Mutagen

Mutagens are agents that cause an increase in frequency of DNA modifications over the naturally occurring spontaneous ones and can range from single base pair alterations to complex genome rearrangements.

From: Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2016

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Mutagenesis

C.W. Theodorakis, in Encyclopedia of Ecology, 2008

Adducts

Numerous mutagens can form DNA adducts, which are molecules that form covalent bonds with DNA. Some chemicals transfer a methyl or ethyl group to a nucleotide base. Figure 2b, 1, illustrates a generalized structure of such a methyl-adducted base. Other chemicals form bulky adducts, so called because they are composed of relatively large and bulky molecules. A number of chemicals are not mutagenic in their native state, but require metabolic oxidation to convert them to mutagenic intermediates. These include polycyclic aromatic hydrocarbons (PAHs). Figure 2b, 2, is a schematic representation of a benzo[a]pyrene (a PAH that is a common environmental contaminant) adduct. Another type of adduct is lipid aldehyde adducts (Figure 2b, 6), which are formed as a result of oxidative damage to lipids, and are discussed in the next section.

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Carcinogenicity of Disinfection Byproducts in Laboratory Animals

R.L. Melnick, M.J. Hooth, in Encyclopedia of Environmental Health, 2011

The codename MX (mutagen X) was originally given to an unknown compound that was a potent bacterial mutagen present in chlorinated water sources. The compound, which is also mutagenic in mammalian cells, was subsequently isolated and identified as 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone. A 2-year drinking water study of MX in Wistar rats demonstrated tumor induction at multiple sites, including follicular cell neoplasms of the thyroid gland, bile duct neoplasms in the liver, neoplasms of the adrenal cortex, and fibroadenomas and adenocarcinomas of the mammary gland (Table 3). Although the concentrations of MX in chlorinated tap water are 100- to 1000-fold lower than the commonly occurring DBPs (e.g., trihalomethanes and haloacetic acids), the potency of the cancer response associated with exposure to this direct-acting mutagen is greater than that of trihalomethanes.

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DNA ADDUCT DETECTION IN MUSSELS EXPOSED TO BULKY AROMATIC COMPOUNDS IN LABORATORY AND FIELD CONDITIONS

P. Venier, in Biomarkers in Marine Organisms, 2001

Abstract

Carcinogens and mutagens of different chemical structures share the ability to bind covalently to DNA, either directly or after biotransformation to electrophilic intermediates. DNA binding basically depends on its molecular structure and functional state (accessibility of nucleophilic target sites) while physiological and biochemical features determine differences in adduct formation among tissues and across species. DNA adducts can be detected by the 32P-postlabelling assay in cells and organisms exposed to model genotoxins or unknown chemical mixtures, thus confirming the biological relevance of exposure and recognizing relationships between initial DNA lesions and ensuing biological effects (e.g. mutations, tumors).

Regarding mussels, sentinel species used world-wide in pollution monitoring, DNA adduct detection presents some drawbacks but can also provide interesting insights into benzo[a]pyrene-induced damage. Compared with vertebrates, lower adduct formation is likely to occur in mussels exposed to 'environmental' genotoxin doses; yet, substantial bioaccumulation of miscellaneous pollutants and diversified intracellular reactions, altogether, may explain the appearance of benzo[a]pyrene-related DNA adducts. Irrespective of molecular mechanisms, the 32P-postlabelling assay can be used to ascertain mussel exposure to genotoxins, being limited only by the complexity and cost of the applied technique. Evidence of unresolved DNA adducts in mussels from one industrial area (Venice lagoon, Italy) is consistent with other studies indicating exposure to genotoxic water pollutants. On the other hand, the non-appearance of specific adducts in mussels from sites still contaminated by polycyclic aromatic hydrocarbons (Galician coast, Spain) suggests that other aromatic compounds could have caused earlier DNA adduct formation.

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Environmental Toxicology

C.P. Gerba, in Environmental and Pollution Science (Third Edition), 2019

28.7 Mutagens

Like carcinogens, mutagens and teratogens affect DNA. Mutagens cause mutations, which are inheritable changes in the DNA, sequences of chromosomes. Mutations involve a random change in the natural functioning of chromosomes or their component genes; such changes rarely benefit the organism's offspring.

