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NEUR 3401 > Quiz 1 > Flashcards

Quiz 1 Flashcards

Lectures 1-4

1
Q

What is Toxicology?

A

A branch of science that studies the adverse effects of chemical, physical or biological agents on living systems and the ecosystem, including the prevention and the amelioration of such adverse effects

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2
Q

Toxicology is an Interdisciplinary field involving… (4)

A

biology, chemistry, pharmacology, and medicine

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3
Q

What is Descriptive Toxicology?

A

Focuses on testing of toxic substances
Typically using animals and then correlating findings to humans
Provides information for safety evaluation and regulation, such as dose-response information

Ex: Assessing the reproductive toxicity of BPA

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4
Q

What is Mechanistic toxicology?

A

Identifying and understanding the mechanisms that underlie the toxic effects of drugs or chemicals on living systems
Also identifies whether the effects are genotoxic, teratogenic, carcinogenic, neurotoxic, etc.

Ex: Study identifying targets of gymnodimines

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5
Q

What is Regulatory toxicology?

A

Assessing whether a drug or chemical poses a risk to human health
Uses information gathered from toxicity testing
Establishes standards and/or guidelines for safe exposure

Ex: guidance for the consumption of bitter apricot kernels

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6
Q

What is Forensic toxicology?

A

Concerned with the medicolegal aspects of the harmful effects of toxic substances, environmental chemicals or poisonous products on human and animals
Determines cause of death in a post-mortem investigation

Ex: Red tide in Florida linked to dolphin deaths

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7
Q

What is Clinical toxicology?

A

Concerned with disease states caused by or associated with toxic substances
Usually involves physicians or individuals specialized in emergency medicine and/or poison management

Ex: New study linked exposure to second-hand tobacco smoke can predict cardiac arrhythmia

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8
Q

What is Environmental toxicology?

A

Concerned with the impact of physical and chemical pollutants in the environment on biological organisms
Includes the effects on human health and non-human organisms (such as fish, birds, and terrestrial animals)

Ex: Microplastics in bottled water

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9
Q

What is Ecotoxicology?

A

Specialized are within environmental toxicology that is concerned with the impacts of toxic substances on population dynamics in an ecosystem
Also evaluates the transport, fate, and interactions of toxic substances in the environment

Ex: Studying the effects of glyphosate (herbicide) on honey bees

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10
Q

What did Paracelsus (16th Century) determine?

A

specific chemicals were responsible for the toxicity of a plant or an animal poison

“All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.”

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11
Q

Who is Orfila (19th Century) and what did he demonstrate?

A

Spanish physician considered the founder of toxicology

Demonstrated the effects of poisons on specific organs by analyzing autopsy materials for poisons and tissue damage associated with them

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12
Q

What is a toxin?

A

Peptides or proteins produced by living cells or organisms (i.e., natural toxins)

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13
Q

What is a toxicant?

A

Substances that are synthetic (man-made

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14
Q

What is a poison?

A

Any synthetic or natural substance that is harmful to health

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15
Q

Define Xenobiotic

A

Foreign substance taken into the body

May produce beneficial effects (i.e. pharmaceuticals) or produce toxic effects (i.e., heavy metals)

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16
Q

What is a toxic agent?

A

Anything that can produce an adverse biological effect

Can be chemical (cyanide), physical (radiation), or biological (snake venom)

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17
Q

What is a toxic substance?

A

Any material that has toxic properties

Can be a discrete toxic chemical (lead) or a mixture of chemicals (gasoline)

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18
Q

9 ways that toxins are classified

A
  • Toxicity (extremely - slightly)
  • Median Lethal Dose (LD50)
  • Physical state (gas, solid, liquid)
  • chemical composition
  • intended use (pesticide, solvent, etc)
  • source (natural/synthetic)
  • mechanism of action
    target organ
  • Special effect (carcinogen, mutagen, endocrine disruptor)
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19
Q

What is toxicity?

Toxicity can be ________, __________, or ________

A

The degree to which a substance can harm humans or animals

Toxicity can be acute, subchronic or chronic

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20
Q

Toxicity can result from adverse… (3) changes

A
  • Cellular changes
    • ex: cell death (cytotoxins)
  • Biochemical changes
    • ex: elevated liver enzymes (hepatotoxins)
  • Macromolecular changes
    • ex: altered insulin signalling (diabetogens)
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21
Q

What is Acute Toxicity (4 points)

A
  • Adverse effects occurring in an organism after a single exposure or short-term exposure (< 24 hours)
  • Exposure to a large dose (weak toxin) or a small dose (potent toxin)
  • Onset of symptoms is sudden and severe in nature
  • Rapidly changing course of progress
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22
Q

What is Subchronic Toxicity? (2 points)

A
  • Due to repeated exposure for several weeks or months
  • The ability of a toxic substance to cause adverse effects for more than one year but less than the lifetime of the exposed organism
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23
Q

What is Chronic Toxicity? (3 points)

A
  • The ability of a toxic substance to cause adverse effects over an extended period, usually upon repeated or continuous exposure, sometimes lasting for the entire life of the exposed organism
  • Cumulative damage
  • Damage becomes so severe that the organ can no longer function as normal
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24
Q

Two types of toxic responses: Exposure Effect

A

Local

  • Effect at site of contact
  • Ex: gastrointestinal tract, lungs

Systemic

  • Effect distant from exposure site
  • Ex: central nervous system, kidneys

Some both

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25
Q

2 Types of Toxic Responses: Target

A

Specific
- Affect only specific target organs

Widespread
- Can damage any cell or tissues that they come in contact with

Sometimes both

  • Target organ may be affected after acute exposure whereas multiple organs affect after chronic exposure
  • May depend on dosage and route of exposure
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26
Q

2 Types of Toxic Responses: Timing

A

Immediate

  • Minutes to hours after a single exposure
  • Ex: azaspiracids

Delayed

  • Days to years after exposure
  • Ex: BMAA (potentially linked to neurodegenerative diseases)

Some both

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27
Q

2 Types of Toxic Responses: Permanence

- 3 factors that influence permanence

A

Reversible

  • Rapidly regenerating tissue
  • Ex: liver, intestinal mucosa, blood cells

Irreversible
- CNS damage, carcinogenesis, mutagenesis, teratogenesis

Factors that influence if reversible or irreversible include:

  • Tissue involved
  • Length of exposure
  • Magnitude of toxic insult
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28
Q

2 Types of Toxic Responses: Effect

A

Direct
- Substances or their metabolites themselves are toxic
Ex: phthalates (DEHP)

Indirect
- Some substances may be toxic by indirectly modifying an essential biochemical function, interfering with nutrition, or altering a physiological mechanism

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29
Q

Three Phases of Toxicology

A

Exposure phase
- How an organism comes in contact with a toxin

Toxicokinetic phase

  • The study of the movement of the toxin within the body
  • Absorption, distribution, metabolism, and excretion (ADME)

Toxicodynamic phase

  • The study of what the toxin does to the body
  • Physiological, biochemical, and/or molecular changes
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30
Q

Exposure Phase of Toxicology: 3 factors

A
  • Sources (everyday items have hundreds of chemicals)
  • Route (oral, dermal, inhalation, injection)
  • Duration
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31
Q

Exposure Phase of Toxicology: Duration of exposure can be … (4)

A

Acute (< 24 hours)
Subacute (< 1 month)
Subchronic (1-3 months)
Chronic (> 3 months)

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32
Q

Exposure Phase of Toxicology:
An individuals exposure to a substance can be assessed based on the relationship between a person’s body weight and… (3)

A
  • Concentration of the substance
  • Amount of a substance taken into the body
  • Duration and frequency of exposure
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33
Q

Exposure VS Dose

A

Exposure (outside)
- Any condition which provides an opportunity for an external environmental substance to enter the body

Dose (inside)

  • The amount of an substance actually deposited within the body
  • Dose can affected by route, duration, frequency, amount, concentration as well as body weight, sex, age, time etc.
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34
Q

What is an administered dose?

