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Neuroscience Envrio Toxins and Mental Health > Nervous System > Flashcards

Nervous System Flashcards

1
Q

Seven factors that make the nervous system vulnerable to toxins and toxicants

A
  1. The complexity of structural and functional integration
  2. Limitations on Repair
  3. Accessibility to lipid-soluble toxins/toxicants
  4. Depending on Glucose
  5. Axonal Transport
  6. Synaptic Transmission
  7. Ion channels
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2
Q

The complexity of structural and functional integration

A

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

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3
Q

Limitations on Repair

A

Often neurons that are destroyed by toxic insults are not replaced

  • Damage can be permanent
  • limits for repair are exacerbated by normal aging processes
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4
Q

Accessibility to lipid-soluble toxins/toxicants

A
  • 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
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5
Q

Axonal Transport

A
  • 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)
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6
Q

Synaptic Transmission

A

Chemical mediated communication is vulnerable to disruption by exogenous chemical (5 disruption patterns)

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7
Q

Ion channels

A

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

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8
Q

Depending on Glucose

A
  • 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
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9
Q

Axonal Transport: Fast Anterograde

A
  • 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
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10
Q

Axonal Transport: Slow Anterograde

A
  • 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
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11
Q

Axonal Transport: Fast retrograde

A
  • 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)
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12
Q

Synaptic Transmission Disruption Patterns

A
  1. Increase the length of effects of neurotransmitters, which can lead to overstimulation (e.x., insecticides)
  2. Mimic the action of a neurotransmitter by interaction with its receptor molecule (e.x., ACh receptors)
  3. Block a neurotransmitter’s access to its receptor molecule (e.x., ACh receptors)
  4. Interfere with the synthesis of a neurotransmitter or prevent the release of a neurotransmitter from an axon (e.x., ACh transmission)
  5. Can be metabolized by neuronal enzymes and produce damaging metabolites (e.x., hydrogen peroxide)
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13
Q

Evidence of Developmental Window of Susceptibly

A
  • 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
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14
Q

utero exposure

A
  • Placental transfer

- Lactation (via breast milk)

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15
Q

Unique Vulnerability of Developing Brian: Placenta

A
  • The fetus is not well protected from environmental chemicals
  • Many chemicals can pass from the mother to the fetus via the placenta
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16
Q

Placental Barrier Development

A
  • Feto-placental maternal circulation established around the 10th week of pregnancy
  • Placenta regulates the exchange of nutrients and metabolites between mother and fetus
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17
Q

Placental Barrier Diffusion

A
  • 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.
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18
Q

Placental Barrier Function

A
  • 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
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19
Q

Placental Barrier loop holes

A
  • 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
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20
Q

Placental Exchange Factors

A

Factors that affect what substances can cross the placental barrier

21
Q

Placental Exchange Factor: Size

A

Molecular weight < 500 Daltons (Da) tend to cross

Molecular weight > 1000 Da usually cannot cross

22
Q

Placental Exchange Factor: Charge

A

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

23
Q

Placental Exchange Factor: Protein Binding

A

Protein-bound substances can cross placenta

24
Q

Placental Exchange Factor: Lipophilicity

A

Lipophilic compounds can cross placental barrier more easily

25
Q

Unique vulnerability of Developing Brain: Breast-feeding

A

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
26
Q

Unique vulnerability of Developing Brain: BBB

A
  • 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
27
Q

Unique vulnerability of Developing Brain: Toxicokinetic (TKs)

A
  • 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
28
Q

Unique vulnerability of Developing Brain: Rapid Brian Growth

A
  • 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
29
Q

Importance of Neurotoxicity Testing

A

Disease originating from exposure to environmental chemicals are preventable

30
Q

Two approaches to disease prevention

A
  1. Primary Prevention

2. Secondary Prevention

31
Q

Primary Prevention

A

Identifying potential neurotoxic hazards before humans are exposed

32
Q

Secondary Prevention

A

Early detection of a disease or dysfunction in exposed persons or populations followed by prevention of additional exposure

33
Q

Difficulty of Neurotoxicity Testing

A
  • 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
34
Q

Tests of Nervous System Function: Behaviour

Pros

A
  • 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
35
Q

Tests of Nervous System Function: Behaviour

Cons

A
  • Behavioural tests often lack specificity for the nervous system
36
Q

Examples of some behavioural indicators of neurotoxicity

A
  • 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
37
Q

Test of Nervous System Function: Neurochemistry

Pros

A

Neuro-chemical endpoints are particularly useful in understanding neurotoxic mechanisms of action

38
Q

Test of Nervous System Function: Neurochemistry

Cons

A

Neuro-chemical changes are not necessarily indicative of neurotoxic effects unless they induce neurophysiological, neuropathological, and/or neuro-behavioural effects

39
Q

Examples of some neuro-chemical endpoints

A
  • Increases in GFAP
  • Alterations in synthesis, release, uptake, degradation of neurotransmitters
  • Alterations in second-messenger-associated signal transduction pathways
  • Inhibition and ageing of acetylcholinesterase
40
Q

Test of Nervous System Function: Morphology

Pros

A
  • 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
41
Q

Test of Nervous System Function: Morphology

Cons

A
  • 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
42
Q

Test of Nervous System Function: Neurophysiology

Pros

A

Can produce reliable indicators of the functional status of affected portions of the neuronal network

43
Q

Test of Nervous System Function: Neurophysiology

Cons

A
  • Are usually post hoc studied

- Results sometimes reflect varies and often unknown exposure

44
Q

Examples of some neurophysiological endpoints

A
  • Changes in velocity, amplitude, or refractory period of nerve conduction
  • Changes in latency or amplitude of the sensory-evoked potential
  • Change in electroencephalographic patterns
45
Q

Test of Nervous System Function: In Vitro Systems

Pros

A
  • In vitro models can be less complicated

- Importation can be easily collected and quantified

46
Q

Test of Nervous System Function: In Vitro Systems

Cons

A

Generalizability of in vitro models can be limited

47
Q

Examples of Neurotoxins: The Frozen Addicts

A
  • 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
48
Q

Examples of Neurotoxins: Acute Flaccid Myelination

A
  • 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

Neuroscience Envrio Toxins and Mental Health (6 decks)

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