Table of Contents
A mutagen is a chemical or agent that alters the DNA sequence by causing DNA impairment. Mutation is the term for this change in DNA sequence.
What is a Mutagen?
A mutagen is a substance that induces mutations in living organisms. Physical, chemical, and biological mutagens are all types of mutagens.
Mutagenicity refers to a substance’s ability to cause changes in the base pairs of DNA, also known as mutation. The hereditary substance of a live cell is DNA. DNA is a polynucleotide that consists of many nucleotide units. Nitrogen-containing nucleobases (cytosine [C], guanine [G], adenine [A], or thymine [T]) are covalently bonded to sugar (typically deoxyribose) and a phosphate group to form these units. All of a cell’s genetic information is encoded in the standard arrangement of nucleic acid bases.
A mutagen alters the pattern and sequence of nucleic acid bases in DNA, resulting in alterations in the protein that results. Depending on whether the alterations occur in somatic or germline cells, they may be inheritable or non-inheritable.
UV radiation, X-rays, reactive oxygen species, alkylating agents, base analogues, transposons, and other mutagens are only a few examples.
Types of Mutations
Mutations are categorised as follows, depending on which cells are impacted by the mutagen:
i. Somatic Mutations
These are mutations that arise in a living being’s non-reproductive cells (somatic cells). Due to the body’s reparative and compensatory processes, many forms of somatic mutations may not develop to impact an individual. A somatic mutation, on the other hand, changes the cell’s cell division processes, can eventually lead to the development of malignant cells or tissue.
ii. Germ-line Mutations
These mutations can happen in gametes or the reproductive cells that make gametes or sex cells. These mutations are inherited and passed on to the following generation in all of their cells (both somatic and germ-line). Chemicals have been categorised based on their ability to cause mutations in germline cells.
1. Chemicals that are known or proved to induce germ-line heritable mutations based on epidemiological data are classified as 1A chemicals.
2. Chemicals classified as 1B induce germ-line heritable mutations based on mutagenicity studies performed on in vivo mammalian germ cells or somatic cells.
3. Chemicals classified as 2 are compounds that, based on in vitro studies or in vivo somatic cell mutagenicity or somatic cell genotoxicity testing in animals, are thought to induce germ-line heritable mutations.
Mutagens are known to enhance the frequency of mutations beyond what occurs naturally. However, it is critical to note that not every DNA impairment or damage may be classified as a mutation. During the cell-repair process, DNA polymerases remove the broken or changed parts of DNA in the vast majority of cases. Mutations induced by mutagens, on the other hand, tend to evade this cellular repair mechanism, resulting in a ‘permanent’ alteration in the DNA.
Type of DNA Mutations
1. Base Substitutions: Single-base substitutions are referred to as “point mutations.” Silent, missense, and nonsense mutations are the most frequent kinds of mutations.
a. Silent Mutations: The substitution of a nucleotide in the codon’s third position. As a result, there’s a good chance that an identical codon will be created, coding for the same amino acid sequence. As a result, there is no silent mutation due to a change in the gene sequence.
b. Missense: A base substitution that causes a gene sequence to code for different amino acids and, subsequently, a new polypeptide sequence to be generated.
c. Nonsense: This mutation is defined as a base substitution that results in the development of a gene sequence that truncates translation or a change that results in the generation of a stop codon that finally results in the formation of a non-functional protein.
2. Deletion: Deletion of one or more base pairs in DNA, as the term implies. When one or more base pairs are lost or removed from the DNA, this might cause a frameshift.
3. Insertions: Frameshifts can also be caused by the insertion of extra base pairs into the DNA. However, whether or whether the addition of base pairs occurs in multiples of three base pairs will determine the frameshift.
Any agent (physical or environmental) that can cause a genetic mutation or enhance the rate of mutation (biology definition). Silent mutations occur when a mutation occurs in the non-functional section of the DNA, whereas deadly mutations occur when a mutation occurs in the actively transcribed area of the DNA, resulting in cell death.
