Mutagen
Overview
 
In genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

, a mutagen (Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...

, literally origin of change) is a physical or chemical agent that changes the genetic material, usually DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

, of an organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...

 and thus increases the frequency of mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s above the natural background level. As many mutations cause cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, mutagens are therefore also likely to be carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...

s. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneous hydrolysis, errors in DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

, repair and recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...

.
The first mutagens to be identified were carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...

s, substances that were shown to be linked to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

.
Encyclopedia
In genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

, a mutagen (Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...

, literally origin of change) is a physical or chemical agent that changes the genetic material, usually DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

, of an organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...

 and thus increases the frequency of mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s above the natural background level. As many mutations cause cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, mutagens are therefore also likely to be carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...

s. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneous hydrolysis, errors in DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

, repair and recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...

.

Discovery of mutagens

The first mutagens to be identified were carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...

s, substances that were shown to be linked to cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

. Tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

s were described more than 2,000 years before the discovery of chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...

s and DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

; in 500 B.C., the Greek
Greece
Greece , officially the Hellenic Republic , and historically Hellas or the Republic of Greece in English, is a country in southeastern Europe....

 physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...

 Hippocrates
Hippocrates
Hippocrates of Cos or Hippokrates of Kos was an ancient Greek physician of the Age of Pericles , and is considered one of the most outstanding figures in the history of medicine...

 named crab-shaped tumors karkinos (from which the word "cancer" is derived via Latin), meaning crab. In 1567, Swiss physician Paracelsus
Paracelsus
Paracelsus was a German-Swiss Renaissance physician, botanist, alchemist, astrologer, and general occultist....

 suggested unidentified substance in mined ore caused a wasting disease in miners, and in England, in 1761, John Hill
John Hill (author)
John Hill , called because of his Swedish honours, "Sir" John Hill, was an English author and botanist. He contributed to contemporary periodicals and was awarded the title of Sir in recognition of his illustrated botanical compendium The Vegetable System.He was the son of the Rev. Theophilus Hill...

 made the first direct link of cancer to chemical substances by noting that excessive use of snuff
Snuff
Snuff is a product made from ground or pulverised tobacco leaves. It is an example of smokeless tobacco. It originated in the Americas and was in common use in Europe by the 17th century...

 may cause nasal cancer. In 1775, Dr. Percivall Pott
Percivall Pott
Sir Percivall Pott London, England) was an English surgeon, one of the founders of orthopedy, and the first scientist to demonstrate that a cancer may be caused by an environmental carcinogen.-Life:...

 wrote a paper on the high incidence of scrotal cancer in chimney sweep
Chimney sweep
A chimney sweep is a worker who clears ash and soot 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 combustion. Chimneys may be straight or contain many changes of direction. During...

s, and suggested chimney soot
Soot
Soot is a general term that refers to impure carbon particles resulting from the incomplete combustion of a hydrocarbon. It is more properly restricted to the product of the gas-phase combustion process but is commonly extended to include the residual pyrolyzed fuel particles such as cenospheres,...

 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
Polycyclic aromatic hydrocarbon
Polycyclic aromatic hydrocarbons , also known as poly-aromatic hydrocarbons or polynuclear aromatic hydrocarbons, are potent atmospheric pollutants that consist of fused aromatic rings and do not contain heteroatoms or carry substituents. Naphthalene is the simplest example of a PAH...

 (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.

The mutagenic property of mutagens was first demonstrated in 1927, when Hermann Muller
Hermann Joseph Muller
Hermann Joseph Muller was an American geneticist, educator, and Nobel laureate best known for his work on the physiological and genetic effects of radiation as well as his outspoken political beliefs...

 discovered that x-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...

s can cause genetic mutations in fruit flies
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...

, producing phenotypic
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...

 mutants as well as observable changes to the chromosomes. 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
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...

 mutants that he used in his studies of genetics
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

. He also found that X-rays not only mutate gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s in fruit flies but also have effects on the genetic makeup of humans. Similar work by Lewis Stadler
Lewis Stadler
Lewis John Stadler was an American geneticist. His research focused on the mutagenic effects of different forms of radiation on economically important plants like maize and barley.- Background :...

 also showed the mutational effect of X-ray on barley in 1928, and ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...

