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VBMS410 > Toxicology Exam 2 > Flashcards

Toxicology Exam 2 Flashcards

1
Q

What are the reactions catalyzed by CYP450?

A
  1. Hydroxylation
  2. Epoxidation
  3. Oxidative group transfer
  4. Cleavage of esters
  5. Dehydrogenation
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2
Q

How are electrons are transferred from NADPH?

A
  1. NADPH-cytochrome P450 oxidoreductase (ER)
  2. Cytochrome b5 (mitochondria)
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3
Q

What is happening in step 1 of this enzymatic cycle?

A

Substrate binds in proximity to the heme group. Substrate binding induces a change in the conformation of the active site, displacing an H2O molecule and changing the state of the heme iron (Ferric 3+ –> ferrous 2+).

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4
Q

What is happening in step 2 of this enzymatic cycle?

A

Substrate binding induces electron transfer from NAD(P)H via cytochrome P450 reductase.

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5
Q

What is happening in step 3 of this enzymatic cycle?

A

Molecular oxygen binds to the resulting ferrous (Fe2+) heme center, initially giving dioxygen (O2) adduct.

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6
Q

What is happening in step 4 of this enzymatic cycle?

A

A second electron is transferred, from either cytochrome P450 reductase, or cytochrome b5, reducing the Fe-O2 adduct to give a peroxo state.

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7
Q

What is happening in step 5 of this enzymatic cycle?

A

The peroxo group formed is rapidly protonated twice, releasing one molecule of H2O and forming the highly reactive species, P450 Compound 1, an iron(IV) oxo (or ferryl 5+) species.

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8
Q

What happens to the enzyme after this cycle is complete?

A

After the product has been released from the active site, the enzyme returns to its original state, with an H2O molecule returning to occupy the coordination position of the iron nucleus.

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9
Q

How does ethanol cause apoptosis and necrosis?

A

Apoptosis: Ethanol –> TNFa

Necrosis: Ethanol –> CYP2E1 –> RIP3

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10
Q

What are the two mechanisms of ethanol-induced liver injury?

A
  1. Cell damage and formation of non-functional scar tissue
  2. Alterations in transport and synthetic processes
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11
Q

Where can ethanol be found?

A

Ethanol, Carbon tetrachloride (CCl4, refrigerants and fire extinguishers), Acetaminophen

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12
Q

What happens when ethanol/alcohol is consumed in excess through an oxidative pathway?

A

Excess alcohol –> CYP2E1 –> acetaldehyde (ROS) –> lipid accumulation, inflammation, fibrosis

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13
Q

What happens when ethanol/alcohol is consumed normally through an oxidative pathway?

A

Alcohol –> ADH –> acetaldehyde –> ALDH –> Acetate –> circulation

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14
Q

What type of damage can alterations in transport and synthetic processes through ethanol-induced liver injury?

A
  • Fibrosis and Cirrhosis
  • Tumors
  • Bile duct damage
  • Sinusoidal damage
  • Disruption of the cytoskeleton
  • Canalicular Cholestasis
  • Fatty liver (Steatosis)
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15
Q

What are the consequences of direct liver injury?

A

Fibrosis and Cirrhosis

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16
Q

What do fibrosis and cirrhosis cause in the liver?

A
  • Accumulation of collagen fibers (Stellate cells)
  • Mediated by both injury and Inflammation
  • Lower functional capacity of the liver
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17
Q

What are fibrosis and cirrhosis?

A

Liver fibrosis is the excessive accumulation of extracellular matrix proteins, including collagen, that occurs in most chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation.

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18
Q

What is Canalicular Cholestasis?

A

Decrease in the volume of bile formed or impaired secretion of solutes.

  • Bilirubin (byproduct of Heme catabolism, jaundice)
  • Bile salts are made of bile acids that are conjugated with glycine or taurine.
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19
Q

What are the mechanisms involved in Canalicular Cholestasis?