The biological impact of these DNA changes is dictated by the location of the change in the DNA, the time of mutation throughout the cell cycle, the length or magnitude of the change, and any previous mutations.
Molecular Mechanisms of Mutagenesis
Mutagens operate on DNA in a number of ways, with the following being some of the most prevalent mechanisms for mutagenesis:
DNA Damage: The particular sequence of purine (guanine and adenine) and pyrimidine (cytosine and thymine) bases connected by hydrogen bonding, i.e. guanine (G)/cytosine (C), that encodes all of a living being’s genetic information. DNA damage can be caused by a mutagen that changes these base sequences.
Spontaneous Damage: The production of apurinic/apyrimidinic (AP) sites is caused by spontaneous base deamination, hydrolysis of purines or pyrimidines, and the deoxyribose link. The sugar-phosphate backbone is eventually exposed to DNA strand breaking as a result of this. There are also tautomeric variants of the bases, which can lead to multiple base mispairing.
Chemical Adducts: Electron-deficient species, or extremely reactive electrophiles, are found in several chemical mutagens. These reactive mutagens can create covalently bound nucleophilic adducts inside DNA, which can stabilise the purine/pyrimidine bases’ alternate tautomeric configurations. The base pair coding will ultimately change as a result of this.
This will result in erroneous base pair information being transcribed, as well as increased vulnerability to DNA hydrolysis and the creation of AP sites. Additionally, some mutagens may increase DNA inter- and intrastrand cross-linking, which prevents DNA strand separation. As a result, difficulties arise during the replication, transcription, and repair of DNA.
Oxidative Damage: Mutagens can cause oxidative stress, which causes free radical production (oxygen or nitrogen). These free radicals might be hydroperoxide, hydroxyl, or superoxide moiety, and are extremely reactive molecules with unpaired electrons. These free radicals interact with DNA, causing DNA strands to break, bases to hydrolyze, or lesions to form on the DNA strand.
DNA Intercalation: Some mutagens bind to the complementary strands of DNA and intercalate between them. The hydrogen bonding between the base pairs is disrupted as a result of this. Intercalation like this eventually leads to misread or erroneous replication and transcription processes.
Metabolic Activation: The normal metabolic process, which takes place mostly in the liver, is divided into two stages: stage I and stage II. These metabolic processes seek to increase the solubility of unwanted chemicals in order to remove them from the body. The hydroxylation process takes place in Stage I, which is carried out by the cytochrome P450 enzyme system.
In Stage II, polar groups are added by the use of glutathione S-transferase, glucuronide transferase, microsomal epoxide hydrase, or acetyltransferase. The bulk of mutagens are inactivated during stage II, although some enzymes, such as flavin monooxygenase and prostaglandin H synthase, have been shown to activate mutagens.
Types and Examples of Mutagens
Mutagens can be divided into three groups;
i. Physical Agents
Radiation was the first agent to be identified as mutagenic. UV rays, X-rays, alpha rays, and neutrons, among other ionising and non-ionizing radiation, have been discovered to be mutagenic. The majority of these radiations cause fatal (i.e., cell death) or sub-lethal (i.e., cell dysfunction) effects by directly destroying DNA or nucleotides via:
1. inducing DNA or protein cross-linking
2. chromosomes are broken
3. strand breakage or chromosomal loss
4. base deletion/DNA strand breaks at a molecular level
Ionizing or high-energy radiation, such as X-rays and-rays, works primarily on dividing cells and damages more than just DNA. Their impact also affects lipids and proteins. These rays produce free radical molecules that damage DNA or chromosomes.
X-rays with a dosage of 350-500 rems are deemed deadly because they cause phosphodiester links to break, causing DNA strands to break. UV rays, unlike X-rays, are non-ionizing radiation because they contain less energy. Sterilization and decontamination processes frequently use them.
UV rays cause mutagenesis through a variety of processes, including base deletion, strand breaking, cross-linking, and the creation of nucleotide dimers.