A

The quantity administered to an organism at one time

The entire dose may not necessarily be absorbed

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35
Q

What is an Internal/absorbed dose?

A

The amount of a toxin that stays in an organism’s body

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36
Q

What is a total dose?

A

Sum of all individuals doses

Total dose = Concentration X Amount X Frequency X Duration

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37
Q

What is a response/endpoint to a dose?

A

The biological response to a substance

Change in structure or function, morbidity, or mortality

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38
Q

Dose-response curve: Point at which toxicity first appears in known as the…

A

threshold dose level

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39
Q

What does NOAEL stand for

A

No Observed Adverse Effect Level (NOAEL)

Highest doses at which no toxic effects observed No

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40
Q

What does LOAEL stand for

A

Lowest Observed Adverse Effect Level (LOAEL)

Lowest dose at which toxic or adverse effects observed

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41
Q

What is Toxicokinetics

A

The study of the movement of the toxin within the body

Absorption, distribution, metabolism, and excretion (ADME)

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42
Q

Absorption: What is Passive Transfer

A

Consists of simple diffusion
No cellular energy or assistance is required
Most common way that toxins cross cell membranes

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43
Q

Two factors that determine the rate of passive transfer

A

Concentration gradient (high to low)

Movement through small pores in membrane or lipophilic interior of the membrane

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44
Q

3 Properties affecting a chemicals substance for passive transfer include:

A

Lipid solubility
Molecular size
Degree of ionization (positive/negative charge)

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45
Q

Absorption: What is Facilitated Diffusion

A
  • Similar to simple diffusion: does not require energy and follows concentration gradient
  • Requires special transport proteins embedded within the cell membrane to facilitate movement of molecules across the membrane
  • Is faster and can move larger molecules than passive transport
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46
Q

Absorption: What is Active Transport

A
  • Requires cellular energy (ATP)

- move through ion channels

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47
Q

Absorption: What is Endocytosis

A

Cell surrounds the substance within a section of its cell wall

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48
Q

What is distribution?

- _______, ________, and _______ can distribute chemicals.

A

Distribution is the process in which an absorbed chemical moves away from the site of absorption to other areas of the body

Blood, lymph, and CSF can distribute chemicals

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49
Q

4 storage sites for chemicals in the body

A

adipose tissue
liver
kidney
bone

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50
Q

Distribution: 3 Barriers that stop chemicals

A

Blood-Brain Barrier (BBB)
Blood-CSF Barrier
Placental Barrier

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51
Q

What is metabolism

A

Also known as biotransformation

Conversion of a chemical from one form to another by a biological organism

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52
Q

Two phases of metabolism:

A

Phase I reactions
- modify the chemical by adding a functional structure

Phase II reactions
- conjugate the modified substance with another substance

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53
Q

Phase I Metabolism

A

Detoxification

  • Chemical substance is converted to a less toxic form
  • Generally speaking lipid-soluble compounds are converted to polar compounds
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54
Q

Phase II Metabolism

A

Bioactivation

- Chemical substance is converted to more reactive or toxic forms

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55
Q

Excretion: where does it occur

A

Kidney is primary excretory organ

- Other sites of excretion include the GI tract, lungs, sweat, tears, and breast milk

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56
Q

What is toxicodynamics

A

The study of what the toxin does to the body
- Physiological, biochemical, behavioural, and/or molecular changes

  • Toxic chemical effects critical target, causes modification to target, causes overt biological response or effect
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57
Q

Factors Influencing Toxicity: Factors Related to the Substance (5)

A
  • Form of a substance (chemical makeup)
  • Innate chemical activity of a substance
  • Dosage
  • Exposure Route
  • Level of absorption
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58
Q

Factors Influencing Toxicity: Factors Related to the Organism (7)

A
  • Species
  • Life stage
  • sex
  • Metabolism
  • Distribution within the body
  • Health and Nutritional status
  • Circadian rhythms
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59
Q

Factors Influencing Toxicity: Other Factors (1)

A
  • interactions with other present chemicals

-

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60
Q

Factors Influencing Toxicity: The combined effects of two or more chemicals can be… (4)

A
  1. additive
  2. synergistic (may occur due to both chemicals using similar metabolism pathways or one of the chemicals can inhibit the metabolism pathway of the other)
  3. Potentiation Effects ( Occurs when one chemical that does not normally have a toxic effect is added to another chemical, making the second chemical more toxic)
  4. Antagonistic effects (Effects of two or more chemicals interfere with each other’s action)
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61
Q

Factors Influencing Toxicity: 4 types of antagonism

A

Physiological antagonism
- Severe drop in blood pressure due to a barbiturate overdose reversed by administration of vasopressor

Chemical antagonism
- Mercury toxicity can be reduced by chelating the mercury ions with dimercaprol

Dispositional antagonism
- Swallowed poison is absorbed by introducing charcoal into the stomach reducing duration of chemical at target organ

Receptor antagonism
- Carbon monoxide poisoning is treated with oxygen to displace the carbon monoxide from the hemoglobin receptors

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62
Q

What is a hazard VS a risk?

A

Hazard

  • The potential of a substance to cause damage
  • 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

Substances which pose only a small hazard but there is frequent or excessive exposure may pose as much risk as substances which have a high degree of hazard but only limited exposure

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63
Q

What is a monotonic dose-response curve?

A

The higher the dose, the greater the response (effect)
“S” shaped curves
linear

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64
Q

What is a non-monotonic dose-response curve?

A
  • 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
  • Inverted “U” shaped curves with high responses at the intermediate doses
  • when the dose is high enough, the response stops increasing and starts to decrease
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65
Q

Why do we get non-monotonic responses:

What is Hormesis?

A
  • Biphasic response to increasing amounts of a substance

- Low doses show beneficial effects whereas high doses show detrimental effects

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66
Q

Why do we get non-monotonic responses: what is the low-dose hypothesis

A

Responses that may occur at doses well below those levels previously tested and determined to be safe

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67
Q

Why do we get non-monotonic responses: Toxins can also be _____________ _____________

A

Need small amounts of these substances to maintain good health
High doses of these substances can be toxic

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68
Q

What is neurotoxicity?