A

Increased biliary reabsorption in the cholangiocytes of the bile duct

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20
Q

What are the types of alterations in liver function induced by xenobiotics?

A

Canalicular Cholestasis and Fatty liver

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21
Q

What is fatty liver?

A

Fatty liver disease (steatosis) is a common condition caused by having too much fat build up in your liver. A healthy liver contains a small amount of fat. It becomes a problem when fat reaches 5% to 10% of your liver’s weight.

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22
Q

What are the mechanisms involved in Fatty liver disease (steatosis)?

A

a) Increased synthesis of lipids

b) Impairment of very low-density lipoprotein (vLDL) release to the plasma, which facilitates the movement of fats and cholesterol

  1. Inhibition of lipoprotein synthesis
    2.Reduced conjugation of triglycerides with lipoprotein (ApoB) to form vLDL
    3.Impaired transfer of vLDL across the plasma membrane
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23
Q

How does the liver metabolize and transport fats?

A

The liver is the central organ for fatty acid metabolism. Fatty acids accrue in the liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or secretion into the plasma within triglyceride-rich, very low-density lipoproteins.

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24
Q

How does the liver metabolize and transport cholesterol?

A

Free cholesterol can be excreted as neutral sterols into bile or transformed into bile acids, or it can be esterified and either stored in the liver as cholesterol esters or assembled into VLDL and secreted into circulation.

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25
Q

What is Immune-mediated hepatotoxicity?

A

Autoimmune hepatitis occurs when the body’s immune system, which ordinarily attacks viruses, bacteria and other pathogens, instead targets the liver. This attack on your liver can lead to chronic inflammation and serious damage to liver cells.

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26
Q

What are the mechanisms of immune-mediated hepatotoxicity?

A

These mechanisms include bile acid-induced liver cell injury during cholestasis, pathophysiological effects of mitochondrial dysfunction, and cell damage by reactive oxygen and nitrogen species.

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27
Q

What are the different types of xenobiotic toxicity in the sinusoidal unit?

A

1) Toxin injury to hepatocytes
2) Injured hepatocyte signals Kupffer and Ito (Stellate) cells
3) Kupffer cells (macrophages) release cytotoxins –> inflammation
4) Ito cells secrete collagen –> Fibrosis

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28
Q

What makes the kidney (and its different regions) susceptible to xenobiotics? Give Examples

A
  • Excretion of metabolic wastes
  • Hormones: Renin (angiotensinogenase) and erythropoietin
  • Regulation of fluid volume, electrolyte composition, and acid-base balance (180L of fluid that is filtered per day (rate); 90% reabsorbed)
  • Xenobiotics are delivered in high amounts to the kidney (25% of cardiac output); and similar to urine, they get concentrated (tubular fluid)
  • Renal transport, accumulation, and biotransformation
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29
Q

What are the two types of kidney injury?

A

Acute and chronic kidney injury

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30
Q

What is acute kidney injury?

A

*Abrupt decline in glomerular filtration rate (GFR, blood across the glomeruli)
*Multiple causative factors
*Chemically-induced changes are counteracted with compensatory adaptations.

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31
Q

What is chronic kidney injury?

A
  • Long-term exposure to chemicals
  • Maladaptive alterations lead to glomerulosclerosis and mechanical damage to capillaries
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32
Q

What is the important intermediate/ enzyme in the drug metabolism of the kidney?

A

Cysteine conjugateB-lyase

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33
Q

What is developmental toxicology?

A

Study of pharmacokinetics, mechanisms, pathogenesis, and outcome following exposure to agents or conditions leading to abnormal development

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34
Q

Teratogenic effects

A

Malformations in a fetus that result from exposure to chemicals in utero

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35
Q

Teratology

A

Study of structural birth defects

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36
Q

When does developmental toxicology occur?

A

At all stages during development

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37
Q

Gametogenesis

A

Process of forming the haploid germ cells: egg or sperm

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38
Q

Organogenesis

A

The period during which most bodily structures are established

  • Extensive proliferation, differentiation, and organization
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39
Q

What are the developmental alterations induced by xenobiotics?