UV A, UV B, and UV C are the three kinds of UV radiation. UV-A is a kind of UV radiation with a wavelength of 320nm (near-visible range) that is known to cause pyrimidine dimerization. This kind of pyrimidine dimerization causes a change in the DNA structure, which prevents the replication fork from forming during the replication process.
Dimerization may cause health problems. UV-B, which has a wavelength of 290-320nm and is particularly deadly to DNA, has a wavelength of 290-320nm. UV-C radiation, which has a wavelength of 180-290nm, is the most damaging and carcinogenic. The ozone layer absorbs the majority of UV-C light.
Temperatures exceeding 95°C are dangerous for DNA. The phosphodiester bonds in DNA break at 95°C, causing the DNA strand to break. As a result, heat causes DNA to break.
ii. Chemical Agents
a. Base Analogues
They are agents that are structurally identical to bases, such as purines and pyrimidines. 5-Bromouracil and aminopurine are the most frequent base analogues that are considered chemical mutagens. Base analogues are integrated into the DNA structure during replication due to structural similarities between these agents and DNA bases.
Aminopurine is identical to adenine and may couple with C or T to create a base pair (though base pairing with C is rare). Tautomeric variants of 5-bromouracil exist. Each tautomeric molecule binds to a distinct base pair. The keto form of 5-bromouracil substitutes thymine in DNA and creates a base pair with adenine, whereas the enol tautomeric produces a base pair with guanine.
As a result, 5-bromo uracil causes a point mutation. As a result, DNA containing 5-Bromouracil switches base pairs from A-T to G-C or from a G-C to an A-T during replication, depending on the tautomeric form.
b. Intercalating Agents
They are compounds with a hydrophobic heterocyclic ring structure that closely resembles the ring structure of base pairs. These agents embed themselves in the DNA helix, causing mutations, most often frameshift mutations, by interfering with replication, translation, and transcription.
Intercalating chemicals include ethidium bromide, proflavine, acridine orange, actinomycin D, or daunorubicin, among others. Daunorubicin, Epirubicin, Epirubicin, and Mitoxantrone are some of the most commonly used anti-cancer or anti-antineoplastic medicines.
c. Metal Ions
Mineral ions such as nickel, chromium, cobalt, cadmium, arsenic, chromium, and iron produce reactive oxygen species (ROS) that induce DNA hypermethylation, increasing DNA damage and obstructing DNA repair.
d. Alkylating Agents
These chemicals cause DNA damage by causing alkyl groups to form in the DNA. The insertion of alkyl groups causes an increase in ionisation, which causes base-pairing mistakes and eventually holes in the DNA strand. Ethylnitrosourea, mustard gas, vinyl chloride, Methylhydrazine, Busulfan, Carmustine, Lomustine, Dimethyl sulphate, Temozolomide, Dacarbazine, Ethyl ethane sulphate, and Thio-TEPA are some of the most frequent alkylating agents.
These chemicals can be eliminated from the DNA during the DNA repair process via the depurination procedure. Depurination is a procedure that is not mutagenic.
iii. Biological Agents
a. Transposons and Insertion Sequences
They are DNA units that perform self-directed DNA fragment displacement and multiplication. Insertion sequences, or IS, are the simplest form of transposons (10-50 base pairs long). IS and transposons are both referred to as jumping genes because they travel across DNA.
The introduction of transposons into chromosomal DNA causes the genes’ functioning to be disrupted. IS and transposons both include information for the enzyme transposases, which aids in the creation of new transposition sites in DNA.
There are three types of transposons that are commonly found:
1. Replicative Transposons: These are transposons that keep the original locus but replicate it.
2. Conservative Transposons: The original transposon translocates itself into these transposons.
3. Retrotransposons Transpose: These transposons go via RNA intermediates to reach their destination.
The insertion of viral DNA into the genome may cause genetic function to be disrupted. The Rous sarcoma virus, for example, has been known to cause cancer. Viruses can therefore be regarded as mutagenic.
Bacteria that cause inflammation, such as Helicobacter pylori, create reactive oxygen species, which cause DNA damage and a reduction in DNA repair. This raises the likelihood of a mutation.