A

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: Neurochemical, neurophysiological, or behavioural changes

structural changes: Neuroanatomical changes (macroscopic and microscopic)

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69
Q

What are adverse neurotoxic effects?

A
  • Persistent structural changes or persistent functional changes in behavioural, neurochemistry, neurophysiology
  • Reversible effects occurring at doses that could endanger performance in the workplace
  • Reversible effects occurring at doses that are associated with a known neurotoxicological mechanism of action
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70
Q

Neurotoxic Effects may have…. (2)

A

both structural and functional effects

localized or far-reaching effects

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71
Q

Manifestations of neurotoxicity can be: (3)

A

immediate
progressive
delayed

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72
Q

What is the Blood Brain Barrier (BBB)

A
  • Physical barrier between the lumen of the cerebral blood vessels and the brain parenchyma
  • Specialized microvascular endothelial cells form luminal tight junctions which occlude or severely attenuate movement through the intercellular spaces
  • Outside of the endothelial cells is a basement membrane which is surrounded by pericytes
  • Around these structures are the astrocytic endfeet from nearby astrocytes
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73
Q

Blood-Brain Barrier: what are endothelial cells? ECs

A
  • Form the walls of blood vessels

- The diameter of large arteries and veins can be made up of dozens of ECs

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74
Q

Blood-Brain Barrier: Specifications of CNS endothelial cells

  • extremely _______
  • held together by tight _____________
  • lack ___________ (pores)
  • express extremely low levels of ______________ ____________ molecules
  • undergo extremely low rates of ________________
  • higher amounts of ________________
  • differential ___________ ______________ altering the physical properties of molecules
A 
thin
junctions
fenestrae
leukocyte adhesion
transcytosis
mitochondria
vascular metabolism
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75
Q

Blood-Brain Barrier: What is the basement membrane?

A
  • 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
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76
Q

Blood-Brain Barrier: What are pericytes?

A
  • 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

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77
Q

BBB: Pericytes have an important role in… (5)

A
  • 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
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78
Q

BBB: CNS Pericyte specifications (2)

A
  • derived from the neural crest rather than the mesoderm

- CNS microvasculatures have the highest CNS PCs coverage of any tissue

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79
Q

Blood-Brain Barrier: what are Astrocytes

A

Astrocytes provide a cellular link between neuronal circuitry and blood vessels

  • This allows astrocytes to relay signals that regulate blood flow in response to neuronal activity
  • Includes contraction and dilation of vascular smooth muscle cells as well as PCs

The endfeet of the basal process of astrocytes almost completely surrounds the vascular tube

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80
Q

Blood-Brain Barrier: Tight Junctions, importance

A
  • CNS ECs are held together by tight junctions
  • This creates a highly resistant paracellular barrier to molecules and ions
  • Have a size elective permeability to uncharged molecules up to 4 nanometers (nm)
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81
Q

Two main categories of transporters in CNS endothelial cells

A

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

Nutrient Transporters

  • Transport specific nutrients across the BBB into the CNS
  • Facilitates the removal of specific waste products from the CNS into the blood
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82
Q

Development of BBB

  • begins with __________________
  • endothelial ______________ cells innervate the embryonic __________________
  • neural ____________ cells secrete factors that guide sprouting ______________ cells
  • Innervation of ______________ cells by ____________ and ____________
  • ____________ of interendothelial ________ ______________ by ____________
A

angiogenesis

progenitor. .. neuroectoderm
progenitor. .. endothelial
endothelial. .. astrocytes… pericytes
sealing. .. tight junctions… astrocytes

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83
Q

In humans, the BBB is fully established prenatally at approximately ___________ weeks of gestation

A

23-32

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84
Q

What is the Blood-CSF Barrier

A

A barrier between the blood and the cerebrospinal fluid (CSF) along the lateral, third, and fourth ventricles

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85
Q

CSF-Brain Barrier in embryos/ development (2)

Gap differences in fetuses/adults (2)

A
  • Only significant barrier in the embryo
  • Created by the separation of the ventricular system from the extracellular fluid of the brain
  • In embryos and fetuses, strap junctions (tight, nothing can get through) between neuroependymal cells
  • In adults, gap junctions (free exchange) between ependymal cells
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86
Q

What is the Meningeal Barrier

A

Blood-brain interface over the outer surface of the brain within the pia-arachnoid
- Arachnoid membrane and blood vessels in the arachnoid and pial surface have tight junctions

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87
Q

Junctions in the meningeal barrier in adults vs fetuses

A

In adults, cells lining these regions are linked by gap junctions

In early brain development, cells lining these regions are linked by strap junctions

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88
Q

Neurotoxic agents can be classified by (3)

A

cellular target sites, neuropathological effects, or mode of action

89
Q

7 types of Neurotoxic agents

A
  1. neuronopathies
  2. axonopathies
  3. myelinopathies
  4. Neurotransmission-associated anomalies
  5. Toxins affecting astrocytes and vascular integrity
  6. developmental neurotoxins
  7. neurocarcinogens
90
Q

NEUROTOXIC AGENTS: What are Neuronopathies (3)

A
  • The neuron cell body is the target site for toxic agents
  • Irreversible loss
  • Damage to the neuron progresses through various stages resulting in apoptosis or necrosis which can lead to axonal and dendritic degeneration
91
Q

NEUROTOXIC AGENTS: What are axonopathies (5)

A
  • 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
  • Longer axons as affected first
92
Q

NEUROTOXIC AGENTS: What are myelinopathies (3)

A
  • Myelin is the primary target of the toxic agent
  • Exposure to the toxin may lead to direct myelin damage or by damage to myelin-producing cells
  • Remyelination in the CNS may occur to a very limited extent
93
Q

NEUROTOXIC AGENTS: What are Neurotransmission-associated anomalies (1)

Different aspects of neurotransmission that may be affected (4)

A
  • Primary target of toxic agent is neurotransmission
  • Different aspects of neurotransmission may be affected depending on the toxic agent:
    1. Interruption of impulse transmission
    2. Blockage of transsynaptic communication
    3. Inhibition of neurotransmitter uptake
    4. Interference with second-messenger systems
94
Q

NEUROTOXIC AGENTS: What are Toxins affecting astrocytes and vascular integrity (3)

A
  • Toxins which disrupt vascular permeability
  • Can lead to increase permeability of the BBB, neuronal cell death, and edema
  • Recent evidence suggests that astrocytes may be the primary target at the BBB
95
Q

NEUROTOXIC AGENTS: What are Developmental Neurotoxins (4)

A
  • Toxic agents that produce functional deficits at…
    1. Doses at which other indications of developmental neurotoxicity are evidence and
    2. Doses with minimal toxicity to adults
  • Some effects may be transient or reversible while others may be permanent
96
Q

NEUROTOXIC AGENTS: What are neurocarcinogens (2)

