Mutagenicity
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In
genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, Augustinian ...
, a mutagen is a physical or chemical agent that permanently changes
genetic material Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nucleic aci ...
, usually
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
, in an
organism An organism is any life, living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have be ...
and thus increases the frequency of
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s above the natural background level. As many mutations can cause
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
in animals, such mutagens can therefore be
carcinogen A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...
s, 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
mutagenesis Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using lab ...
. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneous
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
, errors in
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
, repair and recombination.


Discovery

The first mutagens to be identified were
carcinogen A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...
s, substances that were shown to be linked to
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
.
Tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s were described more than 2,000 years before the discovery of
chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
s and
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
; in 500 B.C., the Greek
physician A physician, medical practitioner (British English), medical doctor, or simply doctor is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through the Medical education, study, Med ...
Hippocrates Hippocrates of Kos (; ; ), also known as Hippocrates II, was a Greek physician and philosopher of the Classical Greece, classical period who is considered one of the most outstanding figures in the history of medicine. He is traditionally referr ...
named tumors resembling a crab ''karkinos'' (from which the word "cancer" is derived via Latin), meaning crab. In 1567, Swiss physician
Paracelsus Paracelsus (; ; 1493 – 24 September 1541), born Theophrastus von Hohenheim (full name Philippus Aureolus Theophrastus Bombastus von Hohenheim), was a Swiss physician, alchemist, lay theologian, and philosopher of the German Renaissance. H ...
suggested that an unidentified substance in mined ore (identified as
radon Radon is a chemical element; it has symbol Rn and atomic number 86. It is a radioactive noble gas and is colorless and odorless. Of the three naturally occurring radon isotopes, only Rn has a sufficiently long half-life (3.825 days) for it to b ...
gas in modern times) caused a wasting disease in miners, and in England, in 1761, John Hill made the first direct link of cancer to chemical substances by noting that excessive use of snuff may cause nasal cancer. In 1775, Sir Percivall Pott wrote a paper on the high incidence of scrotal cancer in
chimney sweep A chimney sweep is a person who inspects then clears soot and creosote from chimneys. The chimney uses the pressure difference caused by a hot column of gas to create a draught and draw air over the hot coals or wood enabling continued combust ...
s, and suggested chimney
soot Soot ( ) is a mass of impure carbon particles resulting from the incomplete combustion of hydrocarbons. Soot is considered a hazardous substance with carcinogenic properties. Most broadly, the term includes all the particulate matter produced b ...
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 in coal tar was identified as a polyaromatic hydrocarbon (PAH), benzo yrene. 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 by
Wilhelm Röntgen Wilhelm Conrad Röntgen (; 27 March 1845 – 10 February 1923), sometimes Transliteration, transliterated as Roentgen ( ), was a German physicist who produced and detected electromagnetic radiation in a wavelength range known as X-rays. As ...
and radioactivity by
Henri Becquerel Antoine Henri Becquerel ( ; ; 15 December 1852 – 25 August 1908) was a French nuclear physicist who shared the 1903 Nobel Prize in Physics with Marie and Pierre Curie for his discovery of radioactivity. Biography Family and education Becq ...
. Georgii Nadson and German Filippov were the first who created fungi mutants under
ionizing radiation Ionizing (ionising) radiation, including Radioactive decay, nuclear radiation, consists of subatomic particles or electromagnetic waves that have enough energy per individual photon or particle to ionization, ionize atoms or molecules by detaching ...
in 1925. The mutagenic property of mutagens was first demonstrated in 1927, when Hermann Muller discovered that
x-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...
s can cause genetic mutations in fruit flies, producing
phenotypic In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
mutants as well as observable changes to the chromosomes, visible due to the presence of enlarged "polytene" chromosomes in fruit fly salivary glands. His collaborator Edgar Altenburg also demonstrated the mutational effect of UV radiation in 1928. Muller went on to use x-rays to create
Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...
mutants that he used in his studies of
genetics Genetics is the study of genes, genetic variation, and heredity in organisms.Hartl D, Jones E (2005) It is an important branch in biology because heredity is vital to organisms' evolution. Gregor Mendel, a Moravian Augustinians, Augustinian ...
. He also found that X-rays not only mutate
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s in fruit flies, but also have effects on the genetic makeup of humans. Similar work by Lewis Stadler also showed the mutational effect of X-rays on barley in 1928, and
ultraviolet Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of ...
(UV) radiation on maize in 1936. 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. Chemical mutagens were not demonstrated to cause mutation until the 1940s, when
Charlotte Auerbach Charlotte "Lotte" Auerbach FRS FRSE (14 May 1899 – 17 March 1994) was a German geneticist who contributed to founding the science of mutagenesis. She became well known after 1942 when she discovered, with A. J. Clark and J. M. Robson, tha ...
and J. M. Robson found that
mustard gas Mustard gas or sulfur mustard are names commonly used for the organosulfur compound, organosulfur chemical compound bis(2-chloroethyl) sulfide, which has the chemical structure S(CH2CH2Cl)2, as well as other Chemical species, species. In the wi ...
can cause
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in fruit flies. A large number of chemical mutagens have since been identified, especially after the development of the
Ames test The Ames test is a widely employed method that uses bacteria to test whether a given chemical can cause mutations in the DNA of the test organism. More formally, it is a bioassay, biological assay to assess the mutagenic potential of chemical com ...
in the 1970s by Bruce Ames that screens for mutagens and allows for preliminary identification of carcinogens. Early studies by Ames showed around 90% of known carcinogens can be identified in Ames test as mutagenic (later studies however gave lower figures), and ~80% of the mutagens identified through Ames test may also be carcinogens.


