Genetic- and radiation toxicity Flashcards
What is Genetic Toxicology?
The assessment of deleterious effects of chemical-, physical- or biological agents on the hereditary material and related to genetic processes of living cells.
Genotoxic effects = DNA damage: disruption of the integrity and function of DNA (at the gene or chromosomal level)
Genotoxicants can have three different targets, which and what kind of effect?
- Somatic cells (detrimental to the exposed individual)
- Germinal cells (potentially heritable effects)
- Mitochondria (detrimental to the exposed individual & progeny via maternal inheritance)
Genotoxicants can lead to micro- or macrolesions, what is included in these classes?
Microlesions: base pair substitutions and frameshift mutations (small targets)
Macrolesions: Change in chromosome number or structure (big targets)
There are two types of base substitutions, which?
– A transition involves a change of a purine for a purine or a pyrimidine for a pyrimidine (this happens more easily and frequently, small change).
– A transversion involves a change of a purine for a pyrimidine or vice versa (harder, more rare and is a bigger change).
There are three types of base substitutions, based on the effect they have. What are these and what are the effects?
A missense mutation lead to a changed amino acid.
(each codon (three nucleotides) code for an amino acid, so if one base change change the amino acid, that is a missense mutation) Can lead to changed function depending on what the gene codes for.
A nonsense mutation lead to a change of an amino acid coding codon to a stop codon. Can lead to protein having no function at all or faulty function, depending on cell and gene it can have varying degrees of problematic effects.
A silent mutation lead do no change at all, possible since several codons code for the same amino acid.
What is a “frameshift mutation”?
Point mutations isn’t only base substitutions, but can also be base deletions or additions. If one, two, four or more (not in multiples of 3 bases, which is the length of one codon) bases are added/deleted, the whole frame of the code changes, as the codons are read 3 by 3. This usually have very detrimental effects as everything gets fucked up.
Besides microlesions, we have the macrolesions. There are five types of chromosomal rearrangements that can occur, which are these and what to they result in?
- Deletion: A chunk of a chromosome is deleted, leads to a decrease in size of the chromosome and only one copy of the deleted genes left.
- Duplication: A chunk of chromosome is added, leads to an increase in size and more copies of the genes in question. Can also be tandem
Repetition (duplicates are in adjacent positions). - Inversion: A chunk is inverted in the chromosome, leading to genes having a new location. No change in size of the chromosome, or change in number of genes, but can lead to changes in expression of the genes as they might end up in a differently regulated region.
- Insertion: One chromosome donates a part of it to another, no change in number of genes, but can also lead to changes in expression.
- Translocation: both chromosomes donates a part to each other, no change in number of genes, but can also lead to changes in expression.
What is “aneuploidy”?
Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46.
What two kinds of aneuploidy are the most common?
-Monosomies: having a single chromosome instead of the usual two copies in a chromosome pair.
-Trisomies: having an extra chromosome instead of the usual two copies in a chromosome pair.
What can aneuploidy be caused by?
Aneuploidies arise from errors in chromosome segregation, and can result from the effects of chemicals on tubulin polymerization or spindle microtubule stability. This happens naturally at a low rate in the body, but can be increased by exposure to chemical-, physical- or biological agents. Most detrimental when it happens in germ cells (gametes).
What types of DNA damage can arise from exposure to genotoxic chemicals? Is it only genotoxic chemicals that produce these damages?
The types of DNA damage produced include:
- single- & double-strand breaks
- crosslinks between DNA bases and proteins
- chemical additions to the DNA bases (adducts).
DNA replication itself can introduce errors via incorrect base substitution, and this happens daily but at a low rate, this process can be exacerbated by some genotoxic agents. Luckily we have some repair systems in place!
How is genetic toxicity testing done today?
Assay to test genetic toxicity are done both in vitro and in vivo (in animals), generally in lab rodents.
In vitro models only give indications of the mutagenic properties of a compound, it’s not yet possible to use it to mimic the complexity of the human body and that’s why we need to complement with animal studies.
Single strand breakage (SSB) is much more common in mammalian cells, what three mechanisms are in place to repair these breaks?
- Base excision repair (BER)
- Nucleotide excision repair (NER)
- Mismatch repair (MMR)
All with their own enzymes and mechanisms for detection.
What happens during base excision repair (BER)?
BER is used when one base is incorrect in the DNA strand. When the incorrect base is detected, it’s removed by enzymes, then the backbone of that base is removed. The hole is then filled with the correct base by base pairing by DNA-polymerase and the strand is sealed again by a ligase.
How does nucleotide excision repair (NER) work?
NER is used when several bases need to be corrected, for example when a dimer has appeared, producing a kink in the DNA strand. When the kink is detected, the DNA strand surrounding the damaged area is opened/unraveled to form a bubble, then enzymes cut the damaged area out (several nucleotides, not just the damaged ones) and DNA polymerase comes in and fill the gap by base pairing and ligase seals the backbone.