A
  • Toxic agents that induce cancer by either genotoxic (mutagenic) or nongenotoxic mechanisms
  • Granular cell tumors and malignant reticuloses originating from the cerebral or cerebellar meninges have been linked with chemical exposure
97
Q

Factors that make the nervous system especially vulnerable to toxins and toxicants:

  1. Complexity of ____________ and _____________ Integration
  2. Limitations on ________
  3. Accessibility to _______-________ toxins/toxicants
  4. Dependence on __________
  5. ________ transport
  6. ___________ transmission
  7. ______ Channels
A 
Structural... functional
repair
lipid-soluble
glucose
Axonal
Synaptic
Ion
98
Q

3 Types of Axonal transport

A 
Fast anterograde (forward)
Slow anterograde (forward)
Fast retrograde (backwards)
99
Q

Types of disruptions to synaptic transmission:

  1. Increase the ________ of effects of ___________________, which can lead to _______________
  2. Mimic the _______ of a ________________ by interaction with its ___________ __________
  3. ________ a neurotransmitter’s __________ to it’s ____________ __________
  4. Interfere with the ____________ of a _________________ or prevent the _________ of a neurotransmitter from an _________
  5. Can be _____________ by neuronal ___________ and produce ___________ _____________
A

length… neurotransmitter… overstimulation
action… neurotransmitter,,, receptor molecule
Block… access… receptor module
synthesis… neurotransmitter… release… axon
metabolized… enzymes… damaging metabolites

100
Q

How are ion channels vulnerable to toxic insults?

A

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

101
Q

How is the Accessibility of lipid-soluble toxins dangerous for the CNS?

A

Many classes of toxins and toxicants dissolve readily in lipids

Can accumulate and reach high local concentrations

Are relatively protected from enzyme degradation and do not enter general circulation

102
Q

How is the CNS vulnerable to toxins due to it’s dependence on glucose?

A

Toxins that inhibit enzymes that metabolize glucose are particularly damaging

103
Q

How does axonal transport make the CNS vulnerable to toxins?

A

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

104
Q

Exposure of the infant in utero to toxins can occur through….

A
  • Placental transfer

- Lactation (via breast milk)

105
Q

Differences in toxicokinetics (TKs) between developing and developed organisms

A
  • Developing organisms may not have the systems in place to metabolize or excrete certain substances
  • May be differences in metabolizing enzyme, rates of excretion, binding affinity to target proteins
106
Q

Two approaches to disease prevention

A
  1. Primary prevention: Identifying potential neurotoxic hazards before humans are exposed
  2. Secondary prevention : Early detection of a disease or dysfunction in exposed persons or populations followed by prevention of additional exposure
107
Q

Tests of Nervous System Function: Behaviour
3 Pros
1 Con

A

PROS: 1. Behaviour is through to be a relatively sensitive indicator of exposure

  1. Behavioural endpoints tend to be non-invasive and can be used to repeated assess participants/animals
  2. Common behavioural endpoints include, acoustic startle, motor activity, learning and memory

CON: 1. Behavioural tests often lack specificity for the nervous system

108
Q

Tests of Nervous System Function: Neurochemistry
1 Pro
1 Con

A

PRO: Neurochemical endpoints are particularly useful in understanding neurotoxic mechanisms of action

CON: Neurochemical changes are not necessarily indicative of a neurotoxic effects, unless they induce neurophysiological, neuropathological, and/or neurobehavioural effects

109
Q

Tests of Nervous System Function: Morphology
2 Pros
2 Cons

A

PROS: 1. Neuroanatomical changes resulting from exposure to toxic substances are always regarded as adverse
2. Most structural changes tend to be detectable only at the light microscopic levels

CONS: 1. Sometimes need to know what you are looking for in order to find it
2. Hard to determine if there are compensatory mechanism in place to adapt to potential CNS damage

110
Q

Tests of Nervous System Function: Neurophysiology
1 Pro
2 Cons

A

PRO: Can produce reliable indicators of the functional status of affected portions of neuronal networks

CONS: 1. Are usually post hoc studies
2. Results sometimes reflect varied and often unknown exposures

111
Q

Tests of Nervous System Function: In Vitro Systems
2 Pros
2 Cons

A

PROS: 1. In vitro models can be less complicated
2. Information can be easily collected and quantified

CONS: 1. Generalizability of in vitro models can be limited
2. CNS complexity can complicate the interpretation of in vivo studies

112
Q

5 Different tests of Nervous System Function

A 
Behaviour
Neurochemistry
Morphology
Neurophysiology
In Vitro Systems
113
Q

How Did MPTP Lead to Parkinsonogenic Effects? (“The Frozen Addicts”)
WHAT IS THE METABOLIC PROCESS

A

MPTP itself is not toxic!

  • MPTP is lipophilic and can easily pass into the brain
  • Once in the brain, it is converted from MPTP into MPDP+ by monoamine oxidase B and then converted into active toxic compound MPP+
  • MPP+ is then released in extracellular space by unknown mechanism
114
Q

How Did MPTP Lead to Parkinsonogenic Effects? (“The Frozen Addicts”)
WHAT IS THE SYNAPTIC PROCESS

A
  • MPP+ has a high affinity for dopamine transporters (DAT)
  • MPP+ taken up via DATs into dopaminergic (DA) neurons
  • Within DA neurons MPP+ inhibits enzymes in the mitochondrial electron transport chain
  • Ultimately leading to cell death of the DA neuron
115
Q

What can slow the progression of MPTP-Induced Parkinsonogenic Effects

A

Monoamine oxidase inhibitors

116
Q

What is Acute Flaccid Myelitis (AFM)

A
  • A medical condition that affects the nervous system, resulting in the weakening of muscles and reflexes
  • Affects the gray matter of the spinal cord (may also be related to inflammation)
  • Affects the gray matter of the spinal cord (may also be related to inflammation)
117
Q

What is the cause of Acute Flaccid Myelitis (AFM)?

What is the treatment for AFM?

A

A singular cause of AFM remains a mystery
- Most promising hypothesis: Enterovirus

  • No effective treatment to date
  • Several drugs have been tried including intravenous immunoglobulins, corticosteroids, and even antidepressant, Fluoxetine. NONE were effective.
118
Q

What are pesticides?

