Mutagen

This article includes a list of general references, but it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (April 2023) (Learn how and when to remove this template message)

In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in animals, such mutagens can therefore be carcinogens, although not all necessarily are. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes.

The process of DNA becoming modified is called

Chemical mutagens were not demonstrated to cause mutation until the 1940s, when Charlotte Auerbach and J. M. Robson found that mustard gas can cause mutations in fruit flies.^[19] A large number of chemical mutagens have since been identified, especially after the development of the Ames test in the 1970s by Bruce Ames that screens for mutagens and allows for preliminary identification of carcinogens.^[20][21] Early studies by Ames showed around 90% of known carcinogens can be identified in Ames test as mutagenic (later studies however gave lower figures),^[22][23][24] and ~80% of the mutagens identified through Ames test may also be carcinogens.^[24][25]

Difference between mutagens and carcinogens

Mutagens are not necessarily carcinogens, and vice versa.

A DNA damaging agent is an agent that causes a change in the structure of DNA that is not itself replicated when the DNA is replicated.^[30] Examples of DNA damage include a chemical addition or disruption of a nucleotide base in DNA (generating an abnormal nucleotide or nucleotide fragment), or a break in one or both strands in DNA. When duplex DNA containing a damaged base is replicated, an incorrect base may be inserted in the newly synthesized strand opposite the damaged base in the complementary template strand, and this can become a mutation in the next round of replication. Also a DNA double-strand break may be repaired by an inaccurate process leading to an altered base pair, a mutation. However, mutations and DNA damages differ in a fundamental way: mutations can, in principle, be replicated when DNA replicates, whereas DNA damages are not replicated. Thus DNA damaging agents often cause mutations as a secondary consequence, but not all DNA damages lead to mutation and not all mutations arise from a DNA damage.^[30] The term genotoxic means toxic (damaging) to DNA.

Effects

Mutagens can cause changes to the DNA and are therefore genotoxic. They can affect the transcription and replication of the DNA, which in severe cases can lead to cell death. The mutagen produces mutations in the DNA, and deleterious mutation can result in aberrant, impaired or loss of function for a particular gene, and accumulation of mutations may lead to cancer. Mutagens may therefore be also carcinogens. However, some mutagens exert their mutagenic effect through their metabolites, and therefore whether such mutagens actually become carcinogenic may be dependent on the metabolic processes of an organism, and a compound shown to be mutagenic in one organism may not necessarily be carcinogenic in another.^[31]

Different mutagens act on DNA differently. Powerful mutagens may result in chromosomal instability,^[32] causing chromosomal breakages and rearrangement of the chromosomes such as translocation, deletion, and inversion. Such mutagens are called clastogens.

Mutagens may also modify the DNA sequence; the changes in

In Ames test, where the varying concentrations of the chemical are used in the test, the dose response curve obtained is nearly always linear, suggesting that there may be no threshold for mutagenesis. Similar results are also obtained in studies with radiations, indicating that there may be no safe threshold for mutagens. However, the no-threshold model is disputed with some arguing for a dose rate dependent threshold for mutagenesis.^[35][10] Some have proposed that low level of some mutagens may stimulate the DNA repair processes and therefore may not necessarily be harmful. More recent approaches with sensitive analytical methods have shown that there may be non-linear or bilinear dose-responses for genotoxic effects, and that the activation of DNA repair pathways can prevent the occurrence of mutation arising from a low dose of mutagen.^[36]

Types

Mutagens may be of physical, chemical or biological origin. They may act directly on the DNA, causing direct damage to the DNA, and most often result in replication error. Some however may act on the replication mechanism and chromosomal partition. Many mutagens are not mutagenic by themselves, but can form mutagenic metabolites through cellular processes, for example through the activity of the cytochrome P450 system and other oxygenases such as cyclooxygenase.^[37] Such mutagens are called promutagens.^[38]

Physical mutagens

• cesium-137
  .
• pyrimidine dimers
  , which can cause error in replication if left uncorrected.
• Radioactive decay, such as ¹⁴C in DNA which decays into nitrogen.

Chemical mutagens

Chemical mutagens either directly or indirectly damage DNA. On this basis, they are of 2 types:

Directly acting chemical mutagens

They directly damage DNA, but may or may not undergo metabolism to produce promutagens (metabolites that can have higher mutagenic potential than their substrates).

• 15-Hydroxyicosatetraenoic acid).^[39]
  A number of mutagens may also generate these ROS. These ROS may result in the production of many base adducts, as well as DNA strand breaks and crosslinks.
• Deaminating agents, for example nitrous acid which can cause transition mutations by converting cytosine to uracil.
• Polycyclic aromatic hydrocarbons (PAH), when activated to diol-epoxides can bind to DNA and form adducts.
• mustard gas and vinyl chloride
  .
• Aromatic amines and amides have been associated with carcinogenesis since 1895 when German physician Ludwig Rehn observed high incidence of bladder cancer among workers in German synthetic aromatic amine dye industry. 2-Acetylaminofluorene
  , originally used as a pesticide but may also be found in cooked meat, may cause cancer of the bladder, liver, ear, intestine, thyroid and breast.
• Alkaloid from plants, such as those from Vinca species,^[40] may be converted by metabolic processes into the active mutagen or carcinogen.
• Bromine and some compounds that contain bromine in their chemical structure.^[41]
• Sodium azide, an azide salt that is a common reagent in organic synthesis and a component in many car airbag systems
• Psoralen combined with ultraviolet radiation causes DNA cross-linking and hence chromosome breakage.
• Benzene, an industrial solvent and precursor in the production of drugs, plastics, synthetic rubber and dyes.

Indirectly acting chemical mutagens

They are not necessarily mutagenic by themselves, but they produce promutagens mutagenic compounds through metabolic processes in cells.

• Polyaromatic hydrocarbons (PAHs)^[42]
• Aromatic amines^[43]
• Benzene^[44]

Base analogs

• Base analog, which can substitute for DNA bases during replication and cause transition mutations. Some examples are 5-bromouracil and 2-aminopurine
  .

• Intercalating agents, such as ethidium bromide and proflavine, are molecules that may insert between bases in DNA, causing frameshift mutation during replication. Some such as daunorubicin may block transcription and replication, making them highly toxic to proliferating cells.^{[citation needed]}

Metals

Many metals, such as arsenic, cadmium, chromium, nickel and their compounds may be mutagenic, but they may act, however, via a number of different mechanisms.^[45] Arsenic, chromium, iron, and nickel may be associated with the production of ROS, and some of these may also alter the fidelity of DNA replication. Nickel may also be linked to DNA hypermethylation and histone deacetylation, while some metals such as cobalt, arsenic, nickel and cadmium may also affect DNA repair processes such as DNA mismatch repair, and base and nucleotide excision repair.^[46]

Biological agents

• Transposons
  , a section of DNA that undergoes autonomous fragment relocation/multiplication. Its insertion into chromosomal DNA disrupts functional elements of the genes.
• Peyton Rous who discovered the Rous sarcoma virus.^[48]
• Bacteria – some bacteria such as Helicobacter pylori cause inflammation during which oxidative species are produced, causing DNA damage and reducing efficiency of DNA repair systems, thereby increasing mutation.

Protection