 (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 more prone to skin cancer.

Chemical mutagens were not demonstrated to cause mutation until the 1940s, when Charlotte Auerbach
Charlotte Auerbach
Charlotte Auerbach FRSE FRS was a German zoologist and geneticist.Born in Germany, she fled to Scotland because of anti-Semitism. She became well known after 1942 when she, with A. J. Clark and J. M. Robson, discovered that mustard gas could cause mutations in fruit flies...

 and J. M. Robson
J. M. Robson
John Michael 'Rab' Rabinovich, later known as J. M. Robson was a geneticist and physicist who co-founded the science of mutagenesis by mutations in fruit flies exposed to mustard gas, and who first observed neutron beta decay.-Biography:...

, found that mustard gas can cause mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

s in fruit flies. A large number of chemical mutagens have since been identified, especially after the development of the Ames test
Ames test
The Ames test is a biological assay to assess the mutagenic potential of chemical compounds. A positive test indicates that the chemical is mutagenic and therefore may act as a carcinogen, since cancer is often linked to mutation. However, a number of false-positives and false-negatives are known...

 in 1970s by Bruce Ames
Bruce Ames
Bruce Nathan Ames is an American biochemist. He is a professor of Biochemistry and Molecular Biology at the University of California, Berkeley, and a senior scientist at Children's Hospital Oakland Research Institute...

 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, and 80% of the mutagens identified through Ames test are also carcinogens. Mutagens are not necessarily carcinogens, and vice versa. Sodium Azide
Sodium azide
Sodium azide is the inorganic compound with the formula NaN3. This colourless azide salt is the gas-forming component in many car airbag systems. It is used for the preparation of other azide compounds. It is an ionic substance and is highly soluble in water. It is extremely...

 for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic.

Effects of mutagens

Mutagen causes changes to the DNA that 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.

Different mutagens act on the DNA differently. Powerful mutagens may result in chromosomal instability, causing chromosomal breakages and rearrangement of the chromosomes such as translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...

, deletion, and inversion
Chromosomal inversion
An inversion is a chromosome rearrangement in which a segment of a chromosome is reversed end to end. An inversion occurs when a single chromosome undergoes breakage and rearrangement within itself. Inversions are of two types: paracentric and pericentric.Paracentric inversions do not include the...

. Such mutagens are called clastogen
Clastogen
A clastogen is a material that can cause breaks in chromosomes, leading to sections of the chromosome being deleted, added, or rearranged. This is a form of mutagenesis, and can lead to carcinogenesis, as cells that are not killed by the clastogenic effect may become cancerous...

s.

Mutagens may also modified the DNA sequence, the changes in nucleic acid
Nucleic acid
Nucleic acids are biological molecules essential for life, and include DNA and RNA . Together with proteins, nucleic acids make up the most important macromolecules; each is found in abundance in all living things, where they function in encoding, transmitting and expressing genetic information...

 sequences by mutations include substitution of nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

 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 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s. Many mutations are silent mutation
Silent mutation
Silent mutations are DNA mutations that do not result in a change to the amino acid sequence of a protein. They may occur in a non-coding region , or they may occur within an exon in a manner that does not alter the final amino acid sequence...

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 sequence due to the redundancy
Redundancy (information theory)
Redundancy in information theory is the number of bits used to transmit a message minus the number of bits of actual information in the message. Informally, it is the amount of wasted "space" used to transmit certain data...

 of codons.

Some mutagens can cause aneuploidy
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...

 and polyploidy due to loss or gain of one or more chromosomes.

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 is no threshold for mutagenesis. Similar results are also obtained in studies with radiations, indicating that there may be no safe threshold for mutagens. However, some proposed that low level of some mutagens may stimulate the DNA repair processes and therefore may not necessarily be harmful.

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. Such mutagens are called promutagens.