A
  • Substances used for preventing, destroying, repelling or mitigating pets
  • Designed to specifically target the undesirable -species
  • Often not highly selective and can be toxic to many nontarget species
119
Q

Four Classes of pesticides

A

Insecticides
Herbicides
Fungicides
Rodenticides

Within each class there are several subclasses of pesticides, which have substantially different chemical and toxicological characteristics

120
Q

Pesticide Exposure

  • 4 types of exposure
  • What is occupational exposure
A

Exposure can occur via oral, inhalation, or dermal routes
- Dermal: 90% of all pesticide exposure

  • Workers involved in production, transport, mixing, loading, and application or pesticides
  • Workers involved in harvesting pesticide-sprayed crops
121
Q

Toxic levels of the 4 types of pesticides

A
  • Insecticides are the most acutely toxic
  • Herbicides have low to moderate acute toxicity (exception of paraquat)
  • Fungicides vary in their acute toxicity – usually low
  • Rodenticides are highly toxic to rats, do not have same toxicity to humans
122
Q

5 potential toxic effects of pesticides in nontarget species

A
  1. Mild irritant effects in the skin (most common)
  2. Disruptions in liver and lung function (Constriction of bronchial tubes, increased secretions, difficulty breathing)
  3. Carcinogenic
  4. Reproductive toxicity
  5. Endocrine disrupting properties (Mimic or block hormones or hormonal activity)
  6. Neurotoxicity
123
Q

Possible effects of pesticides on the reproductivity of women

A
  • Women using pesticides have 1.5 increased odds of longer cycles, missing a period
  • May increase time to pregnancy
  • Pesticide exposure may increase risk of birth defects, such as limb reductions, eye and heart defects, cleft palates, altered brain development, lower birth weight
124
Q

Neurotoxic effects of pesticides

A
  • Self-reported or clinical diagnosis of depression in female spouses of pesticide applicators
  • Self-reported neurological symptoms in pesticide applicators associated with cumulative exposure to moderate levels of pesticides
    EG. Headache, fatigue, insomnia, irritability, depression, numbness in hands or feet
125
Q

Toxic Effects of high doses of pesticides

A
  • Suicide attempts, accidental exposure
  • Severe poisoning and death
  • Approx. 3 million hospital admission per year for pesticide poisoning (WHO)
126
Q

Toxic Effects of chronic low doses of pesticides

A
  • General public
  • Pesticide residues in food
  • Contaminants in drinking water
127
Q

All chemical insecticides in use today are…

Insecticides are not very…

A

neurotoxic

species-selective

128
Q

Four classes of Insecticides (PCON)

A
  • Cholinesterase inhibitors (organophosphates and carbamates)
  • Pyrethroids
  • Organochlorine compounds (DDT)
  • Neonicotinoids
129
Q

INSECTICIDES: Organophosphates (OPs)

  • Compounds with a ______ moiety (_______ bound chemical structure) are _______________ active
  • Most commonly used OPs contain a _________ bound to the _________________ atom
  • Need to _____________ activated to exert _______________ effects
  • ________________ is mediated by enzymes in the _______________ _______ family
A

P=O… double… toxicologically
sulfur… phosphorus
metabolically… toxicological
Bioactivation… cytochrome P450

130
Q

INSECTICIDES: Organophosphates (OPs): Mechanism of Action

  • Primary target is to ….
  • Role of _______ is to….. in the _____ and _____
  • If _______ is inhibited….
  • Resulting in the overstimulation of…..
A

phosphorylate acetylcholinesterase (AChE)
AChE… inactivate acetylcholine (ACh)… CNS and PNS
AChE…. ACh starts to accumulate at cholinergic synapse
muscarinic and nicotinic cholinergic receptors

131
Q

INSECTICIDES: Organophosphates (OPs): Mechanism of Action

After AChE is phosphorylated by OPs, it can be: (3)

A
  1. Hydrolyzed by water
  2. Hydrolysis can be facilitated by certain chemicals (oximes)
  3. Age (Organophosphate Aging)
132
Q

INSECTICIDES: Organophosphates (OPs): Hydrolysis of AChE

  • Being hydrolyzed by water causes the AChe to return to… This process is…
  • Hydrolysis can be facilitated by _________. This returns AChE to it’s _________ __________ much _________. Used in the treatment of ____ __________
A 
active form (original state)... very slow
oximes... active form... faster... OP poisoning
133
Q

INSECTICIDES: Organophosphates (OPs): Ageing of AChE

A
  • AChE cannot regenerate – stays in its inactive form
  • Aging occurs due to the loss of one of the two alkoxy groups
  • Results in chemical stabilization of the phosphate bond to AChE over time
  • This bond cannot be hydrolyzed or broken by oximes
134
Q

INSECTICIDES: Organophosphates (OPs): Acute cholinergic syndrome

  • How does it occur
  • Where does it occur
  • Symptoms (7)
  • How does death occur(3)
A
  • Lasts until AChE levels return to normal
  • Receptors are localized in most organs of the body
  • slurred speech, confusion, depression, lethargy, tremors, muscular twitching, paralysis, death

Death is believed to be related to respiratory failure caused by

  • inhibition of respiratory centers in the brain
  • bronchoconstriction, increased bronchial secretion
  • Flaccid paralysis of respiratory muscles
135
Q

INSECTICIDES: Organophosphates (OPs) Toxicty: Intermediate Syndrome

  • when does it occur
  • mecahnisms
  • symptoms
A
  • Develops a few days after the poisoning
  • Person may have completely recovered from initial cholinergic crisis
  • Not related to the inhibition of AChE
  • Mechanisms are unknown
  • Perhaps nicotinic receptor desensitization?
  • Symptoms include respiratory and muscle weakness
136
Q

Organophosphate-induced delayed polyneuropathy (OPIDP)

  • When does it occur
  • symptoms
  • mechanisms
A
  • Can occur 2 to 3 weeks after a single exposure
- Symptoms include
Tingling of hands and feet
Sensory loss
Progressive muscle weakness and flaccidity
Ataxia
  • Not related to AChE inhibition
  • Axonopathy: lesions to the distal part of axon
137
Q

INSECTICIDES: Long-term low-dose effects of OPs have been linked to (4)

A

cancers, diabetes, depression, neurodegenerative diseases

138
Q

INSECTICIDES: Potential Mechanisms of Long-term low-dose effects of OPs (5)

A
  • disruption of cholinergic system
  • persistent alterations in axonal transport and cytoskeletal proteins
  • induced free radical generation – enhanced oxidative stress
  • disruption of lipid membrane and lipid rafts
  • activation of inflammatory cytokines
139
Q

INSECTICIDES: Carbamates: Similarities and differences from OPs

  • Mechanisms
  • Symptoms
A
  • Mechanism of toxicity is similar to OPs: Inhibit AChE
  • Unlike OPs, Carbamates do not require metabolic bioactivation
  • And inhibition of AChE is transient and rapidly reversible
  • Symptoms of carbamate poisoning are the same as OP poisoning
  • Unlike, OPs, symptoms usually resolve within a few hours
140
Q

INSECTICIDES: Pyrethroids

  • Developed from…
  • Used for…
  • human poisonings
  • Is very….
  • Two classes
A
  • Derived from pyrethrins (chrysanthemum flowers)
  • Widely used as agricultural and household insecticides
  • Used for the topical treatment of scabies and head lice
  • Considered to have low mammalian toxicity
  • very lipophilic, can pass BBB
  • Type I and Type II compounds
141
Q

INSECTICIDES: Type I Pyrethroids

  • duration of effects
  • symptoms
  • Mechanism of Action: Holds _____ channels open for _________
    • ____________ membrane above the ___________ for action potential generation leading to __________ __________
A

Shorter duration of effects

Symptoms of poisoning include:

  • Marked behavioural arousal
  • Reflex hyperexcitability
  • Increased startle response
  • Sympathetic activation
  • Fine body tremor progression to whole-body tremor

Na+…. <10ms
Depolarize… threshold… repetitive firing

142
Q

INSECTICIDES: Type II Pyrethroids

  • duration of effects
  • symptoms
  • Mechanism of Action: Holds _____ channels open for _________
    • Cause greater membrane ______________, diminishing the ______ ________________ gradient and ____________ of subsequent action potentials
    • _______________-____________ Block: Membrane becomes _____________ to a point at which the generation of an ________ ____________ is not _____________
A

Longer acting due to the addition of cyano group (C≡N)

Symptoms of poisoning include:

  • Salivation
  • Coarse tremor
  • Sympathetic activation
  • Seizures
  • Choreoathetosis

Na+… >10ms
depolarization… Na+ electrochemical… amplitude
depolarization-dependent… depolarized… action potential… possible

143
Q

INSECTICIDES: Pyrethroids: Mechanism of action

A

Bind to voltage dependent Na+ channels keeping them in the open confirmation and delaying inactivation
- Allows for the continuous entry of Na+

144
Q

INSECTICIDES: Organochlorine Compounds (OCs)

  • Acute toxicity is __________ (less than _____)
  • Chronic toxicity is thought to be associated with _________ _________ _________
  • EXAMPLE: ______
A

moderate…. OPs
adverse health effects
DDT

145
Q

INSECTICIDES: DDT: Mechanism of Action

  • Similar to….
  • Delays the….
  • Prevents the…..
  • results in…
  • may also inhibit the ability to…
A

Type I pyrethroids
closing of Na+ channels
opening of the potassium gates
repetitive firing (hyperexicitability)

transport Ca+2

146
Q

INSECTICIDES: DDT: Toxicity

5 symptoms

A
  • earliest effect is paresthesia of the mouth and face
  • altered motor function leading to ataxia
  • dizziness, confusion, general malaise, headache, fatigue
  • tremor of the hands
  • concussions
147
Q

INSECTICIDES: Low doses of DDT have been shown to mimic or block certain hormones (4)

A
  • Estrogenic effects
  • Anti-androgenic effects
  • Anti-progestin effects
  • Anti-thyroid effects
148
Q

INSECTICIDES: DDT as an Endocrine Disruptor

- effects

A

Endocrine disruption is not an effect, but a mechanism of toxicity
- Can have many effects including infertility, low sperm count, early puberty, brain development etc.

149
Q

Hyperthyroidism VS hypothyroidism

DDT has been linked to….

A

Hyperthyroidism (overactive): Produce too much thyroxine (T4)
Hypothyroidism (underactive): Don’t produce enough T4

hypothyroidism

150
Q

Herbicides

  • What are they
  • Most mechanisms of action are unique to plants, except for….
  • 3 plant processes inhibited by herbicides
A 
Chemicals that are toxic to plants
paraquat
- Photosynthesis
- Amino acids and proteins
- Growth regulation
151
Q

HERBICIDES: Glyphosate

  • primary ingredient in
  • Inhibits plant enzyme… which is important for the synthesis of…
  • Humans do not have….
A

Roundup
EPSP synthase
aromatic amino acids
EPSP enzymes

152
Q

HERBICIDES: Glyphosate: Neurotoxicity

  • Exposure leads to degeneration of….
  • Linked to increased __________ in…
  • Decreased…. and increased… in rat hippocampal slices
  • Decreased levels of… (3) in rat hippocampal slices
  • interferes with…. causing increased….
  • Associated with __________________ and _______________
A

GABA and dopamine neurons in C. elegans
apoptosis… human umbilical, embryonic, and placental cells
Decreased glutamate uptake and increased glutamate release
glutamine synthetase, aspartate aminotransferase (AST), and alanine amino aminotransferase (ALT)
glutamate metabolism … glutamate in synapse (excitotoxicity)
oxidative stress and neuroinflammation

153
Q

HERBICIDES: Paraquat

  • acute toxicity
  • exposure methods
  • lethal dose
  • accumulates where in the body
A
  • Has one of the highest acute toxicity among herbicides
  • Very toxic when ingested
  • Skin absorption is poor
  • Inhalation is a possible route of exposure
  • Lethal dose is 1-4 grams
  • accumulates in lung and secondarily in the kidney
154
Q

HERBICIDES: Paraquat

  • Paraquat is __________ charged and _______ soluble
  • Argued that it cannot easily pass the…
  • _________ _______ ______ transporters (LAT-1) may transport paraquat into the brain
  • undergoes _______ __________ to form superoxide _______ _________
A

Positively… water
BBB
Neutral amino acid transporters (LAT-1)
redox cycling… free radical

155
Q

HERBICIDES: Paraquat

  • Exposure to paraquat has been linked to the etiology of…
  • Major target of paraquat in the CNS :
  • Exposure to paraquat can also induce…
  • Hypothesized that… reduce….
  • results in accumulation of _________ in the _________
  • In _________, __________ is metabolized by __________________ which generates _____________________
  • May trigger….
A

Parkinson’s disease
dopaminergic neurons (susceptibility of DA neurons to oxidative damage)
α-synuclein aggregation (Lewy bodies) inside neurons
α-synuclein Lewy bodies reduce vesicle number in dopamine neurons
dopamine… cytoplasm
cytosol… dopamine… monoamine oxidase… reactive oxygen speciesoxidative stress and the initiation of the apoptotic cascade

156
Q

What are heavy metals

A
  • naturally occurring elements found throughout the Earth’s crust
  • Sometimes referred to as “trace elements”
  • Have a high atomic weight
157
Q

Some metals may also be essential nutrients including: (5)

Essential heavy metals required for…

A

Copper, Iron, Manganese, Selenium, Zinc

biochemical and physiological functions in plants and animals

158
Q

Most exposure to heavy metals is due to anthropogenic activities, such as… (3)

A
  1. Mining and smelting operations
  2. Industrial production and use
  3. Domestic and agricultural use of metal and metal-containing compounds
159
Q

Heavy Metals: Environmental contamination can also occur through (5)

A
  1. Metal corrosion
  2. Atmospheric deposition
  3. Soil erosion of metal ions and leaching of heavy metals
  4. Sediment re-suspension
  5. Metal evaporation from water resources to soil & ground water
  6. Natural phenomena (volcanic eruptions)
160
Q

Lead (Pb) has been found in three forms

A
  • metallic lead
  • inorganic lead and lead compounds (lead salts)
  • organic lead
161
Q

unique properties of lead (Pb) (5)

A
  • high resistance to corrosion
  • softness
  • low melting point
  • high density
  • relative low conductivity
162
Q

Lead is extremely persistent in …

A

both water and soil

163
Q

Exposure to lead may occur from many sources such as… (7)

A
  • food or beverages stores, cooked or served in lead-containing containers
  • food grown in contaminated soils
  • cosmetics
  • traditional remedies
  • smoking
  • air pollution
  • contaminated water
164
Q

Define body burden

A

the total amount of a particular chemical present in a human’s or animal’s body, typically a radioactive element or other toxic substance.