Difference between mutagens and carcinogens

Mutagens are not necessarily carcinogens, and vice versa.
Sodium azide Sodium azide is an inorganic compound with the formula . This colorless salt is the gas-forming component in some car airbag systems. It is used for the preparation of other azide compounds. It is highly soluble in water and is acutely poisonou ...
for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic. 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. One example of this would be
anabolic steroid Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...
s, which stimulate growth of the prostate gland and increase the risk of
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
among others. Other carcinogens may cause cancer through a variety of mechanisms without producing mutations, such as tumour promotion,
immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
that reduces the ability to fight cancer cells or pathogens that can cause cancer, disruption of the
endocrine system The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant Organ (biology), organs. In vertebrat ...
(e.g. in breast cancer), tissue-specific toxicity, and
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
(e.g. in colorectal cancer).


Difference between mutagens and DNA damaging agents

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.Bernstein, C.; Bernstein, H. (1991). Aging, Sex, and DNA Repair. pgs. 15-16. San Diego: Academic Press. Examples of DNA damage include a chemical addition or disruption of a
nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
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 biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
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. 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. Different mutagens act on DNA differently. Powerful mutagens may result in chromosomal instability, 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
nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...
sequences by mutations include substitution of
nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...
base-pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s and insertions and deletions 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 the
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s. Many mutations are
silent mutation Silent mutations, also called synonymous or samesense mutations, are mutations in DNA that do not have an observable effect on the organism's phenotype. The phrase ''silent mutation'' is often used interchangeably with the phrase '' synonymous mut ...
s, causing no visible effects at all, either because they occur in non-coding or non-functional sequences, or they do not change the
amino-acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
sequence due to the redundancy of
codon Genetic code is a set of rules used by living cells to translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished by the ribosome, which links prote ...
s. Some mutagens can cause
aneuploidy Aneuploidy is the presence of an abnormal number of chromosomes in a cell (biology), cell, for example a human somatic (biology), somatic cell having 45 or 47 chromosomes instead of the usual 46. It does not include a difference of one or more plo ...
and change the number of chromosomes in the cell. They are known as aneuploidogens. 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. Some have proposed that low level of some mutagens may stimulate the
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
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.


Types of Mutagens

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 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
system and other oxygenases such as
cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such a ...
. Such mutagens are called promutagens.


Physical mutagens

*
Ionizing radiation Ionizing (ionising) radiation, including Radioactive decay, nuclear radiation, consists of subatomic particles or electromagnetic waves that have enough energy per individual photon or particle to ionization, ionize atoms or molecules by detaching ...
s such as
X-rays An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...
,
gamma ray A gamma ray, also known as gamma radiation (symbol ), is a penetrating form of electromagnetic radiation arising from high energy interactions like the radioactive decay of atomic nuclei or astronomical events like solar flares. It consists o ...
s and
alpha particle Alpha particles, also called alpha rays or alpha radiation, consist of two protons and two neutrons bound together into a particle identical to a helium-4 nucleus. They are generally produced in the process of alpha decay but may also be produce ...
s cause DNA breakage and other damages. The most common lab sources include
cobalt-60 Cobalt-60 (Co) is a synthetic radioactive isotope of cobalt with a half-life of 5.2714 years. It is produced artificially in nuclear reactors. Deliberate industrial production depends on neutron activation of bulk samples of the monoisotop ...
and
cesium-137 Caesium-137 (), cesium-137 (US), or radiocaesium, is a radioactive isotope of caesium that is formed as one of the more common fission products by the nuclear fission of uranium-235 and other fissionable isotopes in nuclear reactors and nucle ...
. *
Ultraviolet Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of ...
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 Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration, or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is conside ...
, such as 14C in DNA which decays into
nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...
.


