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Ingenetics, amutagen is a physical or chemical agent that permanently changesgenetic material, usuallyDNA, in anorganism and thus increases the frequency ofmutations above the natural background level. As many mutations can causecancer in animals, such mutagens can therefore becarcinogens, although not all necessarily are. All mutagens have characteristicmutational signatures with some chemicals becoming mutagenic through cellular processes.
The process of DNA becoming modified is calledmutagenesis. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneoushydrolysis,errors inDNA replication, repair andrecombination.
The first mutagens to be identified werecarcinogens, substances that were shown to be linked tocancer.Tumors were described more than 2,000 years before the discovery ofchromosomes andDNA; in 500 B.C., the GreekphysicianHippocrates named tumors resembling a crabkarkinos (from which the word "cancer" is derived via Latin), meaning crab.[1] In 1567, Swiss physicianParacelsus suggested that an unidentified substance in mined ore (identified asradon gas in modern times) caused a wasting disease in miners,[2] and in England, in 1761,John Hill made the first direct link of cancer to chemical substances by noting that excessive use ofsnuff may cause nasal cancer.[3] In 1775, SirPercivall Pott wrote a paper on the high incidence of scrotal cancer inchimney sweeps, and suggested chimneysoot as the cause of scrotal cancer.[4] In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer.[5] Subsequently, in the 1930s the carcinogen component in coal tar was identified as apolyaromatic hydrocarbon (PAH),benzo[a]pyrene.[2][6] Polyaromatic hydrocarbons are also present in soot, which was suggested to be a causative agent of cancer over 150 years earlier.
The association of exposure to radiation and cancer had been observed as early as 1902, six years after the discovery of X-ray byWilhelm Röntgen and radioactivity byHenri Becquerel.[7]Georgii Nadson and German Filippov were the first who created fungi mutants underionizing radiation in 1925.[8][9] The mutagenic property of mutagens was first demonstrated in 1927, whenHermann Muller discovered thatx-rays can cause genetic mutations infruit flies, producingphenotypic mutants as well as observable changes to the chromosomes,[10][11] visible due to the presence of enlarged"polytene" chromosomes in fruit fly salivary glands.[12] His collaboratorEdgar Altenburg also demonstrated the mutational effect of UV radiation in 1928.[13] Muller went on to use x-rays to createDrosophila mutants that he used in his studies ofgenetics.[14] He also found that X-rays not only mutategenes in fruit flies,[10] but also have effects on the genetic makeup of humans.[15][better source needed] Similar work byLewis Stadler also showed the mutational effect of X-rays on barley in 1928,[16] andultraviolet (UV) radiation on maize in 1936.[17] The effect of sunlight had previously been noted in the nineteenth century where rural outdoor workers and sailors were found to be more prone to skin cancer.[18]
Chemical mutagens were not demonstrated to cause mutation until the 1940s, whenCharlotte Auerbach andJ. M. Robson found thatmustard gas can causemutations in fruit flies.[19] A large number of chemical mutagens have since been identified, especially after the development of theAmes test in the 1970s byBruce 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]
Mutagens are not necessarily carcinogens, and vice versa.Sodium azide for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic.[26] Meanwhile, compounds which are not directly mutagenic but stimulate cell growth which can reduce the effectiveness of DNA repair and indirectly increase the chance of mutations, and therefore that of cancer.[27] One example of this would beanabolic steroids, which stimulate growth of the prostate gland and increase the risk ofprostate cancer among others.[28] Other carcinogens may cause cancer through a variety of mechanisms without producing mutations, such astumour promotion,immunosuppression that reduces the ability to fight cancer cells or pathogens that can cause cancer, disruption of theendocrine system (e.g. in breast cancer), tissue-specific toxicity, andinflammation (e.g. in colorectal cancer).[29]
ADNA damaging agent is an agent that causes a change in the structure of DNA that is not itself replicated when theDNA is replicated.[30] Examples of DNA damage include a chemical addition or disruption of anucleotide 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 amutation 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 necessarily 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.
Mutagens can cause changes to the DNA and are thereforegenotoxic. 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 astranslocation,deletion, andinversion. Such mutagens are calledclastogens.
