Nerotoxicology Flashcards
Hazard
the potential of a substance to cause damage. Need exposure to it.
I.e., the inherent toxicity of a substance
Risk
A measure of the probability that harm will occur under defined conditions of exposure to a substance
- Higher risk substances have greater effects with little exposure compared to low risk
- Low risk substances have severe effects with higher exposure
Threshold dose
range of NOALE and LOALE, falling some place between. We only know through mathematical modelling or experiments
Monotonic dose-response cure (linear)
The higher the dose, the greater the response (effect)
- “S” shaped curve
- Movement up and to the right
Non-monotonic dose-response curves (non-linear)
The shape of the dose response curve reverses as the dose increases
“U” or “j” shaped curves with high responses at low and high doses
Non-monotonic dose-response curve “inverted U”
As you reach a certain point, the response will decrease. Highest dose response at intermediate doses
Non-monotonic dose-response curve “J shape”
High responses at low, nothing at intermediate, high at high doses as well.
Low response at low, medium at intermediate, and high at high
Importance of Non-monotonic responses
The way that we determine safety for chemicals is done with a monotonic curve.
- No effects/lowest dose
- Uncertainty factors
- Safety factors for humans
- Tested mainly on animals
How non-monotonic responses occur
Hormetic
- Biphasic response to increasing amounts of a substance
- Mechanism underlying this response not well understood
Non-monotonic: Low- dose hypothesis
- Low doses show beneficial effects whereas high doses show detrimental effects
ex: alcohol - Responses that may occur at doses well below those levels previously tested and determined to be safe
Problems with Low-dose hypothesis
- how “low dose” is defined
- data unavailable for independent scientific verification
- not all observations at low doses are necessarily adverse of precursors to adverse effects in living organisms
- outstanding scientific evidence
- significant results do not equal significant effects
Neurotoxicity
The capacity of chemical, biological, or physical agents to cause adverse functional or structural changes in the nervous system at any time in the life cycle
Functional changes
Neuro-chemical, neurophysiological, or behavioural changes
Structural changes
Distinct neuroanatomical changes (macroscopic and microscopic)
Neurotoxins/Neurotoxicants
- A wide range of chemicals have been associated with neurotoxicity
- Estimated that approximately 3 of 28% of all commercial chemical may be neurotoxic
- Can act on
- Central Nervous System (CNS)
- Peripheral nerve fibers
- Peripheral nerve endings or muscles or other effector organs
Neurotoxic Effects: transient modifications
You may see an Increase in neurotransmitter at a synapse with low exposure but this doesn’t mean it’s an adverse effect
Adverse Neurotoxic effects
Persistent structural changes or persistent functional changes in behavioural, neurochemistry, neurophysiology
Structural and Functional Effects
Many regions within the nervous system are functionally and anatomically interrelated
Localized of far-reaching effects
A localized lesion may have significant effects on more distant parts of the nervous system
Manifestations of neurotoxicity can be…
- Immediate: Quick or rapid effects
- Progressive: Happens over a long period of time, slow build up
- Delayed: Not seeing effects until a person reaches a certain age (e.c., Autism)
Neurotoxic effects on the nervous system
- Motor (ataxia, convulsions, paralysis)
- Sensory (vision disorders, equilibrium changes)
- Cognitive (confusion, memory problems)
- Affective or personality (excitability, depression)
- General (CNS depression, cholinesterase inhibition)
Blood Brain Barrier
- Physical barrier between the lumen of the cerebral blood vessels and the brain parenchyma
BBB function
Specialized microvascular endothelial cells form luminal tight junctions which occlude or severely attenuate movement through the intercellular spaces
BBB location
- Outside of the endothelial cells is a basement membrane which is surrounded by pericytes
BM
basement membrane (connective tissue between endothelial cells and astro cite)
Ec’s
endothelial cell (lines interior of vessels)
PC’s
pericytes (impacts transport of vessels within the brain)
As Endfoot
astrocytic end foot (extra protection)
BBB Ec’s function
- Form the walls of blood vessels
- The diameter of large arteries and veins can be made up of dozens of ECs
- Thin and differ from those found elsewhere
- Tight junctions exist- limiting the amount of movement through the cell
Unique properties of Ec’s (6)
- CNS ECs are extremely thin (39% thinner then muscle Ec)
- CNS ECs are held together by tight junctions
- CNS ECs express extremely low levels of leukocyte adhesion molecules
- CNS ECs undergo extremely low rats of transcytosis
- CNS ECs contain higher amounts of mitochondria
- CNS ECs have differential vascular metabolism altering the physical properties of molecules
Basement Membrane (BM) function
- Attach layers of tissue in the body (connecting ECs to neural tissue)
- Provide an anchor for many signalling processes at the vasculature
- Provide an additional barrier for molecules to cross before reaching neural tissue
- Slows down the path of a substance to reach the brain tissue
Pericytes (PC’s) function
- Embedded in the BM and do not touch the endothelium
- Are contractile proteins, and have the ability to contract to control the diameter of the capillary