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). *
Reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(ROS) – These may be
superoxide In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of t ...
, hydroxyl radicals and
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...
, and large number of these highly reactive species are generated by normal cellular processes, for example as a by-products of mitochondrial electron transport, or
lipid peroxidation Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...
. As an example of the latter, 15-hydroperoxyeicosatetraenoic acid, a natural product of cellular cyclooxygenases and lipoxygenases, breaks down to form 4-hydroxy-2(''E'')-nonenal, 4-hydroperoxy-2(''E'')-nonenal, 4-oxo-2(''E'')-nonenal, and ''cis''-4,5-epoxy-2(''E'')-decanal; these bifunctional electophils are mutagenic in mammalian cells and may contribute to the development and/or progression of human cancers (see
15-Hydroxyicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S'' ...
). 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 Nitrous acid (molecular formula ) is a weak and monoprotic acid known only in solution, in the gas phase, and in the form of nitrite () salts. It was discovered by Carl Wilhelm Scheele, who called it " phlogisticated acid of niter". Nitrous ac ...
which can cause transition mutations by converting
cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...
to
uracil Uracil () (nucleoside#List of nucleosides and corresponding nucleobases, symbol U or Ura) is one of the four nucleotide bases in the nucleic acid RNA. The others are adenine (A), cytosine (C), and guanine (G). In RNA, uracil binds to adenine via ...
. *
Polycyclic aromatic hydrocarbon A Polycyclic aromatic hydrocarbon (PAH) is any member of a class of organic compounds that is composed of multiple fused aromatic rings. Most are produced by the incomplete combustion of organic matter— by engine exhaust fumes, tobacco, incine ...
s (PAH), when activated to diol-epoxides can bind to DNA and form adducts. * 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 thymine. Some may cause DNA crosslinking and breakages.
Nitrosamine Nitrosamines (or more formally ''N''-nitrosamines) are organic compounds produced by industrial processes. The chemical structure is , where R is usually an alkyl group. Nitrosamines have a nitroso group () that are "probable human carcinogens", ...
s are an important group of mutagens found in tobacco, and may also be formed in smoked meats and fish via the interaction of amines in food with nitrites added as preservatives. Other alkylating agents include
mustard gas Mustard gas or sulfur mustard are names commonly used for the organosulfur compound, organosulfur chemical compound bis(2-chloroethyl) sulfide, which has the chemical structure S(CH2CH2Cl)2, as well as other Chemical species, species. In the wi ...
and
vinyl chloride Vinyl chloride is an organochloride with the formula H2C =CHCl. It is also called vinyl chloride monomer (VCM) or chloroethene. It is an important industrial chemical chiefly used to produce the polymer polyvinyl chloride (PVC). Vinyl chloride is a ...
. * 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 Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...
from plants, such as those from
Vinca ''Vinca'' (; Latin: ''vincire'' "to bind, fetter") is an Old World genus of flowering plants in the family Apocynaceae, The English name periwinkle is shared with the related genus '' Catharanthus'' (and with the mollusc '' Littorina littorea'') ...
species, may be converted by metabolic processes into the active mutagen or carcinogen. *
Bromine Bromine is a chemical element; it has chemical symbol, symbol Br and atomic number 35. It is a volatile red-brown liquid at room temperature that evaporates readily to form a similarly coloured vapour. Its properties are intermediate between th ...
and some compounds that contain bromine in their chemical structure. *
Sodium azide Sodium azide is an inorganic compound with the formula . This colorless salt is the gas-forming component in some car airbag systems. It is used for the preparation of other azide compounds. It is highly soluble in water and is acutely poisonou ...
, an
azide In chemistry, azide (, ) is a linear, polyatomic anion with the formula and structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formula , containing the azide functional group. The dominant ...
salt that is a common reagent in organic synthesis and a component in many car airbag systems *
Psoralen Psoralen (also called psoralene) is the parent compound in a family of naturally occurring organic compounds known as the linear furanocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered a ...
combined with ultraviolet radiation causes DNA cross-linking and hence chromosome breakage. *
Benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...
, an industrial solvent and precursor in the production of drugs, plastics,
synthetic rubber A synthetic rubber is an artificial elastomer. They are polymers synthesized from petroleum byproducts. About of rubber is produced annually in the United States, and of that amount two thirds are synthetic. Synthetic rubber, just like natural ru ...
and dyes. *
Chromium trioxide Chromium trioxide (also known as chromium(VI) oxide or chromic anhydride) is an inorganic compound with the formula . It is the acidic anhydride of chromic acid, and is sometimes marketed under the same name. This compound is a dark-purple solid ...
, a highly toxic and oxidizing substance used in electroplating.