Mutagens may also modify the DNA sequence; the changes innucleic acid sequences by mutations include substitution ofnucleotidebase-pairs andinsertions anddeletions of one or more nucleotides in DNA sequences. Although some of these mutations are lethal or 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 theproteins. Many mutations aresilent mutations, causing no visible effects at all, either because they occur in non-coding or non-functional sequences, or they do not change theamino-acid sequence due to theredundancy ofcodons.[33]Some mutagens can causeaneuploidy and change the number of chromosomes in the cell. They are known as aneuploidogens.[34]
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 beno safe threshold for mutagens. However, the no-threshold model is disputed with some arguing for adose rate dependent threshold for mutagenesis.[35][10] Some have proposed that low level of some mutagens may stimulate theDNA 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]
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 thecytochrome P450 system and otheroxygenases such ascyclooxygenase.[37] Such mutagens are calledpromutagens.[citation needed]
Chemical mutagens either directly or indirectly damage DNA. On this basis, they are of 2 types:
They directly damage DNA, but may or may not undergo metabolism to produce promutagens (metabolites that can have higher mutagenic potential than their substrates).
They are not necessarily mutagenic by themselves, but they produce promutagens mutagenic compounds through metabolic processes in cells.
Some chemical mutagens additionally requireUV orvisible light activation for their mutagenic effect. These are thephotomutagens, which includefurocoumarins andlimettin.[45]
Many metals, such asarsenic,cadmium,chromium,nickel and their compounds may be mutagenic, but they may act, however, via a number of different mechanisms.[46] 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 andhistone deacetylation, while some metals such ascobalt, arsenic, nickel and cadmium may also affect DNA repair processes such asDNA mismatch repair, andbase andnucleotide excision repair.[47]
Antioxidants are an important group ofanticarcinogenic compounds that may help removeROS or potentially harmful chemicals. These may be found naturally infruits andvegetables.[50] Examples of antioxidants arevitamin A and itscarotenoid precursors,vitamin C,vitamin E,polyphenols, and various other compounds.β-Carotene is the red-orange colored compounds found in vegetables likecarrots andtomatoes. Vitamin C may prevent some cancers by inhibiting the formation of mutagenicN-nitroso compounds (nitrosamine).Flavonoids, such asEGCG ingreen tea, have also been shown to be effective antioxidants and may have anti-cancer properties. Epidemiological studies indicate that a diet rich in fruits and vegetables is associated with lower incidence of some cancers and longer life expectancy,[51] however, the effectiveness of antioxidant supplements in cancer prevention in general is still the subject of some debate.[51][52]
Other chemicals may reduce mutagenesis or prevent cancer via other mechanisms, although for some the precise mechanism for their protective property may not be certain.Selenium, which is present as a micronutrient in vegetables, is a component of important antioxidant enzymes such as gluthathione peroxidase. Many phytonutrients may counter the effect of mutagens; for example,sulforaphane in vegetables such asbroccoli has been shown to be protective againstprostate cancer.[53] Others that may be effective against cancer includeindole-3-carbinol fromcruciferous vegetables andresveratrol from red wine.[54]
An effective precautionary measure an individual can undertake to protect themselves is by limiting exposure to mutagens such as UV radiations and tobacco smoke. In Australia, where people with pale skin are often exposed to strong sunlight,melanoma is the most common cancer diagnosed in people aged 15–44 years.[55][56]
In 1981, human epidemiological analysis byRichard Doll andRichard Peto indicated that smoking caused 30% of cancers in the US.[57] Diet is also thought to cause a significant number of cancer fatalities, and it has been estimated that around 32% of cancer deaths may be avoidable by modification to the diet.[58] Mutagens identified in food includemycotoxins from food contaminated with fungal growths, such asaflatoxins which may be present in contaminated peanuts and corn;heterocyclic amines generated in meat when cooked at high temperature; PAHs in charred meat and smoked fish, as well as in oils, fats, bread, and cereal;[59] and nitrosamines generated from nitrites used as food preservatives incured meat such asbacon (ascorbate, which is added to cured meat, however, reduces nitrosamine formation).[50] Overly-browned starchy food such as bread, biscuits and potatoes can generateacrylamide, a chemical shown to cause cancer in animal studies.[60][61] Excessivealcohol consumption has also been linked to cancer; the possible mechanisms for its carcinogenicity include formation of the possible mutagenacetaldehyde, and the induction of thecytochrome P450 system which is known to produce mutagenic compounds from promutagens.[62]
For certain mutagens, such as dangerous chemicals and radioactive materials, as well as infectious agents known to cause cancer, government legislations and regulatory bodies are necessary for their control.[63]
Many different systems for detecting mutagen have been developed.[64][65] Animal systems may more accurately reflect the metabolism of human, however, they are expensive and time-consuming (may take around three years to complete), they are therefore not used as a first screen for mutagenicity or carcinogenicity.
Systems similar to Ames test have been developed in yeast.Saccharomyces cerevisiae is generally used. These systems can check for forward and reverse mutations, as well as recombinant events.