Physical mutagens

  • Ionizing radiation
    Ionizing radiation
    Ionizing radiation is radiation composed of particles that individually have sufficient energy to remove an electron from an atom or molecule. This ionization produces free radicals, which are atoms or molecules containing unpaired electrons...

    s such as X-rays, gamma ray
    Gamma ray
    Gamma radiation, also known as gamma rays or hyphenated as gamma-rays and denoted as γ, is electromagnetic radiation of high frequency . Gamma rays are usually naturally produced on Earth by decay of high energy states in atomic nuclei...

    s and alpha particle
    Alpha particle
    Alpha particles consist of two protons and two neutrons bound together into a particle identical to a helium nucleus, which is classically produced in the process of alpha decay, but may be produced also in other ways and given the same name...

    s may cause DNA breakage and other damages.
  • Ultraviolet
    Ultraviolet
    Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...

     radiations with wavelength above 260 nm are absorbed strongly by bases, producing pyrimidine dimers
    Pyrimidine dimers
    Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via photochemical reactions. Ultraviolet light induces the formation of covalent linkages by reactions localized on the C=C double bonds. In dsRNA, uracil dimers may also accumulate as a result of UV radiation...

    , which can cause error in replication if left uncorrected.
  • Radioactive decay
    Radioactive decay
    Radioactive decay is the process by which an atomic nucleus of an unstable atom loses energy by emitting ionizing particles . The emission is spontaneous, in that the atom decays without any physical interaction with another particle from outside the atom...

    , such as 14C
    Carbon-14
    Carbon-14, 14C, or radiocarbon, is a radioactive isotope of carbon with a nucleus containing 6 protons and 8 neutrons. Its presence in organic materials is the basis of the radiocarbon dating method pioneered by Willard Libby and colleagues , to date archaeological, geological, and hydrogeological...

     in DNA.

DNA reactive chemicals

A large number of chemicals may interact directly with DNA. However, many such as PAHs, aromatic amines, benzene are not necessarily mutagenic by themselves, but through metabolic processes in cells they produce mutagenic compounds.
  • Reactive oxygen species
    Reactive oxygen species
    Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

     (ROS) - These may be superoxide, hydroxyl radicals and hydrogen peroxide, 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. A number of mutagens may also generate these ROS.
  • Deaminating
    Deamination
    Deamination is the removal of an amine group from a molecule. Enzymes which catalyse this reaction are called deaminases.In the human body, deamination takes place primarily in the liver, however glutamate is also deaminated in the kidneys. Deamination is the process by which amino acids are...

     agents such as nitrous acid
    Nitrous acid
    Nitrous acid is a weak and monobasic acid known only in solution and in the form of nitrite salts.Nitrous acid is used to make diazides from amines; this occurs by nucleophilic attack of the amine onto the nitrite, reprotonation by the surrounding solvent, and double-elimination of water...

  • Polycyclic aromatic hydrocarbon
    Polycyclic aromatic hydrocarbon
    Polycyclic aromatic hydrocarbons , also known as poly-aromatic hydrocarbons or polynuclear aromatic hydrocarbons, are potent atmospheric pollutants that consist of fused aromatic rings and do not contain heteroatoms or carry substituents. Naphthalene is the simplest example of a PAH...

     (PAH)
  • Alkylating
    Alkylation
    Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...

     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. Some may cause DNA crosslinking and breakages. Nitrosamine
    Nitrosamine
    Nitrosamines are chemical compounds of the chemical structure R1N-N=O, some of which are carcinogenic.-Usages:Nitrosamines are used in manufacture of some cosmetics, pesticides, and in most rubber products. -Occurrences:...

    s are an important group of mutagens found in tobacco, and may also be formed in in smoked meats and fish via the interaction of amines in food with nitrites added as preservatives. Other alkylating agents include mustard gas and vinyl chloride
    Vinyl chloride
    Vinyl chloride is the organochloride with the formula H2C:CHCl. It is also called vinyl chloride monomer, VCM or chloroethene. This colorless compound is an important industrial chemical chiefly used to produce the polymer polyvinyl chloride . At ambient pressure and temperature, vinyl chloride...

