Mutagen

In genetics, a mutagen (Latin, literally origin of change) is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations cause cancer, mutagens are typically also carcinogens. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to errors in DNA replication, repair and recombination.

Discovery of mutagens
The first mutagens to be identified were carcinogens, substances that were shown to be linked to cancer. Tumors were described more than 2,000 years before the discovery of chromosomes and DNA; in 500 B.C., the Greek physician Hippocrates named crab-shaped tumors karkinos (from which the word "cancer" is derived via Latin), meaning crab. In England in 1775, Dr. Percivall Pott wrote a paper on the high incidence of scrotal cancer in chimney sweeps, and suggested chimney soot as the cause of scrotal cancer. In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer. Subsequently in the 1930s the carcinogen component was identified as a polyaromatic hydrocarbon (PAH), benzo(a)pyrene. Polyaromatic hydrocarbons are also present in soot which was suggested to be a causative agent of cancer over 150 years earlier.

In the 1920s, Hermann Muller discovered that x-rays caused genetic mutations in fruit flies, with observable changes to the chromosomes noted. He went on to use x-rays to create Drosophila mutants that he used in his studies of genetics. He also found that x-rays not only mutate genes in fruit flies but also have effects on the genetic makeup of humans. Muller further proposed that mutation is the cause of cancer. Similar work by Lewis Stadler also showed the mutational effect of X-ray on barley in 1928, and ultraviolet (UV) radiation on maize in 1936. The effect of sunlight had previously been noted in France in the 1890s, where Bordeaux wine workers showed an unusually high incidence of skin cancer on the back of the neck. These workers spend their days bending over in the fields picking grapes, exposing the back of their necks to the sun.

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. A large number of chemical mutagens have since been identified, especially after the development of the Ames test by Bruce Ames that screens for mutagens and allows for preliminary identification of carcinogens. Around 90% of the mutagens identified through Ames test are also carcinogens. While changes to the chromosome caused by mustard gas were readily observable, other changes to the DNA induced by other chemicals such as PAHs were not so easily observable. It was proposed in 1950 that the carcinogenic form of PAH are the epoxides produced as metabolites from cellular processes. The metabolic process was later identified as interaction with cytochrome P450 which produces reactive species that interact with the DNA to form adducts, resulting in depurination of the DNA.

Effects of mutagens
Mutagens cause changes to the DNA in a number of ways. Powerful mutagens may result in chromosomal instability, causing chromosomal breakages and rearrangement of the chromosomes such as translocation and inversion. Mutagens may also modified the DNA sequence, the changes in nucleic acid sequences by mutations include substitution of nucleotide base-pairs and insertions and deletions of one or more nucleotides in DNA sequences. Although some of these mutations are lethal or can cause serious disease, many have minor effects as they do not result in residue changes that have significant effect on the structure and function of the proteins. Many mutations cause no visible effects at all, either because they occur in non-coding sequence such as introns, or they do not change the amino-acid sequence due to the redundancy of codons.

Types of mutagens
Mutagens may be of physical, chemical or biological origin. It may cause direct damage to the DNA, and most often result in replication error.

The Ames test is one method to determine how mutagenic an agent is.

Physical mutagens

 * Ionizing radiations such as X-rays, gamma rays and alpha particles may cause DNA breakage and other damages.
 * Ultraviolet radiations with wavelength above 260 nm are absorbed strongly by bases, producing pyrimidine dimers which can cause error in replication if left uncorrected.
 * Radioactive decay, such as 14C in DNA.

DNA reactive chemicals
A large number of chemicals may interact directly with DNA. However, some such as benzene are not necessarily mutagenic by themselves, but through metabolic processes in cells they produce mutagenic compounds.


 * Deaminating agents such as nitrous acid
 * Alkylating agents such as ethylnitrosourea. The compounds transfer methyl or ethyl group to bases or the backbone phosphate groups.  Guanine when alkylated may be mispaired with thiamine.
 * Alkaloid from plants, such as those from Vinca species, may be converted by metabolic processes into the active mutagen or carcinogen
 * Bromine and some compounds that contain bromine in their chemical structure
 * 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.

Base Analogs

 * Base analog, which can substitute for DNA bases and cause copying errors.

Intercalating agents

 * Intercalating agents such as ethidium bromide and proflavine are molecules that may insert between bases in DNA, causing frameshift mutation during replication.

Biological agents

 * Transposon, a section of DNA that undergoes autonomous fragment relocation/multiplication. Its insertion into chromosomal DNA disrupt functional elements of the genes.
 * Virus - Virus DNA may be inserted into the genome and disrupts genetic function.
 * Bacteria - some bacteria such as Helicobacter pylori cause inflammation during which oxidative species are produced, causing DNA damage by reducing efficiency of DNA repair systems thereby increasing mutation.

Mutagens in fiction
In science fiction, mutagens are often represented as substances that are capable of completely changing the form of the recipient. This is seen in the Teenage Mutant Ninja Turtle franchise, comic books such as Marvel Comics's Inhumans, television series, computer and video games, like the The Witcher, Metroid Prime Trilogy, Resistance: Fall of Man, Resident Evil, Infamous, and Command & Conquer, and even toys.