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Genetic toxicology Flashcards

1
Q

What is genetic toxicology?

A

The study of genetic damage that results in alterations to heritable information

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2
Q

What does DNA damage involve?

A
  • Chromosome breakage (clastogenesis)
  • Alteration of the DNA base sequence
  • Mis-segregation of chromosomes (aneugenesis)
  • Interchange of sections of chromosomes altering gene regulation (recombination)
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3
Q

What is clastogenesis?

A

Chromosome breakage

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4
Q

What is aneugenesis?

A

Mis-segregation of chromosomes

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5
Q

What do dominant mutation cause?

A

-they immediately cause disease

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6
Q

What do recessive mutations cause?

A

-Mutations may be silent

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7
Q

What is the difference between germ cells and somatic cells?

A

Germ cells - produce gametes and undergo meiosis

Somatic cells - Other cells which undergo only mitosis

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8
Q

What are the potential consequences if somatic cells undergo mutation?

A
  • Carcinogenicity

- Teratogenesis

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9
Q

What are the consequences when germ cells undergo mutation?

A
  • Inherited genetic change

- Potential for reproductive toxicity (teratogenic. fertility), carcinogenicity or other genetic disorders

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10
Q

Teratogenicity can be caused by non genetic mechanisms. TRUE OR FALSE?

A

TRUE

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11
Q

How do drugs cause DNA damage?

A
  • The drug covalently binds to DNA (causing helix to twist)
  • The drug chemically modifies DNA bases e.g alkylate
  • The drug is incorporated instead of DNA base
  • Drug binds non covalently to DNA (e.g intercalators)
  • Strand breaks
  • Inter and intrastrand crosslinks
  • Crosslink DNA to protein
  • Drug interferes with DNA replication mechanisms
  • Potentially - drug interferes with DNA repair mechanism
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12
Q

Give examples of some DNA damaging agents?

A
  • X rays
  • Oxygen radicals
  • Alkylating agents
  • UV light
  • Replication errors
  • Spontaneous reactions
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13
Q

What are the consequences for DNA damage caused by damaging agents?

A

-Inhibition of transcription, replication, chromosomes segregation, mutation, chromosome aberrations (cancer, ageing and inborn disease)

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14
Q

What are some of the repairing processes?

A
  • Base excision repair (BER)
  • Nucleotide excision repair (NER)
  • Recombinational repair
  • Mismatch repair
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15
Q

Give an example of an intercalating agent?

A

Ethidium bromide

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16
Q

How do intercalating agents work?

A
  • They bind between DNA strands
  • Causing misalignment during replication
  • These can be sequence specific
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17
Q

Biotransformation can render a drug more reactive and may create an electrophile. TRUE OR FALSE?

A

TRUE

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18
Q

Describe what occurs in mis-match repair?

A
  • It repairs mismatched bases
  • Damage is recognised by a specific protein that binds to the mismatch
  • It cuts DNA at a distance from mismatch
  • Excision past mismatch
  • Resynthesis and ligation
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19
Q

Describe what occurs in Base excision repair?

A
  • It removes damaged base
  • The gap left is filled by DNA polymerase
  • Followed by ligation to the parent DNA
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20
Q

Describe what occurs in Homologous recombination?

A
  • It repairs double strand breaks

- Single strand tail forms which invades an undamaged homologous chromatid and uses this as template to repair

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21
Q

Describe what occurs in non-homologous end-joining ?

A
  • It repairs double strand break
  • Broken ends are directly ligated
  • No template so more error prone
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22
Q

Which of these two is more prone to errors during repair, Homologous recombination or non-homologous end-joining and provide reason for this?

A

Non-homologous end-joining - because there is no template

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23
Q

What are the potential errors that can occur during DNA repair?

A
  • Repair enzymes may not determine which is the correct base
  • Excision repair polymerase - lower fidelity than in replication
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24
Q

What are the consequences of errors?