Mutagen vs Carcinogen
It’s critical to know the distinction between mutagens and carcinogens at this point. These two words are often used interchangeably since they are so closely related. These are, however, two distinct words.
Mutagens are substances that cause heritable or non-heritable changes in DNA.
Carcinogens are substances that cause uncontrolled cell division, resulting in the formation of tumours that may or may not be malignant.
Though both words are commonly linked, mutagenic chemicals can cause changes in a cell’s genetic material, which can lead to carcinogenesis. As a result, carcinogenesis might be a side effect of mutagen-induced mutagenic alterations.
Mutagens have also been linked to an increase in the frequency of carcinogenic occurrences.
It’s also crucial to remember that while certain mutations aren’t life-threatening, carcinogenesis produces life-threatening consequences.
Teratogens is a word that is commonly used interchangeably with teratogens. Teratogens are substances that can cause abnormalities or birth defects in a foetus while having no impact on the mother. Teratogenic chemicals include ethanol, mercury compounds, phenol, lead compounds, carbon disulfide, xylene, and toluene.
Thalidomide is the most well-known teratogenic medication, which was first administered to pregnant women in the early 1950s for morning sickness. Thalidomide caused extensive congenital abnormalities such as missing legs, limbs, and ears, among other things. As a result of these numerous incidents, the medication was withdrawn from use.
Thalidomid was reintroduced for the treatment of myeloma and leprosy in the early 2000s. Phenobarbital, Valproic acid, Tretinoin, Tetracyclines, fluoroquinolones, warfarin, Propylthiouracil (PTU), methimazole (MMI), carbimazole, high dosages of Vitamin A, Diethylstilbestrol, and other teratogenic medicines are also well-known. Diethylstilbestrol has been found to be both carcinogenic and teratogenic.
All three types of agents, i.e. mutagens, carcinogens, and teratogens, have one thing in common: they are all very powerful and exhibit their impact at very low doses.
Effects of Mutagens
Changes in a cell’s genetic makeup are known as mutations. These mutations can be fatal or non-lethal, and they can also be inheritable or non-inheritable. Mutations, in any event, change the genetic makeup of a population.
Many mutations can result in a variety of illnesses. Certain mutational illnesses are passed down through the generations and are caused by mutations in the germ cells.
Sickle cell anaemia is a condition caused by a single missense mutation in the -globin gene at codon 6 in germ cells. The glutamic acid at position 6 in the normal protein is replaced by valine in this mutation. This alteration has a significant impact on haemoglobin, the oxygen-carrying protein. The oxygen-carrying capacity of mutant haemoglobin is greatly decreased, and erythrocytes become stiff, resulting in painful blood cell passage, capillary blockage, and tissue injury.
The faulty erythrocytes are resistant to malaria, so the mutation has been passed down through the African population. Retinoblastoma or retinal tumours in children, Tay-Sachs disease, phenylketonuria, colorblindness, and cystic fibrosis are some of the illnesses caused by mutation.
It’s crucial to remember, though, that mutations aren’t always fatal or detrimental. The vast majority of mutations are completely harmless. In truth, mutations are to blame for the changes in the gene pool that have led to the development of life on the planet throughout the centuries.
Populations with a wide range of mutations have been able to withstand natural selection and adapt to meet their needs. Populations that were unable to adapt or change in response to changes in their surroundings eventually died out.
Mutation is, in reality, the initial step toward evolution. One such evolutionary genetic step is the development of coat colour by insects and animals for concealment. Apolipoprotein A1-Milano, a mutant protein Apolipoprotein, was discovered in a tiny Italian town with an unusual advantageous mutation (or Apo A1M).
Normal apolipoprotein is the protein responsible for cholesterol transport. Apo A1M, a mutant form of Apolipoprotein, not only eliminates cholesterol but also dissolves plaques and possesses antioxidant properties. As a result, the Italian community with the altered Apo A1M gene is protected against heart disease.
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