic of microplastics
bioaccumulate
microplastic source and route of exposure
- in air (inhalation)
- in food (ingestion)
- can be absorbed dermally
what is the Trojan-horse effect in the context of microplastics?
can mask the presence of other contaminants/pathogens, permitting them access into different organs they normally could not access
effects of microplastics (on brain)
- can mask pathogen/contaminants that can cause neuroinflammation or can modulate brain activity that can lead to behavior changes
- modify gut microbiome; can affect gut-brain axis
process of toxic algae bloom
bloom periodically:
- in between blooms, algae cysts settle on ocean floor
- when blooming, algae rise to surface, multiplying and releasing their toxin
- then they settle to ocean floor
where does domoic acid come from
produced by pseudo-nitzschia, a marine algae
property of domoic acid
heat-stable and can bioaccumulate
effect/mechanism of domoic acid
- act on excitatory pre- and postsynaptic glutamate receptors (Kainate glutamate receptors) – is structurally similar to glutamic acid
- prolongs opening of the sodium channel – more frequent opening of calcium channel, so more neurotransmitter release
- can lead to seizures and neuronal death
what are some regulation to protect humans and the environment against domoic acid?
human:
- international safety level
- monitoring programs in seafood and waters
no environmental regulation, and still a big issue for wildlife
- in California, perform gastric lavage to sea lions to protect them
what are some proposed reasons for the domoic acid crisis?
- higher level of international transport (some think that transported water bring algae to areas they didn’t thrive before0
- climate change (change in temperature permit them to grow in new places)
effect of okadaic acid (produced by algae)
diarrhetic shellfish poisoning
effect of saxitoxin (produced by algae)
block sodium channels, cause paralytic shellfish poisoning
effect of brevetoxin (produced by algae)
activate sodium channels, causing neurotoxicity in shellfish