Play an important role in
- Regulating angiogenesis,
- Wound healing,
- Regulating immune cell infiltration
- Regulation of blood flow in response to neural activity
- Regulating the formation of the BBB during development
- Area of brain used, more blood to the brain, controlled by these parasites
CNS PC's vs Tissue PC's Unique properties (2)
- CNS PCs are derived from the neural crest
2. CNAS microvasculature have the highest CNS PCs coverage of any tissue
BBB Tight junctions
- CNS ECs are held together by tight junctions
- This creates a highly resistant paracellular barrier to molecular and ions
- Have a size selective permeability to uncharged molecules up to 4 nanometers (nm)
BBB Transporters
- Efflux Transporters
2. Nutrient Transporters
Efflux Transporters
- Transport a wide variety of small lipophilic molecules into the blood that could otherwise passively diffuse across the EC membrane to the CNS
- Kick back into the blood system all things not welcome in the brain
Nutrient Transporters
- Transport specific nutrients across the BBB into the CNS
- Facilitates the removal of specific waste products from the CNS into the blood
BBB development steps
- Angiogenesis
- Endothelial progenitor cells innervate the embryonic neuroectoderm (form cell wall)
- Neural progenitor cells secrete factors that guide sprouting endothelial cells
- Innervation of endothelial cells by pericytes and astrocytes
- Sealing of inter endothelial tight junction (regulated by astrocytes and progenitor cells)
BBB Rates
- In humans, the BBB is fully established prenatally at approximately 23-32 weeks of gestation
- In rats, the BBB is fully developed at approximately postnatal day 1 to 3
BB- Cerebrospinal Fluid Barrier Formation
- A barrier between the blood and the cerebrospinal fluid (CSF) along the lateral, third, and fourth ventricles
- Blood vessels are fenestrated and form a non-restrictive barrier
- Epithelial cells (EPs) have tight junctions are restrict intercellular passage of molecules
- Created by the separation of the ventricular system from the extracellular fluid of the brain
BB- Cerebrospinal Fluid Barrier Function
- Minimizing the transfer of potential contaminants
- Allows nutrients and needed molecules/cells to pass
strap junctions
- between nerve ependymal cells
- Occludes intercellular passage of most molecules (except for the smallest molecules)
- Free exchange between either side of the barrier
- in embryos and fetuses
gap junctions
- between epidermal cells
- Allows intercellular passage of molecules
- in adults
BB- Cerebrospinal Fluid Barrier
Blood-brain interface over the outer surface of the brain within the pia-arachnoid
Meningeal Barrier
- Endothelial cells forming tight junction preventing the movement of things you don’t want into the brain
- Also in the arachnoid membrane
- Allows to keep in nutrients
Classification of Toxins: Mechanisms of Neurotoxicity
- Neurotoxic agents can be classified by their cellular target sites, neuropathological effects, or mode of action
- Classify neurotoxins based on cellular target sites and neuropathological effects
Seven Classifications of Toxins
- Neuronopathies
- Axonopathies
- Myelinopathies
- Neurotransmission-associated anomalies
- Astrocytes and vascular
- Developmental Neurotoxins
- Neuro-Carcinogens
Neuronopathies
- The neuron cell body is the target site for toxic agents
- Damage to the neuron progresses through various stages resulting in apoptosis (cell suicide: incur too much damage causing shrinking) or necrosis (metabolized compounds causes cell death) which can lead to axonal and dendritic degeneration
- Irreversible loss/cell most likely to die
- E.x., Manganese
Axonopathies
- The axon is the target site for toxic agents
- The disruption of axonal transport appears to be the toxic mechanisms for most axonotoxic chemicals
- Damage to the axon will result in secondary myelin degeneration, but the neuron cell body will remain intact
- Irreversible in the CNS
- E.x., Acrylamide: toxic potential, producing agent (water treatment)
Myelinopathies
- Myelin is the primary target of the toxic agent
- Interferes with axon functioning
- Exposure to the toxin may lead to direct myelin damage or by damage to myelin-producing cells
- Re-myelination in the CNS may occur to a very limited extent
- E.x., Lead
Neurotransmission-associated anomalies
- neurotransmission is the primary target of the toxic agent
- Difference aspects of neurotransmission may be affected depending on the toxic agent
- interruption of impulse transmission (block sodium channel)
- blockage of transsynaptic communication (prevent pre-post communication)
- inhibition of neurotransmitter uptake (removing neurotransmitters from post synaptic cleft > serotonin binds continuously to postsynaptic side> increasing stimulation)
- E.x., Cocaine
Astrocytes and vascular
- Astrocytes and vascular integrity are the primary targets of the toxic agent
- disruption of vascular permeability (BBB)
- neuronal cell death and edema (swelling and dying)
- E.x., Lead
Developmental Neurotoxins
- Toxic agents that produce functional deficits at certain doses
- other indications of development neurotoxicity are evidence
- minimal toxicity to adults
- some effects may be transient or reversible while others may be permanent
- E.x., Ethanol while preganent
Neuro-Carcinogens
- Toxic agents that induce cancer by either genotoxic (mutagenic) or non-genotoxic mechanisms
Granular cell tumours and malignant reticulosis originating from the cerebral or cerebellar meninges have been linked with chemical exposure
Ex: Ethylene oxide
