Mutagen

In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer, mutagens are therefore also likely to be carcinogens, although not always necessarily so. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes. Not all mutations are caused by mutagens: so-called 'spontaneous mutations' occur due to spontaneous hydrolysis, errors in DNA replication, repair and recombination. In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer, mutagens are therefore also likely to be carcinogens, although not always necessarily so. All mutagens have characteristic mutational signatures with some chemicals becoming mutagenic through cellular processes. Not all mutations are caused by mutagens: so-called 'spontaneous mutations' occur due to spontaneous hydrolysis, errors in DNA replication, repair and recombination. The first mutagens to be identified were carcinogens, substances that were shown to be linked to cancer. Tumors were described more than 2,000 years before the discovery of chromosomes and DNA; in 500 B.C., the Greek physician Hippocrates named tumors resembling a crab karkinos (from which the word 'cancer' is derived via Latin), meaning crab. In 1567, Swiss physician Paracelsus suggested that an unidentified substance in mined ore (identified as radon 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 sweeps, and suggested chimney soot as the cause of scrotal cancer. In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer. Subsequently, in the 1930s the carcinogen component in coal tar was identified as a polyaromatic hydrocarbon (PAH), benzopyrene. 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 and radioactivity by Henri Becquerel. Georgii Nadson and German Filippov were the first who created fungi mutants under ionizing radiation in 1925. The mutagenic property of mutagens was first demonstrated in 1927, when Hermann Muller discovered that x-rays can cause genetic mutations in fruit flies, producing phenotypic mutants as well as observable changes to the chromosomes, visible due to 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 mutants that he used in his studies of genetics. He also found that X-rays not only mutate genes in fruit flies, but also have effects on the genetic makeup of humans. Similar work by Lewis Stadler also showed the mutational effect of X-rays on barley in 1928, and ultraviolet (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 and J. M. Robson found that mustard gas can cause mutations in fruit flies. A large number of chemical mutagens have since been identified, especially after the development of the Ames test 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. Mutagens are not necessarily carcinogens, and vice versa. Sodium azide for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic. 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 the 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 sequences by mutations include substitution of nucleotide base-pairs and insertions and deletions of one or more nucleotides in DNA sequences. Although some of these mutations are lethal or cause serious disease, many have minor effects as they do not result in residue changes that have significant effect on the structure and function of the proteins. Many mutations are silent mutations, 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 of codons. Some mutagens can cause aneuploidy 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 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.