Nervous System Flashcards
Seven factors that make the nervous system vulnerable to toxins and toxicants
- The complexity of structural and functional integration
- Limitations on Repair
- Accessibility to lipid-soluble toxins/toxicants
- Depending on Glucose
- Axonal Transport
- Synaptic Transmission
- Ion channels
The complexity of structural and functional integration
Proper functioning of the nervous system depends on the complex interactions among different cell types in many anatomical locations that communicate via electrical and chemical signals
- many have compensatory mechanisms for small lesions
- widespread lesions often lead to loss of functional capacity
E.x., minor insulin to dopaminergic system cause no effect, large insulin to the same system may lead to impaired motor coordination
Limitations on Repair
Often neurons that are destroyed by toxic insults are not replaced
- Damage can be permanent
- limits for repair are exacerbated by normal aging processes
Accessibility to lipid-soluble toxins/toxicants
- Lipid content of the nervous system is very high
- Many classes of toxins and toxicants dissolve readily in lipids- Toxins/ toxicants can gradually leach out of lipid depots
- Internal exposure may last longer than external exposure
Axonal Transport
- Unlike most cells, neurons need to provide support to dendrites and axons
- Intracellular transport down the axon is highly vulnerable to interruption by toxic chemicals
- Functional integrity of the neuronal cell body often depends on a reciprocal supply of trophic factors from cells that it innervates (which are supplied via axonal transport)
Synaptic Transmission
Chemical mediated communication is vulnerable to disruption by exogenous chemical (5 disruption patterns)
Ion channels
Nerve impulses depend on the proper functions of ion-specific channels in the membrane
- Substances that inhibit metabolic enzymes may cause sodium to accumulate and potassium to be lost resulting in membrane depolarization and then the loss of excitability
Depending on Glucose
- Nervous system depends almost exclusively on glucose for energy and as a precursor in the synthesis of other molecules
- Disruption of the energy in the body and the brain, it will have a big impact because they need a large energy resource originally
- pumps will not work properly > detrimental effects to the axon
Axonal Transport: Fast Anterograde
- forward
- Carries macromolecular assemblies along microtubules from the cell body to distal axons
- Primarily membrane-associated glycosylated or sulphated proteins
- The rate of about 400 mm/day
Axonal Transport: Slow Anterograde
- forward
- Carries soluble enzymes involved in metabolism and neurotransmission
- A rate of 1-2 mm/day (microtubules or neurofilaments)
Larger, less flexible: a scaffolding of cell shape - A rate of 5-10 mm/day (microfilaments)
Smaller, more flexible: help axon move better
Axonal Transport: Fast retrograde
- Carries a variety of materials up the axons to the cell body
- A rate of 250 mm/day
- May carry endogenous molecules (glycoproteins) or exogenous materials (lead)
Synaptic Transmission Disruption Patterns
- Increase the length of effects of neurotransmitters, which can lead to overstimulation (e.x., insecticides)
- Mimic the action of a neurotransmitter by interaction with its receptor molecule (e.x., ACh receptors)
- Block a neurotransmitter’s access to its receptor molecule (e.x., ACh receptors)
- Interfere with the synthesis of a neurotransmitter or prevent the release of a neurotransmitter from an axon (e.x., ACh transmission)
- Can be metabolized by neuronal enzymes and produce damaging metabolites (e.x., hydrogen peroxide)
Evidence of Developmental Window of Susceptibly
- UTERO
- Low levels of exposure during these time periods may lead to permanent brain damage
- The same dose may have little to no adverse effect in an adult
- Depending on the contaminant, when it was introduced, where it affects your body, we can see effects up into your 20s
utero exposure
- Placental transfer
- Lactation (via breast milk)
Unique Vulnerability of Developing Brian: Placenta
- The fetus is not well protected from environmental chemicals
- Many chemicals can pass from the mother to the fetus via the placenta
Placental Barrier Development
- Feto-placental maternal circulation established around the 10th week of pregnancy
- Placenta regulates the exchange of nutrients and metabolites between mother and fetus
Placental Barrier Diffusion
- Diffusion form both sides
Mother’s blood > space > villi barrier > fetus - Compounds move from the mother to the fetus against a concentration gradient
Ensures adequate levels of essential substances - Requires energy: if energy metabolism is affected, this transfer will be affected.