A

Alterations in development include death, malformations, growth retardation, function/cognitive defects

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40
Q

Examples (classes) of human developmental toxicants

A

Thalidomide
Ethanol

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41
Q

What was thalidomide originally used for? What effects did it have on human development? What is its mechanism of effect?

A

Original use:
- Aleviate nausea and vomiting during pregnancy
- Considered safe –> prolonged sleep, not death
- No apparent toxicity or addiction in adults

Effects on development:
- Retardation or absence of limb growth
- Heart, ocular, intestinal, and renal abnormalities

Mechanism:
No clear mechanism of toxicity has been identified

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42
Q

What effects does ethanol have on human development?

A

Fetal Alcohol Spectrum Disorders (FASD)
- A group of conditions that can occur as a result of alcohol consumption during pregnancy
- Alterations:
Craniofacial dysmorphism
Growth retardation
Retarded development
Microcephaly

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43
Q

What are the mechanisms of effect of ethanol in developmental toxicosis?

A
  • The placenta allows free entry of ethanol and toxic metabolites (acetaldehyde).
  • Fetal liver is incapable of metabolizing ethanol. No Alcohol (ADH) or Aldehyde (ALDH) dehydrogenases
  • The nervous system appears to be particularly sensitive
    to ethanol during the development
    Neurogenesis, Migration, Differentiation, Plasticity, Survival, and Synaptogenesis.
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44
Q

Stages of susceptibility to xenobiotics during prenatal development

A
  1. Pre-differentiation stage
  2. Embryonic stage
  3. Fetal stage
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45
Q

Pre-differentiation stage of susceptibility to xenobiotics during prenatal development

A
  • Embryo is not susceptible to teratogenic agents.
  • Death only occurs when most or all cells are damaged
  • Remaining cells can compensate and form a normal embryo (5-9 days)
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46
Q

Embryonic stage of susceptibility to xenobiotics during prenatal development

A
  • Cells undergo extensive differentiation, mobilization, and organization
    Most of organogenesis takes place.
  • Very susceptible to teratogens
    *Not all organs are susceptible at the same time.
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47
Q

Fetal stage of susceptibility to xenobiotics during prenatal development

A
  • Growth and functional maturation
  • Unlikely morphological effects now
  • Maybe functional effects
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48
Q

Mechanisms of action susceptibility to xenobiotics during prenatal development

A
  1. Interference with gene replication and transcription
    Ionizing radiation & genotoxic carcinogens
  2. Oxidative stress
    Lipid, protein, and DNA-damage
  3. Energy deficiency
  4. Enzyme inhibition
    Alterations in growth and differentiation
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49
Q

What do the teratogenic effects of thalidomide stem from?

A

The teratogenic effects of thalidomide stem from the drug binding to cereblon (CRBN), a component in an E3 ubiquitin ligase complex. This E3 complex ubiquitinates its substrates, allowing subsequent proteasome degradation. Inhibition of the E3 ligase function by
thalidomide leads to the aberrant accumulation of substrates and irregular signaling during development.

The oxidative metabolite of thalidomide[α-(N-phthalimido)glutarimide], dihydroxy thalidomide, is responsible for generating ROS and causing DNA damage.

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50
Q

What are the maternal factors affecting development?

A
  1. Genetics background
  2. Disease state
  3. Nutritional state
  4. Stress
  5. Placental toxicity
  6. Maternal toxicity
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51
Q

How does genetic background from the maternal side affect development?

A

Incidence of cleft lip and/or palate is higher in offsprings of white mothers

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52
Q

How does disease state from the maternal side affect development?

A

Diabetes, infections, and hyperthermia

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53
Q

How does the nutritional state from the maternal side affect development?

A

Folate supplementation reduces neural tube defects by 70%

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54
Q

How does stress from the maternal side affect development?

A

Low birth weight and congenital malformations

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55
Q

How does placental toxicity from the maternal side affect development?