165
Q

Most common source of lead exposure in children

A

Paint chips and leaded dust and soils released from ageing painted surfaces or during renovation

166
Q

Average amount of lead exposure per day in USA

A

USA exposure ranged from 2 to 9 μg/day for various age groups

Approx. 4 μg/day for children 2 years or younger

167
Q

Biological Markers of Exposure to lead: BONE

A

Exposure to lead over time results in the progressive accumulation in bone
Greater than 95% of total lead body burden
Great indicator of lifetime exposure to lead

168
Q

Biological Markers of Exposure to lead: BLOOD/PLASMA

A
  • Intervention level in blood is 10 μg/dL in US
  • Reflect both recent and past exposures
  • 90% or more of blood lead consists of mobilized bone-lead in exposed children
169
Q

Biological Markers of Exposure to lead: 4 reliable measures

A
  • Bone
  • Blood/plasma
  • teeth
  • urine
170
Q

Biological Markers of Exposure to lead: TEETH

A

Suitable for children only (baby teeth)

171
Q

Biological Markers of Exposure to lead: URINE

A

Has been used to monitor relative levels of exposure in workers with chronic occupational exposure

172
Q

Biological Markers of Exposure to lead: 4 Ineffective measures

A
  • nails
  • hair
  • saliva
  • placenta (not evenly distributed)
173
Q

Main target of lead toxicity is

A

the CNS

174
Q

8 Early symptoms of lead poisoning

A

lethargy, abdominal cramps, irritability, headache, encephalopathy, hallucinations, memory loss

175
Q

Over a period of days to weeks, symptoms of lead poisoning progresses to… (6)

A

vomiting, clumsiness, ataxia, coma, seizures, death

176
Q

Lifetime blood lead exposure < 5μg/dL may produce…

A

learning deficits greater than higher exposures

177
Q

Greater number of children are being exposed to greater levels of lead in … countries

A

developing and industrialized nations

- Latin American, Russia, China

178
Q

Developmental Effects of Lead (Bellinger et al., 1987)

  • Infants in the high ______________ group scored __________ than infants in the medium and low groups
  • Blood lead and measures of _______________ are __________ related
A

in utero… lower

intelligence… inversely

179
Q

Developmental Effects of Lead (Rosen et al., 1992)

  • Evidence of direct link between low-level lead exposure during early development and…
  • ______ _____ point reduction associated with an _________ in blood lead levels from 2.4 to 30 μg/dL
  • Impact of increase in blood lead levels on ______________ __________ was greater for children with ________ blood lead levels
A

deficits in intellectual impairment late in childhood
6.9 IQ… increase
intellectual functioning… lower

180
Q

Developmental Effects of Lead (Wright et al., 2008)
Increased blood lead levels before birth and during early childhood associated with …

  • Increased _____________ associated with blood lead levels of 15 μg/dL in children aged 4 to 5
A
  • higher rates of arrest for any reason
  • higher rates of arrest for violent crimes

aggression

181
Q

Lead and Socioeconomic Status (Brody et al., 1994)

  • _______________ and _______________ is associated with blood lead levels
  • Could be related to increased likelihood of living in ______________ or ____________________
A

Location of home and family income

older homes… unmaintained homes

182
Q

Lead and Socioeconomic Status

- Could be related to poor nutrition (3)

A
  • Deficiencies in calcium, iron, and zinc are risk factors
  • Calcium and iron deficiency increased retention of lead and severity of its toxic effects
  • Zinc deficiency increases lead absorption which in turn increase zinc excretion (vicious cycle)
183
Q

Lead and Environmental Enrichment

A
  • Environmental enrichment can reverse the learning deficits resulting from developmental lead exposure
184
Q

Lead Exposure and Attention Deficit Hyperactivity Disorder (ADHD)

A
  • Blood lead levels of < 10 μg/dL and even < 5 μg/dL have been linked to ADHD
  • Increased odds ratio of 2.52 of having ADHD with every log unit increase in blood lead levels
185
Q

Lead Exposure and Alzheimer’s Disease (AD)
- Associated with overexpression of __________________ (APP) and aggregation of _________________
- Increased ________________, senile __________ deposition, and upregulates
__________
- enhances expression of AD-associated _________ _____, alters ____________ markers of AD, and __________ ________________ in mice

A

amyloid precursor protein… amyloid beta plaques
amyloidogenesis… plaque… APP proteins
protein tau… epigenetic… cognitive impairment

186
Q

Lead Exposure and Schizophrenia
Chronic exposure of mDISC1 mice to Pb2+ (1500 ppb) produced phenotypes relevant to schizophrenia:
- _____________
- Mildly ___________ __________ inhibition (PPI) of the acousitc startle
- Enlarged _______ __________

A

hyperactivity
impaired prepulse
lateral ventricles

187
Q

Lead Toxicokinetics

  • _____________ exposure to lead is a more efficient route of absorption than ingestion
  • Absorption from the ____________ is mediated by passive and facilitated diffusion
A

Inhalation

intestine

188
Q

Lead Toxicokinetics:

- Calcium binding protein “calbindin”

A

can bind to both calcium and lead

189
Q

Lead Toxicokinetics:

- Divalent metal transporter 1 (DMT1)

A
  • overexpression of DMT1 increased lead absorption

- knockdown of DMT1 does not abolish lead transfer

190
Q

Lead Toxicokinetics:

  • Once in the ____________, lead most likely crosses the _____ through __________ ___________
  • Lead can accumulate in _____________ _______ of the _____ and ____________ cells of the blood-CSF barrier causing them to become _______
  • Lead exposure can decrease the _______ and protein levels of _________
  • ________ are ______________ proteins that form the backbone of the tight junctions at the _____
A

bloodstream… BBB… passive diffusion
endothelial cells… BBB… epithelial… leaky
mRNA… claudin-1
claudins… transmembranal… BBB

191
Q

Lead Toxicokinetics

  • Lead may also be transferred across the _____ by _________ transporters like _______
  • Brain efflux may also be mediate via _____-dependent _________ _______
  • Lead can substitute for _________ _____ and _______ the _____
A

BBB… cation… DMT1
ATP… calcium pumps
calcium ions… cross… BBB

192
Q

Brain Calcification

  • Related to increased calcium in the ________ or _______________ or __________ to the brain
  • Significant correlation between calcification in the brain and _________ ________ lead levels
  • Associated with _________, loss of ________ _______, __________ episodes
A

blood… inflammation… damage
raised blood
dementia… visual acuity… psychotic

193
Q

Modifying Factors of Lead Exposure

  • Children deficient in ________ and ______ are more likely to have _____________ blood lead levels
  • ______ deficient diets increase the levels of ______ _______, which increases the levels of _______ proteins
A

calcium… iron… elevated

Iron… DMT1 mRNA… DMT1

194
Q

Absorption of lead can be regulated through…

______ is regulated at the…..

A

the DMT1

DMT1 … the mRNA level by iron

195
Q
  • Lead reduces cell proliferation in the…
  • Lead reduces cell survival in the…
  • Lead reduces the _________ and _________ of DCX-labelled fibres in the _______ ____________ ________ (OML) of the dorsal dentate gyrus (DG)
  • Lead alters ______ _____________ of DCX-positive neurons in the ______ DG
  • In lead exposed rats, ________ cells frequently had
    ___________ ____________of apical dendrites
A 
hippocampus dentate gyrus (DG)
dorsal dentate gyrus (DG)
length... density... outer molecular layer
cell morphology... dorsal
granule... irregular orientation
196
Q