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) *
Aromatic amine In organic chemistry, an aromatic amine is an organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be a ...
s *
Benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...
Some chemical mutagens additionally require UV or
visible light Light, visible light, or visible radiation is electromagnetic radiation that can be perceived by the human eye. Visible light spans the visible spectrum and is usually defined as having wavelengths in the range of 400–700 nanometres (nm ...
activation for their mutagenic effect. These are the , which include
furocoumarin The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutacea ...
s and limettin.


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

* Intercalating agents, such as
ethidium bromide Ethidium bromide (or homidium bromide, chloride salt homidium chloride) is an intercalating agent commonly used as a fluorescent tag (nucleic acid stain) in molecular biology laboratories for techniques such as agarose gel electrophoresis. It ...
and proflavine, are molecules that may insert between bases in DNA, causing
frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet natur ...
during replication. Some such as daunorubicin may block transcription and replication, making them highly toxic to proliferating cells.


Metals

Many metals, such as
arsenic Arsenic is a chemical element; it has Symbol (chemistry), symbol As and atomic number 33. It is a metalloid and one of the pnictogens, and therefore shares many properties with its group 15 neighbors phosphorus and antimony. Arsenic is not ...
,
cadmium Cadmium is a chemical element; it has chemical symbol, symbol Cd and atomic number 48. This soft, silvery-white metal is chemically similar to the two other stable metals in group 12 element, group 12, zinc and mercury (element), mercury. Like z ...
,
chromium Chromium is a chemical element; it has Symbol (chemistry), symbol Cr and atomic number 24. It is the first element in Group 6 element, group 6. It is a steely-grey, Luster (mineralogy), lustrous, hard, and brittle transition metal. Chromium ...
,
nickel Nickel is a chemical element; it has symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive, but large pieces are slo ...
and their compounds may be mutagenic, but they may act, however, via a number of different mechanisms. 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 In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...
deacetylation, while some metals such as
cobalt Cobalt is a chemical element; it has Symbol (chemistry), symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. ...
, arsenic, nickel and cadmium may also affect DNA repair processes such as
DNA mismatch repair DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of nucleobase, bases that can arise during DNA replication and Genetic recombination, recombination, as well as DNA repair, ...
, and base and
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. Intercalation (biochemistry), intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single ...
.


Biological agents

*
Transposon A transposable element (TE), also transposon, or jumping gene, is a type of mobile genetic element, a nucleic acid sequence in DNA that can change its position within a genome. The discovery of mobile genetic elements earned Barbara McClinto ...
s, a section of DNA that undergoes autonomous fragment relocation/multiplication. Its insertion into chromosomal DNA disrupts functional elements of the genes. *
Oncovirus An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term ''oncornaviruses'' was used to denote their RNA virus origin. With the let ...
es – Virus DNA may be inserted into the genome and disrupts genetic function. Infectious agents have been suggested to cause cancer as early as 1908 by Vilhelm Ellermann and Oluf Bang, and 1911 by Peyton Rous who discovered the Rous sarcoma virus. *
Bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
– some bacteria such as ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
'' cause inflammation during which oxidative species are produced, causing DNA damage and reducing efficiency of DNA repair systems, thereby increasing mutation.


Protection

Antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...
s are an important group of anticarcinogenic compounds that may help remove Reactive oxygen species, ROS or potentially harmful chemicals. These may be found naturally in fruits and vegetables. Examples of antioxidants are vitamin A and its carotenoid precursors, vitamin C, vitamin E, polyphenols, and various other compounds. beta-Carotene, β-Carotene is the red-orange colored compounds found in vegetables like carrots and tomatoes. Vitamin C may prevent some cancers by inhibiting the formation of mutagenic N-nitroso compounds (nitrosamine). Flavonoids, such as Epigallocatechin gallate, EGCG in green 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, however, the effectiveness of antioxidant supplements in cancer prevention in general is still the subject of some debate. 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 as broccoli has been shown to be protective against
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
. Others that may be effective against cancer include indole-3-carbinol from cruciferous vegetables and resveratrol from red wine. 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. In 1981, human epidemiological analysis by Richard Doll and Richard Peto indicated that smoking caused 30% of cancers in the US. 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. Mutagens identified in food include mycotoxins from food contaminated with fungal growths, such as aflatoxins 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; and nitrosamines generated from nitrites used as food preservatives in cured meat such as bacon (Vitamin C, ascorbate, which is added to cured meat, however, reduces nitrosamine formation). Overly-browned starchy food such as bread, biscuits and potatoes can generate acrylamide, a chemical shown to cause cancer in animal studies. Excessive Alcohol and cancer, alcohol consumption has also been linked to cancer; the possible mechanisms for its carcinogenicity include formation of the possible mutagen acetaldehyde, and the induction of the
cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
system which is known to produce mutagenic compounds from promutagens. 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.