A
  • Nutrition and waste removal
  • Hormones
  • Metabolizing enzymes
  • Metals, cigarette smoke, ethanol, APAP
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56
Q

What are the paternal factors affecting development?

A
  • Toxicants primarily affect spermatogenesis (formation of
    sperm cells) and spermiogenesis (final maturation stage)
  • Exposures positively associated with adversely affecting semen
    quality –>
    Viability and motility
    Count (# of germ cells)
    Morphology (spermiogenesis)
  • Genetic damage is difficult to detect in human sperm
    Epidemiological studies have demonstrated an increased frequency of spontaneous abortions in pregnancies from men working as motor vehicle mechanics
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57
Q

What is cancer?

A
  • Second leading cause of death in the US (heart disease is 1st)
  • A disease of cellular mutation, proliferation, and aberrant cell growth associated with the accumulation of neoplastic lesions.
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58
Q

What is a Neoplastic lesion?

A
  • Neoplastic lesion or neoplasm (tumor) is a heritably altered, relatively autonomous tissue growth with abnormal gene expression.Benign or Malign. Cancer is always malign.
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59
Q

What is Metastasis?

A

Secondary growth of cells from primary neoplasms

60
Q

What is Carcinogenesis (oncogenesis)?

A

Refers to the process leading to the formation of cancer, whereby normal cells are transformed into cancer cells.

  • The division of normal cells is controlled precisely. New cells are only formed for growth or to replace dead ones.
  • Cancerous cells divide repeatedly out of control; they function abnormally and alter the correct functioning of major organs.
61
Q

What kind of disease is cancer?

A

Cancer is a genetic disease.

62
Q

Carcinogen mutations that result in altered proteins occur……

A
  • During cell division
  • By exposure to external agents
  • As random events
    Internal metabolism
63
Q

What causes Cancer?

A
  • Cancer arises from the mutation of normal genes (alterations in DNA).
  • It is thought that several mutations need to occur to give rise to cancer. You cannot inherit cancer, but you can inherit genomic instability (the acquisition of high frequency of mutations within the genome of a cellular lineage)
  • Cells that are old or not functioning properly self-destruct and are replaced by new cells.
  • Cancerous cells do not self-destruct and continue to divide rapidly, producing millions of new cancerous cells.
64
Q

What are oncogenes?

A

Mutated genes that cause cancer

65
Q

What are the risk factors associated with cancer incidence?

A
  • In the United States, 4 out of 10 cancer cases and almost half of all cancer-related deaths are associated with preventable risk factors.
  • Tobacco use is the leading preventable cause of cancer.
  • Nearly 20 percent of U.S. cancer diagnoses are related to excess body weight, alcohol, poor diet, and physical inactivity.

*Many cases of skin cancer could be prevented by protecting the skin from ultraviolet radiation from the sun and indoor tanning devices.

*Nearly all cases of cervical cancer could be prevented by HPV vaccination, but 46 percent of U.S. adolescents have not received the recommended doses of the vaccine

66
Q

What is the environmental contribution to carcinogenesis?

A
  • The clearest evidence against a predominantly genetic basis for cancer comes from twin studies. Identical twins share identical genes and share similar environmental influences if brought up together. On average, fraternal twins only share 50% genetic material, the same as any siblings. The effects can be genetic, shared environment (e.g., passive smoking, similar diets), and non-shared environment (e.g., occupational exposure, viral infections). The overwhelming majority of the risk in the causation of cancer is NOT genetic.
  • For breast cancer, the BRCA1 gene (breast cancer death sentence) only accounts for an
    underwhelming 27% of the risk. For most cancers, the attributable risk is only 20–30%.
  • This is also clear from migration studies. The risk of breast cancer in a Japanese woman in Hawaii is far higher than that of a Japanese woman in Japan.
67
Q

What are the stages of Multistage Carcinogenesis?

A
  1. Initiation
  2. Promotion
  3. Progression
68
Q

What is the initiation stage of Multistage Carcinogenesis?