A
  • Mutations within a single gene or within a restricted number of genes
  • Chromosomal aberrations
  • Genomic mutations
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25
Mutation outside coding region can affect gene expression if mutation occurs within a single gene. TRUE OR FALSE?
TRUE
26
What is chromosomal aberrations?
Structural change in the chromosome
27
What is genomic mutations?
Change in in number of chromosomes (aneuploidy)
28
State the three types of single gene mutation and state the consequences that each one has?
1. Base pair substitution - can obtain errors during replication/ wrong base 2. Spontaneous base change - can be silent/missense or nonsense - this may have no effect/intermediate effect or drastic effect on protein function 3. Addition and deletion of bases - Can occur during DNA repair or during replication (e.g intercalating agent) - can cause frameshift and is potentially devastating
29
Spontaneous base changes may be important with drugs which interfere with DNA repair. TRUE OR FALSE?
TRUE
30
addition and deletion of bases can have a wild type and mutant type effect. TRUE OR FALSE?
TRUE
31
What causes chromosomal strands to break during chromosomal aberrations?
Ionizing radiation
32
What drugs cause strands to break in chromosomal aberrations?
E.g Bleomycin , topoisomerase inhibitors
33
Drug induced strand breaks do not result from error in DNA synthesis suing damaged template or repair of bulky adduct. TRUE OR FALSE?
FALSE
34
What does break in DNA create?
-Creates cohesive end causing fragments to rejoin inappropriately
35
What is aneuploidy?
Altered number of chromosomes
36
What is polyploid?
Extra copy of complete set of chromosomes (4n tetraploid)
37
What are the causes of genomic changes?
- (any drug affecting chromosome replication or chromatid segregation will cause genomic changes) - Drugs affecting nuclear spindle microtubules eg paclitaxel, colchicine
38
Cohesive ends can be loss of part of chromosome/amplification of part of chromosome etc. TRUE OR FALSE?
TRUE
39
Anticancer drugs cannot increase the likelihood of a different type of cancer. TRUE OR FALSE?
FALSE
40
Anticancer drug such as paclitaxel and carboplatin (used to treat ovarian cancer) can increase chances of acquiring what other type of cancer?
Leukemia
41
Anticancer drug Melphalan (used to treat breast cancer) increases chances if acquiring what type of cancer?
Leukemia
42
Carcinogens cause mutation within a single gene. TRUE OR FALSE?
TRUE
43
What are primary carcinogens?
Can cause mutation
44
What are secondary carcinogens?
Require biotransformation to cause mutation
45
What do co-carcinogens do?
Enhances ability of carcinogen to cause mutation
46
Carcinogens cause mutations within a single gene. TRUE OR FALSE?
TRUE
47
Initiated cells have no clear morphological change. TRUE OR FALSE?
TRUE
48
What do tumour promoters do?
They promote the development of cancer after mutation
49
Tumour promoters do not cause disease on own but cause increased incidence and decrease latency. TRUE OR FALSE?
TRUE
50
Are tumour promoters reversible or irreversible?
Reversible, mutation is not required (epigenetic)
51
Tumour promoters do not cause proliferation of initiated cells. TRUE OR FALSE?
FALSE
52
Carcinogen mutations are irreversible. TRUE OR FALSE?
TRUE
53
Some compounds are both initiators and promoters. TRUE OR FALSE?
TRUE
54
What occurs in the progression phase of the "chemical carcinogenesis model"?
- Becomes clinical observable (neoplasia) - Genomic instability - Chromosomal aberrations and genomic mutations - Develops into maligant form - Becomes invasive with high mitotic index and becomes metastatic
55
What are the different phases of the chemical carcinogenesis model?
- Initiation (initial damage) - Promotion (expansion) - Progression (uncontrolled growth)
56
What occurs when oncogenes are activated?
- Mutation of oncogene itself - Increased expression of the oncogene due to genetic changes in regulatory elements - Amplification of gene - Translocation to fuse with a highly expressed gene
57
What occurs when tumour suppressors are inhibited?
- Mutation is inactivated - There is a decreased expression of the oncogene due to genetic changes in regulatory elements - Deletion of the gene - Translocation to separate from an active promoter
58
What are teratogens?
-This is an agent (drug) which when administered to a woman or sometimes to a man causes structural or functional abnormalities in a foetus
59
Give some examples of teratogens and their effects?
- Alcohol : Fetal alcohol syndrome - Anti cancer agents : multiple congenital defects - Tetracycline : yellow teeth, inhibition of bone growth - Warfarin : multiple congenital defects
60
What are the 8 mechanisms for teratogenesis?
- Mutations within a single gene - Chromosome aberrations - Genomic changes - Enzyme inhibition - Receptor antagonism - Altered cell-cell interactions - Altered metabolism. reduced energy supply - Alteration of cell migration
61
Teratogenesis is not just genetic toxicity. TRUE OR FALSE?
TRUE
62
Toxic drugs are likely to cause spontaneous abortion. TRUE OR FALSE?
TRUE
63
What trimester during pregnancy is the most critical that toxic drugs can cause structural abnormalities?
First trimester
64
During the second and third trimester, toxic drugs affect growth, maturation and integrity of structures. TRUE OR FALSE?
TRUE
65
Organogenesis is the most critical period. TRUE OR FALSE?
TRUE
66
The period of most susceptibility to damage coincides with the development of each structure. TRUE OR FALSE?
TRUE

Carolyn's lectures (3 decks)

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