Effects of Lead at Cellular Level

  • Overall, chronic lead exposure in early life alters _________ cell ________________ and _____________ in the ______________ of young adult rats
  • These effects are likely to alter __________ _________ in the ________________ with detrimental effects on __________ ___________ and ____________
A

granule.. neurogenesis… morphology… hippocampus

neuronal circuitry… hippocampus… synaptic plasticity… learning

197
Q

Mechanisms of Lead Toxicity

The main reason lead is so toxicity is due to its ability to substitute for…

A

diverse polyvalent cations, including calcium, zinc, and magnesium at their binding sites

198
Q

Calcium, zinc, magnesium have 3 diverse functions within the body

A
  • Are used in many proteins as structural components
  • Signalling networks are based on the association and dissociation of these cations from the proteins which they bind
  • Catalytic roles
199
Q

One of the most important targets of lead in the nervous system are

A

voltage-gated calcium channels

- NMDA receptor

200
Q

Mechanisms of Lead Toxicity: Role of Calcium

  • The higher affinity of lead for the 4 __________ (EEEE) locus on VGCCs causes
  • Lead to displace __________ from the locus,
  • Lead to slowly flow through the _______ acting as a _________ blocker
  • The peak ____________ of ______-induced currents are preferentially __________ by lead
A

glutamate
calcium
pore… channel
amplitude… NMDA… inhibited

201
Q

Mechanisms of Lead Toxicity: Role of Calcium

  • ______ expression is a key __________ dependent pathway
  • Exposure to lead can reduce _______ ____________ and ________ levels
  • _______ _______________ can fully _________ the effects of lead exposure on _____________ function and _________ expression
A

BDNF… calcium
BDNF… transcripts… protein
BDNF transcripts… protein
BDNF supplementation… mitigate… presynaptic

202
Q

Mechanisms of Lead Toxicity: Role of Calcium

  • ____________________ (PKC) is another calcium dependent pathway
  • Lead can ___________ for calcium and can result in the activation of _____
  • Impaired _____ function can compromise __________ ______________ systems within the cells
  • May lead to altered _______ expression and _________ synthesis
A

Protein Kinase C
substitute… PKC
PKC… second messenger
Gene… protein

203
Q

Mechanisms
of Lead Toxicity: Oxidative Stress
- Lead can accumulate in ________________, which regulate _______________ calcium concentrations
- Increased ________ into ______________ can increase the production of __________ ___________ _________ (ROS)
- Results in ______________ stress, ______________ and ____________

A

mitochondria. .. intracellular
calcium. .. mitochondria… reactive oxygen species
oxidative. .. inflammation… apoptosis

204
Q

Exposure to lead in vitro and in vivo can inhibit…

A

Long-term Potentiation

205
Q

The most toxicologically important forms of mercury is

A

Methylmercury (MeHg)

206
Q

MeHg: Toxicokinetics

  • Absordbed through….
  • Bound to ______ containing molecules such as ________
  • Binds to ______ and looks similar to L-methionine, mimics it to cross _____ and __________ via neutral _______ ________ systems
A

Well absorbed from the gastrointestinal tract

thiol. .. cysteine
cysteine. .. BBB… placenta… amino acid

207
Q

Methylmercury

  • MeHg is slowly metabolized to… by….
  • 90% is eliminated via…
  • Half-life of MeHg is….
  • Accumulates in…
A

inorganic Hg… microflora in intestines
- feces
- 45-70 days
hair

208
Q

Clinical Symptoms of ACUTE Mercury Poisoning: CNS

A

Tremors, convulsions
Irritability, lethargy, confusion
Decreased reflexes, nerve conduction, hearing

209
Q

Clinical Symptoms of CHRONIC Mercury Poisoning: CNS

A 
Tremors, ataxia, unsteady gait
 Insomnia, memory loss
 Shyness, depression, anorexia
 Headache, dysarthria, paresthesias 
 Death
210
Q

Developing organisms are more vulnerable to mercury intoxication due to 2 reasons:

A
  • They are undergoing a period of rapid development

- They have not fully developed the capacity to breakdown and excrete MeHg

211
Q

MeHg Toxicity

  • MeHg readily crosses the…
  • Also found in…
A

placenta

maternal milk

212
Q

MeHg: Toxicity
- _______________ are the preferential site of MeHg accumulation
- However, _________
seem to be more susceptible to MeHg-induced toxicity

A

Astrocytes

neurons

213
Q

MeHg: Cerebellum

Post-mortem analyses of brain tissue of human infants exposed in utero to high levels of dietary MeHg revealed … (3)

  • In vivo, MeHg intoxication resulted in ___________ (or the abnormal _________ in astrocytes)
A
  • Reductions in cerebellar white matter volume and cerebellar width
  • Abnormal migration of cerebellar granulae and Purkinje cells
  • Large numbers of gemistocytic astrocytes

astrocytosis… increase

214
Q

MeHg: Astrocytes

  • Astrocytes do what in response to neuronal damage
  • MeHg prevents…
A

Astrocytes also swell in response to neuronal damage

Astrocytes also swell in response to neuronal damage

215
Q

Behavioural outcomes related to cerebellar damage following MeHg exposure include impairments in… (4)

A

balance, motor coordination, fine motor movement, and locomotor activity

216
Q

Mechanisms of MeHg Toxicity: Oxidative Stress

  1. Interaction with ______________ (GSH): Hg atom interacts with ______ group of GSH, _________ levels of GSH, making the brain susceptible to ______
  2. Interferes with normal ____________ of the _______________ GSH system during weanling period
  3. Disrupts _______________ electron __________ chain
A

glutathione
Thiol… reducing… ROS
maturation…. antioxidant
mitochondrial… transport

217
Q

_______________ _________________ is another critical target of MeHg toxicity:

  1. Increases the _________ of ___________ in synaptic cleft
  2. Inhibits ________ _______
A

Glutamate dyshomeostasis
release… glutamate
glutamate uptake

218
Q

Mechanisms of MeHg Toxicity
- Increased glutamate in the synapse can leads to the overactivation of NMDA glutamate receptors resulting in increased calcium influx into neurons, resulting in the calcium having 2 effects…

A

The influx of calcium can active important pathways involved in cell death

The calcium can be taken up by mitochondria where it can stimulate the generation of ROS

NEUR 3401 (2 decks)

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