A
  • A rapid and irreversible process that results in a mutation (a change in the DNA sequence that alters its transcription).
69
Q

What is the promotion stage of Multistage Carcinogenesis?

A

Clonal expansion that produces a pre-neoplastic lesion.

70
Q

What is the progression stage of Multistage Carcinogenesis?

A
  • Conversion from a benign pre-neoplastic lesion to a malignant neoplastic cancer
    Irreversible
71
Q

What are Carcinogens?

A

An agent that leads to a statistically significant increase in the incidence of neoplasms when compared to the expected incidence

72
Q

Genotoxic carcinogen

A

Induce DNA damage directly

73
Q

Nongenotoxic carcinogen

A

Change DNA transcription without modifying its structure or promote
DNA damage

74
Q

What are the types of carcinogens?

A
  1. Ionizing radiation
  2. Chemicals
  3. Virus infection
  4. Hereditoart predisposition
  5. Environmental, dietary, and behavioral factors
75
Q

Ionizing radiation carcinogen

A

X Rays, UV light

The most pervasive environmental DNA-damaging agent is ultraviolet light (UV). While the ozone layer absorbs the most dangerous part of the solar UV spectrum (UV-C), residual UV-A and UV-B in strong sunlight can induce ~100,000 lesions per exposed cell per hour.

76
Q

What is an example of a chemical carcinogen?

A

Smoking

77
Q

Give an example of how a Virus infection could be a carcinogen.

A

Papillomavirus can be responsible for cervical cancer.

78
Q

How could hereditary predisposition be a carcinogen?

A

Some families are more susceptible to getting certain cancers. Remember, you can’t inherit cancer it’s just that you may be more susceptible to getting it.

79
Q

What defines a Carcinogen?

or

What criteria does an agent have to meet to be considered a carcinogen?

A

Carcinogens should meet one or more criteria based on human data and tests in laboratory animals using chronic exposures:

  1. An increase in the frequency of one or several types of tumors that also occur in the controls
  2. The development of tumors not seen in the controls
  3. The occurrence of tumors earlier than in the controls
  4. An increase in the number of tumors in individual animals compared to that in controls
80
Q

What are Genotoxic Carcinogen mechanisms?

A

Misreading, deletions, frame shifting and broken strands of DNA sequence

81
Q

What are the mechanisms of action of genotoxic carcinogens?

A
  • Direct interaction with DNA
    Radiation
    Alkylating agents (electrophiles)
    DNA is a potent nucleophile (DNA bases and phosphodiester bonds)
  • Metabolic activation
    Bioactivation of xenobiotics (CYP450)
    Formation of ROS
82
Q

What do Non-genotoxic Carcinogens do?

A

Promote a decrease in genome stability

The stability of the genome depends on conditions that preserve the integrity of the genome to ensure the faithful passage of genetic information

83
Q

Co-carcinogens of non-genotoxic carcinogens and mechanisms

A

Co-carcinogens are agents that promote the carcinogenic effect of an agent. They are not carcinogenic by themselves
- Alter DNA repair
- Metabolism or bioactivation of carcinogens
- Absorption and elimination

84
Q

Promoters of non-genotoxic carcinogens

A

increase the effect of initiators

  • Mechanisms
    Cytotoxicity and Hyperplasia
    Epigenetics
    Hormone signaling and cell cycle disruption
    Immunosuppression
85
Q

What are the hallmarks of cancer?

A
  1. Sustaining proliferative signaling
  2. Evading growth suppressors
  3. Activating invasion and metastasis
  4. Enabling replicative immortality
  5. Inducing angiogenesis
  6. Resisting cell death
86
Q

Temporal Origin of the Hallmarks

A

a) A different version includes genomic instability and consolidates the self-sufficiency in growth signals and insensitivity to anti-growth signals into the single hallmark of activated growth signaling.

b) In hereditary cancers, the establishment of genomic instability is probably the initiating
event.

c) In sporadic (non-hereditary) cancers, dysregulation of growth-regulating genes can be the initiating event –> DNA damage and DNA replication stress –> lead to genomic instability and selective pressure for tumor suppressor inactivation –> evasion from cell
death.