Test systems

Many different systems for detecting mutagen have been developed. 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.


Bacterial

* Ames test – This is the most commonly used test, and ''Salmonella typhimurium'' strains deficient in histidine biosynthesis are used in this test. The test checks for mutants that can revert to wild-type. It is an easy, inexpensive and convenient initial screen for mutagens. * Resistance to 8-azaguanine in ''S. typhimurium'' – Similar to Ames test, but instead of reverse mutation, it checks for forward mutation that confer resistance to 8-Azaguanine in a histidine revertant strain. * ''Escherichia coli'' systems – Both forward and reverse mutation detection system have been modified for use in ''Escherichia coli, E. coli''. Tryptophan-deficient mutant is used for the reverse mutation, while galactose utility or resistance to 5-methyltryptophan may be used for forward mutation. * DNA repair – ''E. coli'' and ''Bacillus subtilis'' strains deficient in DNA repair may be used to detect mutagens by their effect on the growth of these cells through DNA damage.


Yeast

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.


''Drosophila''

Sex linkage, 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.


Plant assays

Plants such as ''Zea mays'', ''Arabidopsis thaliana'' and ''Tradescantia'' have been used in various test assays for mutagenecity of chemicals.


Cell culture assay

Mammalian cell lines such as Chinese hamster V79 cells, Chinese hamster ovary cell, Chinese hamster ovary (CHO) cells or mouse lymphoma cells may be used to test for mutagenesis. Such systems include the Hypoxanthine-guanine phosphoribosyltransferase, HPRT assay for resistance to 8-azaguanine or 6-thioguanine, and ouabain-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.


Chromosome check systems

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. In micronucleus 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.


Animal test systems

Rodents are usually used in Animal testing on rodents, animal test. The chemicals under test are usually administered in the food and in the drinking water, but sometimes by dermal application, by Feeding tube, gavage, 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 for dominant 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 the uterine horns. Genetically modified mouse, Transgenic mouse assay using a mouse strain infected with a viral shuttle 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 infect ''E. coli''. Using similar method as the blue-white screen, the plaque formed with DNA containing mutation are white, while those without are blue.


In anti-cancer therapy

Many mutagens are highly toxic to proliferating cells, and they are often used to destroy cancer cells. Alkylating agents such as cyclophosphamide and cisplatin, as well as intercalating agent such as daunorubicin and doxorubicin may be used in chemotherapy. 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 in radiation therapy.


In fiction

In science 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 the superheroes in Marvel Comics's Fantastic Four, Daredevil (Marvel Comics series), Daredevil, and Hulk, while in the Ninja Turtles franchise the MUTAGEN "ooze" for Inhumans the mutagen is the Terrigen Mist. Mutagens are also featured in video games such as ''Cyberia (video game), Cyberia,'' System Shock, ''The Witcher (video game), The Witcher'', ''Metroid Prime: Trilogy'', ''Resistance: Fall of Man'', ''Resident Evil'', ''Infamous (video game), Infamous'', ''Freedom Force (2002 video game), Freedom Force, Command & Conquer'', ''Gears of War 3'', ''StarCraft'', ''BioShock'', ''Fallout (video game), Fallout'', ''Underrail'', and ''Maneater (video game), Maneater''. In the "nuclear monster" films of the 1950s, nuclear radiation mutates humans and common insects often to enormous size and aggression; these films include ''Godzilla (1954 film), Godzilla'', ''Them!'', ''Attack of the 50 Foot Woman'', ''Tarantula!'', and ''The Amazing Colossal Man''.


See also

* Carcinogenesis * DNA damage (naturally occurring) * Linear no-threshold model


References

{{Genotoxicity Mutagens, Mutation Radiation health effects Radioactivity it:Mutazione genetica#Mutazioni indotte