    .
  • Aromatic aminess and amides have been associated with carcinogenesis since 1895 when German physician Ludwig Rehn
    Ludwig Rehn
    Ludwig Wilhelm Carl Rehn was a German surgeon. Rehn was born in 1849, in the village of Allendorf, the youngest of five children...

     observed high incidence of bladder cancer among workers in German synthetic aromatic amine dye industry. 2-Acetylaminofluorene
    2-Acetylaminofluorene
    2-Acetylaminofluorene is a carcinogenic and mutagenic derivative of fluorene. It is used as a biochemical tool in the study of carcinogenesis. It induces tumors in a number of species in the liver, bladder and kidney.The metabolism of this compound in the body by means of biotransformation...

    , 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
    Alkaloid
    Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

     from plants, such as those from Vinca
    Vinca
    Vinca is a genus of six species in the family Apocynaceae, native to Europe, northwest Africa and southwest Asia. The English name periwinkle is shared with the related genus Catharanthus .-Description:Vinca plants are subshrubs or herbaceous, and have slender trailing stems 1–2 m long...

     species, may be converted by metabolic processes into the active mutagen or carcinogen
  • Bromine
    Bromine
    Bromine ") is a chemical element with the symbol Br, an atomic number of 35, and an atomic mass of 79.904. It is in the halogen element group. The element was isolated independently by two chemists, Carl Jacob Löwig and Antoine Jerome Balard, in 1825–1826...

     and some compounds that contain bromine in their chemical structure
  • Sodium azide
    Sodium azide
    Sodium azide is the inorganic compound with the formula NaN3. This colourless azide salt is the gas-forming component in many car airbag systems. It is used for the preparation of other azide compounds. It is an ionic substance and is highly soluble in water. It is extremely...

    , an azide salt that is a common reagent in organic synthesis and a component in many car airbag systems
  • Psoralen
    Psoralen
    Psoralen is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone...

     combined with ultraviolet radiation causes DNA cross-linking and hence chromosome breakage
  • Benzene
    Benzene
    Benzene is an organic chemical compound. It is composed of 6 carbon atoms in a ring, with 1 hydrogen atom attached to each carbon atom, with the molecular formula C6H6....

    , an industrial solvent and precursor in the production of drugs, plastics, synthetic rubber and dyes.

Intercalating agents

  • Intercalating agents such as ethidium bromide
    Ethidium bromide
    Ethidium bromide is an intercalating agent commonly used as a fluorescent tag in molecular biology laboratories for techniques such as agarose gel electrophoresis. It is commonly abbreviated as "EtBr", which is also an abbreviation for bromoethane...

     and proflavine
    Proflavine
    Proflavine , also called proflavin and diaminoacridine, is an acriflavine derivative, a disinfectant bacteriostatic against many gram-positive bacteria...

     are molecules that may insert between bases in DNA, causing frameshift mutation
    Frameshift mutation
    A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence...

     during replication. Some such as daunorubicin
    Daunorubicin
    Daunorubicin or daunomycin is chemotherapeutic of the anthracycline family that is given as a treatment for some types of cancer. It is most commonly used to treat specific types of leukaemia...

     may block transcription and replication, making them highly toxic to proliferating cells.

Metals

Many metals, such as arsenic
Arsenic
Arsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...

, cadmium
Cadmium
Cadmium is a chemical element with the symbol Cd and atomic number 48. This soft, bluish-white metal is chemically similar to the two other stable metals in group 12, zinc and mercury. Similar to zinc, it prefers oxidation state +2 in most of its compounds and similar to mercury it shows a low...

, chromium
Chromium
Chromium is a chemical element which has the symbol Cr and atomic number 24. It is the first element in Group 6. It is a steely-gray, lustrous, hard metal that takes a high polish and has a high melting point. It is also odorless, tasteless, and malleable...

, nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...

 and their compounds may be mutagenic, they may however act via different mechanisms. Arsenic, chromium, iron, and nickel may be associated with the production of reactive oxygen species, nickel may also be linked to DNA hypermethylation and histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...

 deacetylation, while cadmium may inhibit DNA mismatch repair.

Biological agents

  • Transposon
    Transposon
    Transposable elements are sequences of DNA that can move or transpose themselves to new positions within the genome of a single cell. The mechanism of transposition can be either "copy and paste" or "cut and paste". Transposition can create phenotypically significant mutations and alter the cell's...

    , a section of DNA that undergoes autonomous fragment relocation/multiplication. Its insertion into chromosomal DNA disrupt functional elements of the genes.
  • Virus
    Virus
    A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

     - Virus DNA may be inserted into the genome and disrupts genetic function.
  • Bacteria
    Bacteria
    Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

     - 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.

Protection against mutagens

Antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

s are important groups of compounds that may help remove ROS or potentially harmful chemicals. These may be found naturally in fruit
Fruit
In broad terms, a fruit is a structure of a plant that contains its seeds.The term has different meanings dependent on context. In non-technical usage, such as food preparation, fruit normally means the fleshy seed-associated structures of certain plants that are sweet and edible in the raw state,...

s and vegetables. Example of antioxidants are vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...

 and its carotenoid
Carotenoid
Carotenoids are tetraterpenoid organic pigments that are naturally occurring in the chloroplasts and chromoplasts of plants and some other photosynthetic organisms like algae, some bacteria, and some types of fungus. Carotenoids can be synthesized fats and other basic organic metabolic building...

 precursors, vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...

, vitamin E
Vitamin E
Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

, polyphenol
Polyphenol
Polyphenols are a structural class of natural, synthetic, and semisynthetic organic chemicals characterized by the presence of large multiples of phenol structural units...

s, and various other compounds. β-Carotene
Beta-carotene
β-Carotene is a strongly-coloured red-orange pigment abundant in plants and fruits. It is an organic compound and chemically is classified as a hydrocarbon and specifically as a terpenoid , reflecting its derivation from isoprene units...

, the red-orange colored compounds found in carrot
Carrot
The carrot is a root vegetable, usually orange in colour, though purple, red, white, and yellow varieties exist. It has a crisp texture when fresh...

s, tomatoes and other fruits and vegetables have been shown to be effective in cancer prevention. Vitamin C may prevent various cancers by inhibiting the formation of mutagenic N-nitroso compounds (nitrosamine). Flavonoid
Flavonoid
Flavonoids , are a class of plant secondary metabolites....

s such as EGCG
Epigallocatechin gallate
Epigallocatechin gallate , also known as epigallocatechin 3-gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin....

 in in green tea
Green tea
Green tea is made solely from the leaves of Camellia sinensis that have undergone minimal oxidation during processing. Green tea originates from China and has become associated with many cultures throughout Asia. It has recently become more widespread in the West, where black tea is traditionally...

 have also been shown to be effective antioxidants.

Other chemicals may reduce mutagenesis via other mechanisms, although the precise mechanism for their protective property may not be certain. Selenium
Selenium
Selenium is a chemical element with atomic number 34, chemical symbol Se, and an atomic mass of 78.96. It is a nonmetal, whose properties are intermediate between those of adjacent chalcogen elements sulfur and tellurium...

, which is present as a micronutrient in vegetable, is a component of selenoproteins, which are important antioxidant enzymes such as gluthathione peroxidase. Sulforaphane
Sulforaphane
Sulforaphane is an organosulfur compound that exhibits anticancer, antidiabetic, and antimicrobial properties in experimental models. It is obtained from cruciferous vegetables such as broccoli, Brussels sprouts or cabbages. The enzyme myrosinase transforms glucoraphanin, a glucosinolate, into...

 in vegetables such as broccoli
Broccoli
Broccoli is a plant in the cabbage family, whose large flower head is used as a vegetable.-General:The word broccoli, from the Italian plural of , refers to "the flowering top of a cabbage"....

 has been shown to be protective against prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

.