87
Q

Emerging hallmarks of cancer

A

1.The capability to modify, or reprogram, cellular metabolism to support neoplastic proliferation most effectively.
2.The capability to evade immunological destruction.

88
Q

Enabling characteristics of cancer

A
  1. Genomic instability and, thus, mutability endows cells with genetic alterations
    that drive tumor progression.
  2. Inflammation.
89
Q

DNA damage repair response in carcinogenesis

A

The DNA damage response (DDR) involves a complex network of genes responsible for sensing and responding to specific types of DNA damage, encompassing specific machinery mediating DNA repair, cell cycle regulation, replication stress responses, and apoptosis.

90
Q

Types of mutations and DNA repair

A
  1. Base mismatches/ insertions and deletions –> mismatch repair
  2. ssDNA breaks –> base excision repair
  3. DNA adducts / intrastrand crosslinks –> nucleotide-excision repair –> transcription-coupled and global genome repair
91
Q

Mismatch Repair

A

Repair of spontaneous mutations (single strand) that lead to apurinic sites
Apurinic endonucleases cut DNA
Cut is extended by exonucleases
Resultant gap is repaired by DNA polymerases and ligases

92
Q

Excision Repair

A
  • DNA regions containing chemically modified DNA bases or adducts are excised and repaired
93
Q

Nucleotide Excision Repair

A

Eliminates the widest range of structurally unrelated DNA lesions, including dimers, bulky adducts, and crosslinks.

94
Q

Base Excision Repair

A

Protects from non-bulky oxidation, alkylation, and deamination

95
Q

Double Strand Break (DSBs) Repair

A

Joining the free DNA strands

96
Q

Homologous recombination

A

The sister chromatid is used as a homologous template, and thus it restricts cell division.

97
Q

Non-homologous end joining

A

joins DNA ends with no build-in potential capacity to restore the original sequence, resulting in the loss of base pairs (information)

Predominant in multicellular organisms

98
Q

Oncogenes

A

A gene that has the potential to cause cancer.

In tumor cells, they are often mutated or expressed at high levels.

99
Q

Growth factors and their receptors of oncogenes

A

Gain-of-function (regions that “switch on” the activation of the receptor)

Loss of function (regions “switch off” the receptor)

100
Q

What are the types of oncogenes?

A
  1. Growth factors and their receptors
  2. Proteins involved in signal transduction
  3. Transcription activators
  4. Cell cycle regulators
101
Q

Tumor Suppressor

A

A gene that protects a cell from one step on the path to cancer. Prevent transformation

All human tumors have more than one tumor suppresser gene that is inactivated.

102
Q

Properties of a tumor suppressor

A
  • Inhibit uncontrolled growth
  • Promote differentiation
  • Stimulate cell death (apoptosis)
  • Inhibit metastasis
103
Q

Types of tumor suppressors

A

Retinoblastoma RB1
p16
p53
APC/ B-catenin
Transforming growth factor (TGF)-B receptor
E-cadherin

104
Q

Retinoblastoma RB1

A
  • Regulation of cell cycle
105
Q

p16

A
  • Regulation of cell cycle by inhibition of CDK
106
Q

p53

A
  • Cell cycle arrest and apoptosis (mutated in half of the human cancers)
107
Q

APC/ B-catenin

A
  • Inhibition of signal transduction
108
Q

Transforming growth factor (TGF)-B receptor

A
  • Growth inhibition
109
Q

E-cadherin

A
  • Cell adhesion
110
Q

Nervous system organization and cellular composition

A

It is defined by the presence of neurons or nerve cell components.
- Central Nervous System (CNS)
Brain and Spinal Cord
- Peripheral Nervous System (PNS)
Nerve fibers or axons
Somatic (voluntary)
Autonomic (sympathetic or emergency-activated,
parasympathetic or relaxed-activated, and enteric or gastro-i.
intestinal system)

111
Q

Function of the nervous system

A

The nervous system coordinates the actions of organisms by transmitting signals to and from a centralized location.