Placental Barrier Function
- Helps provide nutrients and minerals to the fetus through the blood, and provides a pathway to remove waste from the fetus back to the mother
Placental Barrier loop holes
- Some substances can mimic essential compounds or may be bound to essential compounds to use existing transport mechanisms
E.x., BMAA (phycotoxin) – mimics amino acids
Placental Exchange Factors
Factors that affect what substances can cross the placental barrier
Placental Exchange Factor: Size
Molecular weight < 500 Daltons (Da) tend to cross
Molecular weight > 1000 Da usually cannot cross
Placental Exchange Factor: Charge
Non-ionized substances tend to cross
The fetus usually has a lower PH than the mother (more acidic)
- Non Ionized substances can become ionized by gaining H+
- This can lead to “ion trapping”- substance unable to cross back and remaining on the fetus side of the placental barrier
- Results in greater concentrations in the fetus
Placental Exchange Factor: Protein Binding
Protein-bound substances can cross placenta
Placental Exchange Factor: Lipophilicity
Lipophilic compounds can cross placental barrier more easily
Unique vulnerability of Developing Brain: Breast-feeding
Chemicals can accumulate over time in fatty tissues in women (e.x.,dioxins, PCB)
- These chemicals can find their way into breast milk
- unclear what quantities of these are in breast mild
- unclear effects on infant
Unique vulnerability of Developing Brain: BBB
- The blood-brain barrier (BBB) is not developed until 23-32 weeks gestation (humans)
- Fetal brain may be more permeable to substances prior to the development of the BBB
- More vulnerable before the BBB has fully developed
Unique vulnerability of Developing Brain: Toxicokinetic (TKs)
- Developing organism may not have the systems in place to metabolize or excrete certain substances
- Can affect how substances end up accumulating within a fetus. No way of metabolizing them or excreting them.
- May be differences in metabolizing enzyme, rates of excretion, binding affinity to target proteins
Unique vulnerability of Developing Brain: Rapid Brian Growth
- In humans, the brain develops rapidly during the 3rd trimester and continues throughout the first years of life
- Neural stem cells are very sensitive to neurotoxic substances
plays in synapse formation - Epigenetic changes may affect subsequent gene expression in the brain
- Substances that interfere with cell proliferation, survival, differentiation, synaptic pruning, myelination, gliosis
Importance of Neurotoxicity Testing
Disease originating from exposure to environmental chemicals are preventable
Two approaches to disease prevention
- Primary Prevention
2. Secondary Prevention
Primary Prevention
Identifying potential neurotoxic hazards before humans are exposed
Secondary Prevention
Early detection of a disease or dysfunction in exposed persons or populations followed by prevention of additional exposure
Difficulty of Neurotoxicity Testing
- The nervous systems exhibit a greater degree of cellular, structural, and chemical heterogeneity
- Toxic substances can potentially affect any functional or structural component
- When designing test methods need to take into consideration many factors including
Tests of Nervous System Function: Behaviour
Pros
- Behaviour is through to be a relatively sensitive indicator of exposure
- Behavioural endpoints tend to be non-invasive and can be used to repeated assess participants/animals
- Common behavioural endpoints include acoustic startle, motor activity, learning and memory
Tests of Nervous System Function: Behaviour
Cons
- Behavioural tests often lack specificity for the nervous system
Examples of some behavioural indicators of neurotoxicity
- An increase or decrease in motor activity
- Changes in touch, sight, sound, taste, or smell sensations
- Changes in rate or temporal patterning of schedule-controlled behaviour
- Changes in learning, memory, and attention
- Overt clinical signs of neurotoxicity
Test of Nervous System Function: Neurochemistry
Pros
Neuro-chemical endpoints are particularly useful in understanding neurotoxic mechanisms of action
Test of Nervous System Function: Neurochemistry
Cons
Neuro-chemical changes are not necessarily indicative of neurotoxic effects unless they induce neurophysiological, neuropathological, and/or neuro-behavioural effects
Examples of some neuro-chemical endpoints
- Increases in GFAP
- Alterations in synthesis, release, uptake, degradation of neurotransmitters
- Alterations in second-messenger-associated signal transduction pathways
- Inhibition and ageing of acetylcholinesterase
Test of Nervous System Function: Morphology
Pros
- Neuroanatomical changes resulting from exposure to toxic substances are always regarded as adverse
- Most structural changes test to be detectable only at the light microscopic level
Test of Nervous System Function: Morphology
Cons
- Sometimes need to know what you are looking for in order to find it
- Hard to determine if there is a compensatory mechanism in place to adapt to potential CNS damages
Test of Nervous System Function: Neurophysiology
Pros
Can produce reliable indicators of the functional status of affected portions of the neuronal network
Test of Nervous System Function: Neurophysiology
Cons
- Are usually post hoc studied
- Results sometimes reflect varies and often unknown exposure
Examples of some neurophysiological endpoints
- Changes in velocity, amplitude, or refractory period of nerve conduction
- Changes in latency or amplitude of the sensory-evoked potential
- Change in electroencephalographic patterns
Test of Nervous System Function: In Vitro Systems
Pros
- In vitro models can be less complicated
- Importation can be easily collected and quantified
Test of Nervous System Function: In Vitro Systems
Cons
Generalizability of in vitro models can be limited
Examples of Neurotoxins: The Frozen Addicts
- synthetic heroin MPTP
- metabolite (MMP+ was responsible for its toxicity
- MPTP is lipophilic and can easily pass into the brain
- Once in the brain, converted to MPDP+ then into MPP+
- MPP+ released into extracellular space
- MPP+ has a high affinity for dopamine transporters and is taken up via DAT+ into dopaminergic neurons
- leads to death of DA neurons
Examples of Neurotoxins: Acute Flaccid Myelination
- A medical condition that affects the nervous system, resulting in the weakening of muscles and reflexes
- Affects the grey matter of the spinal cord
- Majority of patients present with a fever consistent with a viral infection or a respiratory virus prior to becoming symptomatic
- A singular cause of AFM remains a mystery
- Nerve transfer surgery