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
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...

 is the most common cancer diagnosed in people aged 15-44 years. In 1981, human epidemiological analysis by Richard Doll
Richard Doll
Sir William Richard Shaboe Doll CH OBE FRS was a British physiologist who became the foremost epidemiologist of the 20th century, turning the subject into a rigorous science. He was a pioneer in research linking smoking to health problems...

 and Richard Peto
Richard Peto
Sir Richard Peto FRS is Professor of Medical Statistics and Epidemiology at the University of Oxford.He attended Taunton's School in Southampton and subsequently studied Natural Sciences at Cambridge University....

 indicated that smoking caused 30% of cancers in the US. Doll and Peto also estimated that diet may cause perhaps around 35% of cancers. Mutagens identified in food include mycotoxin
Mycotoxin
A mycotoxin is a toxic secondary metabolite produced by organisms of the fungus kingdom, commonly known as molds. The term ‘mycotoxin’ is usually reserved for the toxic chemical products produced by fungi that readily colonize crops...

s from food contaminated with fungal growths, such as aflatoxins, which may be present in contaminated peanuts (prevalent in Southern China) and corn, heterocyclic amines generated in meat when cooked at high temperature, PAHs in charred meat and smoked fish, and nitrosamines generated from nitrites used as food preservatives in cured meat such as bacon
Bacon
Bacon is a cured meat prepared from a pig. It is first cured using large quantities of salt, either in a brine or in a dry packing; the result is fresh bacon . Fresh bacon may then be further dried for weeks or months in cold air, boiled, or smoked. Fresh and dried bacon must be cooked before eating...

 (ascobate
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...

, which is added to cured meat, however, reduces nitrosamine formation). Excessive alcohol consumption
Alcohol and cancer
Alcohol is associated with an increased risk of a number of cancers. 3.6% of all cancer cases and 3.5% of cancer deaths worldwide are attributable to consumption of alcohol. Breast cancer in women is linked with alcohol intake...

 has also been linked to carcinogenesis, the possible mechanisms for its carcinogenicity include formation of acetaldehyde
Acetaldehyde
Acetaldehyde is an organic chemical compound with the formula CH3CHO or MeCHO. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale industrially. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants as part...

 which may be mutagenic and the induction of cytochrome P450 system which is known to produce mutagenic compounds from promutagens.

For certain mutagens, government legislations and regulatory bodies are necessary for their control, such as dangerous chemicals and radiations, as well as infectious agents known to cause cancer.

Mutagen 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 systems

  • Ames test - This is the most commonly used test using Salmonella typhimurium strains deficient in histidine biosynthesis. The test checks for mutants that can be reverted back 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 E. coli. Tryptophane-deficient mutant is used for the reverse mutation, while galactose utility or resistance to 5-methyltryptophane 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
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...

 is general used. These systems can check for forward and reverse mutations, as well as recombinant events.

Drosophila

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 maize, Arabidopsis
Arabidopsis
Arabidopsis is a genus in the family Brassicaceae. They are small flowering plants related to cabbage and mustard. This genus is of great interest since it contains thale cress , one of the model organisms used for studying plant biology and the first plant to have its entire genome sequenced...

 and Tradescantia
Tradescantia
Tradescantia , the Spiderworts, is a genus of an estimated 71 species of perennial plants in the family Commelinaceae, native to the New World from southern Canada south to northern Argentina. They are weakly upright to scrambling plants, growing to 30–60 cm tall, and are commonly found...

 have been used in various test assays for mutagenecity of chemicals.