112
Q

Malfunction of the nervous system

A

Malfunction of the nervous system can occur as a result of genetic defects, damage due to trauma or toxicity, infection at any stage during development or simply of aging

113
Q

Blood brain barrier and its role in xenobiotic toxicity

A

Restricts the entry of xenobiotics and metabolites to the nervous system

114
Q

Organization and location of the blood-brain barrier

A
  • Tight junctions between endothelial cells.
    Molecules must pass through the cells.
    Xenobiotic transporters
  • Absent in circumventricular organs:
    The posterior pituitary gland, pineal gland, the median eminence of the hypothalamus
  • Incompletely developed in premature infants and at birth (4 months to 1 year)
115
Q

What makes it different from other blood barriers? Examples

A

The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain.

116
Q

Types of transport for xenobiotics

A
  1. Paraceullar aqueous pathway (water-soluble agents)
  2. Transcellular lipophilic pathway (lipid-soluble agents)
  3. Transport proteins (glucose, amino acids, nucleotides)
  4. Receptor-mediated transcytosis (insulin, transferrin)
  5. Adsorptive transcytosis (albumin, other plasma proteins)
117
Q

Why do xenobiotics easily affect the nervous system?

A

The nervous system is a susceptible target for toxicity because of its complex anatomy, specialized function, high metabolic requirements, limited ability to repair itself and the potential for life-threatening complications when disequilibrium occurs

118
Q

Mechanisms of Neurotoxicity

A
  1. Neuropathies
  2. Myopathies
  3. Axonopathies
  4. Transmission toxicity and pesticides and neurotransmission
119
Q

Types of neuropathies

A
  • Ethanol (microcephaly)
    Methylmercury
    Neuronal degeneration
  • Arsenic
    Axonal degeneration
    Cognitive dysfunction (development)
  • Carbon monoxide
    Neuronal loss
  • Manganese
    Striatal degeneration
  • Trimethyltin (Insect, Bacteria and Fungus)
    Neuronal loss
120
Q

What is an example of a myelopathy causing agent

A

Mitochondrial poisons

121
Q

How to pesticides affect the nervous system?

A
  • Pyrethroids and DDT block voltage-gated sodium channels.
  • Organophosphate (OP) and carbamate insecticides inhibit acetylcholinesterase (AChE) which plays an important role in terminating nerve impulses.
122
Q

What makes neurons susceptible to xenobiotics?

A
  • Neurons depend on oxidative phosphorylation (aerobic metabolism) to meet their energy demands (maintenance of ionic gradients/excitability and homeostasis)
  • High levels of metabolism lead to a higher degree of oxidative damage
  • Higher content of lipids (lipid peroxidation)
123
Q

Types of Neurotoxic Effects

A

General effects
Sensory effects
Mood and personality effects
Cognitive effects
Motor effects

124
Q

Examples of neurotoxic general effects

A

Appetite loss, headache, depression, drowsiness, and thirst.

125
Q

Examples of neurotoxic sensory effects

A

Impaired color vision, night-increased olfactory and auditory threshold, ringing in the ears, equilibrium changes, dizziness, pain, tingling, numbness, and increased cold sensitivity.

126
Q

Examples of Mood and personality neurotoxic effects

A

Sleep disturbances, excitability, depression, anxiety, irritability, delirium, hallucinations, restlessness, nervousness, and tension.

127
Q

Examples of Cognitive neurotoxic effects

A

Concentration impairment, fatigue, memory problems, confusion, learning and speech impairment, mental slowing, reduced initiative, delirium, and hallucinations.

128
Q

Examples of neurotoxic Motor effects

A

Convulsions, weakness, tremors, twitching, lack of coordination, reflex abnormalities.