Sex-Linked Recessive Lethal Test – Males from a strain with yellow bodies are used in this test. The gene for the yellow body lies on the X-chromosome. The fruit flies are fed on a diet of test chemical, and progenies are separated by sex. The surviving males are crossed with the females of the same generation, and if no males with yellow bodies are detected in the second generation, it would indicate a lethal mutation on the X-chromosome has occurred.
Plants such asZea mays,Arabidopsis thaliana andTradescantia have been used in various test assays for mutagenecity of chemicals.
Mammalian cell lines such as Chinese hamster V79 cells,Chinese hamster ovary (CHO) cells or mouse lymphoma cells may be used to test for mutagenesis. Such systems include theHPRT assay for resistance to 8-azaguanine or6-thioguanine, andouabain-resistance (OUA) assay.
Rat primary hepatocytes may also be used to measure DNA repair following DNA damage. Mutagens may stimulate unscheduled DNA synthesis that results in more stained nuclear material in cells following exposure to mutagens.
These systems check for large scale changes to the chromosomes and may be used with cell culture or in animal test. The chromosomes are stained and observed for any changes.Sister chromatid exchange is a symmetrical exchange of chromosome material between sister chromatids and may be correlated to the mutagenic or carcinogenic potential of a chemical. Inmicronucleus Test, cells are examined for micronuclei, which are fragments or chromosomes left behind at anaphase, and is therefore a test for clastogenic agents that cause chromosome breakages. Other tests may check for various chromosomal aberrations such as chromatid and chromosomal gaps and deletions, translocations, and ploidy.
Rodents are usually used inanimal test. The chemicals undertest are usually administered in the food and in the drinking water, but sometimes by dermal application, bygavage, or by inhalation, and carried out over the major part of the life span for rodents. In tests that check for carcinogens, maximum tolerated dosage is first determined, then a range of doses are given to around 50 animals throughout the notional lifespan of the animal of two years. After death the animals are examined for sign of tumours. Differences in metabolism between rat and human however means that human may not respond in exactly the same way to mutagen, and dosages that produce tumours on the animal test may also be unreasonably high for a human, i.e. the equivalent amount required to produce tumours in human may far exceed what a person might encounter in real life.
Mice with recessive mutations for a visible phenotype may also be used to check for mutagens. Females with recessive mutation crossed with wild-type males would yield the same phenotype as the wild-type, and any observable change to the phenotype would indicate that a mutation induced by the mutagen has occurred.
Mice may also be used fordominant lethal assays where early embryonic deaths are monitored. Male mice are treated with chemicals under test, mated with females, and the females are then sacrificed before parturition and early fetal deaths are counted in theuterine horns.
Transgenic mouse assay using a mouse strain infected with a viralshuttle vector is another method for testing mutagens. Animals are first treated with suspected mutagen, the mouse DNA is then isolated and the phage segment recovered and used to infectE. coli. Using similar method as theblue-white screen, the plaque formed with DNA containing mutation are white, while those without are blue.
Many mutagens are highly toxic to proliferating cells, and they are often used to destroy cancer cells. Alkylating agents such ascyclophosphamide andcisplatin, as well as intercalating agent such asdaunorubicin anddoxorubicin may be used inchemotherapy. However, due to their effect on other cells which are also rapidly dividing, they may have side effects such as hair loss and nausea. Research on better targeted therapies may reduce such side-effects. Ionizing radiations are used inradiation therapy.
Inscience fiction, mutagens are often represented as substances that are capable of completely changing the form of the recipient or granting them superpowers. Powerful radiations are the agents of mutation for thesuperheroes inMarvel Comics'sFantastic Four,Daredevil, andHulk, while in theNinja Turtles franchise the MUTAGEN "ooze" forInhumans the mutagen is theTerrigen Mist. Mutagens are also featured in video games such asCyberia,System Shock,The Witcher,Metroid Prime: Trilogy,Resistance: Fall of Man,Resident Evil,Infamous,Freedom Force,Command & Conquer,Gears of War 3,StarCraft,BioShock,Fallout,Underrail, andManeater.In the "nuclear monster" films of the 1950s, nuclear radiation mutates humans and common insects often to enormous size and aggression; these films includeGodzilla,Them!,Attack of the 50 Foot Woman,Tarantula!, andThe Amazing Colossal Man.
Bereits kurz nach der Entdeckung der Möglichkeit einer Auslösung von Mutationen durch ionisierende Strahlen (Nadson u. Filippov 1925, 1928; Muller 1927)
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