Cell culture assay

Mammalian cell lines such as Chinese hamster V79 cells, Chinese hampter ovary (CHO) cells or mouse lymphoma cells may be used to test for mutagenesis. Such systems include the HPRT
Hypoxanthine-guanine phosphoribosyltransferase
Hypoxanthine-guanine phosphoribosyltransferase is an enzyme encoded in humans by the HPRT1 gene.HGPRT is a transferase that catalyzes conversion of hypoxanthine to inosine monophosphate and guanine to guanosine monophosphate. This reaction transfers the 5-phosphoribosyl group from...

 assay for resistance to 8-azaguanine
8-Azaguanine
8-Azaguanine is a purine analog with the chemical formula C4H4N6O. It has been widely studied for its biological activity. It shows antineoplastic activity and has been used in the treatment of acute leukemia.-Use in chemotherapy:...

 or 6-thioguanine, and ouabain
Ouabain
Ouabain which is also named g-strophanthin, is a poisonous cardiac glycoside.-Sources:Ouabain is found in the ripe seeds of African plants Strophanthus gratus and the bark of Acokanthera ouabaio.-Function:...

-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
Animal testing on rodents
Rodents are commonly used in animal testing, particularly guinea pigs, hamsters, gerbils, rats, and mice.-The statistics:In the UK in 2004, 1,910,110 mice, 464,727 rats and 37,475 other rodents were used...

 are usually used for test. The chemicals under
test are usually administered in the food and in the drinking water, but sometimes by dermal application, by gavage
Feeding tube
A feeding tube is a medical device used to provide nutrition to patients who cannot obtain nutrition by swallowing. The state of being fed by a feeding tube is called gavage, enteral feeding or tube feeding...

, 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 tumors on the animal test may also be unreasonably high for a human, i.e. the equivalent amount required to produce tumors 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.

Transgenic Mouse
Genetically modified mouse
A genetically modified mouse is a mouse that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly used for research or as animal models of human diseases.-History:...

 Assay using a mouse strain infected with a viral shuttle vector
Shuttle vector
A shuttle vector is a vector constructed so that it can propagate in two different host species . Therefore, DNA inserted into a shuttle vector can be tested or manipulated in two different cell types. The main advantage of these vectors is they can be manipulated in E. coli then used in a...

 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.

Use of mutagen 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
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....

 and cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...

, as well as intercalating agent such as daunorubicin
Daunorubicin
Daunorubicin or daunomycin is chemotherapeutic of the anthracycline family that is given as a treatment for some types of cancer. It is most commonly used to treat specific types of leukaemia...

 and doxorubicin
Doxorubicin
Doxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....

 may be used in chemotherapy. Ionizing radiations are used in radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...

.

Mutagens in fiction

In science fiction
Science fiction
Science fiction is a genre of fiction dealing with imaginary but more or less plausible content such as future settings, futuristic science and technology, space travel, aliens, and paranormal abilities...

, 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 book
Comic book
A comic book or comicbook is a magazine made up of comics, narrative artwork in the form of separate panels that represent individual scenes, often accompanied by dialog as well as including...

s such as Marvel Comics
Marvel Comics
Marvel Worldwide, Inc., commonly referred to as Marvel Comics and formerly Marvel Publishing, Inc. and Marvel Comics Group, is an American company that publishes comic books and related media...

's Inhumans, television series, computer and video games, like the The Witcher
The Witcher
The Witcher, or , by Polish writer Andrzej Sapkowski is a cult series of fantasy short stories and five novels about the witcher Geralt of Rivia...

, Metroid Prime Trilogy, Resistance: Fall of Man
Resistance: Fall of Man
Resistance: Fall of Man is a first-person shooter video game for the PlayStation 3. It was developed by Insomniac Games and published by Sony Computer Entertainment. The game is set in an alternate history 1951, and follows Sgt...

, Resident Evil, Infamous, and Command & Conquer
Command & Conquer
Command & Conquer, abbreviated to C&C and also known as Tiberian Dawn, is a 1995 real-time strategy computer game developed by Westwood Studios for MS-DOS and published by Virgin Interactive. It was the first of twelve games to date to be released under the Command & Conquer label, including a...

, and even toys.

See also

  • Carcinogen
    Carcinogen
    A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...

  • DNA repair
    DNA repair
    DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...

  • Genetics
    Genetics
    Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....

  • Genotoxicity
  • Mutation
    Mutation
    In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...

  • Pesticide
    Pesticide
    Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...

  • Teratogen
The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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