129
Q

Axonopathies

A

Broadly defined as functional or structural defects in the axon or its terminal

130
Q

Peripheral axon regeneration

A
  • Macrophages and Schwann cells clear the debris.
  • Schwann cells de-differentiate, proliferate, and provide guidance for axon re-growth (trophic factors)
  • In contrast, astrocyte scarring and inhibitory molecules released from damaged myelin inhibit axonal regeneration in the CNS.
131
Q

Types of axonopathies

A
  • Hexanedione (glues)
  • Iminodipropionitrile (IDPN, solvent
  • Pyridinethione (shampoos)
132
Q

Hexanedione (glues)

A

Neurofilament aggregates at the distal or proximal axon

133
Q

Iminodipropionitrile (IDPN, solvent)

A

Neurofilament aggregates in the proximal axon with axon atrophy

134
Q

Pyridinethione (shampoos)

A

Impairs axonal transport (retrograde)

135
Q

How do xenobiotics affect neurotransmission?

A
  1. Sodium channel prolongers
  2. Potassium channel blockers
  3. Calcium channel blockers
  4. Nicotinic receptor antagonists
  5. Muscarinic receptor antagonists
  6. Sodium channel blockers
  7. Sodium channel activators
136
Q

What are microglia, and where do they originate from?

A
  • Microglia are the macrophages of the brain.
  • They are derived from embryonic yolk sac precursors and maintain their population via local self-renewal.
137
Q

What do microglia do during development vs. in adults?

A
  • During development, microglia prune immature synapses, eliminate redundant neural precursor cells,, and promote developmental neuronal apoptosis and remove cell corpses.
  • In the adult, they survey the local environment able to cover the entire parenchyma within a few hours via comprehensive signaling machinery (Receptors)
138
Q

Anti- and Pro-inflammatory roles of Microglia

A

Good: alternate activation M2, Release of trophic factors
Bad: Acute insult like hypoxia-ischemia, classical activation M1, the release of inflammatory cytokines

139
Q

What are the types of microglial cell activation?

A

Microglial cell activation has been described as polarization into pro-inflammatory ‘M1’ and reparative ‘M2’ phenotypes (macrophage)

140
Q

Microglial M1 response

A

M1 in response to IFNγ: ROS, NO and lysosomal enzymes –> to kill microorganisms

141
Q

Microglial M2 response

A

M2 induced by IL-4: Express enzymes for collagen synthesis and fibrosis to promote tissue repair.

142
Q

What is the role of environmental exposures in neurodegeneration?

A

Air Pollution and Alzheimer’s
Neurodegenerative diseases
Environmental agents and Parkinson’s disease

143
Q

Air Pollution and Alzheimer’s

A
  • Ultrafine PM 2.5 particles are dangerous (Burning just about anything: oil and gas, firewood, vegetation).
    Microglia activation and Demyelination
    DNA damage, ROS
    Less than a third of U.S. counties have ozone or particle pollution monitors
  • Air pollution could account for 21% of cases of dementia. 14% of Alzheimer’s could be linked to smoking
    APOE4 increases the risk.
  • People living 50 m close to a major road are 12% more likely to develop dementia.
  • Demented dogs: Amyloid deposits
144
Q

Neurodegenerative diseases

A
  • Neurodegenerative diseases are defined as hereditary and/or sporadic conditions that are characterized by progressive nervous system dysfunction.
  • These disorders are often associated with atrophy of the affected central or peripheral structures of the nervous system and include Alzheimer’s Disease and other dementias, Parkinson’s Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig’s Disease), Huntington’s Disease, Prion Diseases, and others.
  • Aging is the primary risk factor
  • There is no cure for these diseases.
145
Q

What are examples of neurodegenerative diseases

A
  • Several genes involved in familial or inherited, forms of neurodegenerative diseases have been identified:

Alzheimer’s disease (APP, PSEN)
Parkinson’s disease (synuclein)
Amyotrophic Lateral Sclerosis (SOD).

VBMS410 (6 decks)

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