A mutation is a change in the genetic code that may or may not have an effect on the organism. Harmful effects from mutations depend on the type of cell that is affected and whether the mutation leads to metabolic malfunctions. Mutations that occur in somatic cells (nonreproductive cells of the body) may or may not prove to be a threat to the organism. Mutations occur naturally, most commonly from ionizing radiation. Humans and other organisms have enzymes that can repair damaged DNA. However, not all mutations are repaired, and some mutations will cause the cell's metabolism to become out of control, which may result in cancer.

Numerous types of mutations have been documented. The simplest type of genetic damage results when there is a mutation of the DNA sequence. Referred to as a point mutation, this mutation represents a change in the chromosome involving a single nucleotide (base) within the gene. These changes may result in the substitution, deletion, or insertion of a base (Fig. 28.14).

Fig. 28.14. Types of base mutations.

A base substitution occurs when a nucleotide is substituted for a normally occurring base. If the substituted base does not alter the amino acid coded for in that position, then it will have no effect on the protein being made from the DNA. This outcome is possible, since each amino acid is coded for by more than one codon (see Fig. 28.14). Two additional outcomes, missense and nonsense, result when the mutated triplet codon codes for a different amino acid or stop signal, respectively. Base substitutions usually do not result in significant mutagenic activity. Because of the redundancy of the genetic code, one base substitution will not likely result in a major change in the translation of the genetic information. Moreover, if a mutation results in an inappropriate amino acid in a protein that functions as an enzyme, it may not even change the enzymatic activity if it is not at or near the active site on the enzyme.

Frameshift mutations are the result of the addition between base pairs, which shifts the triplet code down the DNA strand. Such shifts essentially change the entire coding of proteins, with consequent high potential for malfunction of the protein. The effects of some physical and chemical mutagens are shown in Table 28.7.

Table 28.7. The Effects of Selected Physical and Chemical Mutagens

MutagenEffect on DNA/RNAType of MutationUltraviolet radiationC, T, and U dimers that cause base substitutions, deletions, and insertionsNo effect, missense, or nonsenseX raysBreaks in DNAChromosomal rearrangements and deletionsAcridines (tricyclic ring present in dyes)Adds or deletes a nucleotideMissense or nonsenseAlkylating agentsInterferes with specificity of base pairing (e.g., C with T or A, instead of G)No effect, missense, or nonsense5-BromouracilParis with A and G, replacing AT with GC, or GC with ATNo effect, missense, or nonsense

C = cytosine.

T = thymine.

U = uracil.

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Cigarette Smoke, DNA Damage Repair, and Human Health

A.S. Jaiswal, ... C.G. Gairola, in Encyclopedia of Environmental Health, 2011

Cigarette Smoke-Induced Carcinogenesis and Individual Susceptibility

Among the carcinogens and mutagens present in the cigarette smoke, the most important chemical families are PAHs, aromatic amines, and nitroso compounds. These potent carcinogens induce tumors in several organs. Individual susceptibility to cancer is cumulative effect of several factors including differences in the metabolism of carcinogens, carcinogen-induced DNA damage and DNA repair, altered expression of proto-oncogenes and tumor suppressor genes, and nutritional status. Each individual factor plays a critical role in the individual's susceptibility to cancer. Since most carcinogens require metabolic activation before binding to DNA, the individual's capacity to metabolize the cigarette smoke carcinogens can be an essential factor in cigarette smoke-induced carcinogenesis. Also, the interindividual variation in susceptibility to chemical carcinogenesis also depends on carcinogen metabolism and DNA repair. For example, the level of in vivo tobacco smoke-induced DNA adducts is determined by an equilibrium between the metabolism of tobacco carcinogens, such as benzo(a)pyrene, and the rate of adduct removal by DNA repair enzymes. Biomarkers reflecting such susceptibility may therefore be useful for identifying high-risk individuals. Variation in an individual's metabolic phenotype has also been observed to be related to the genetic polymorphisms. The evidence also suggest that smoking and family history of cancer are separate risk factors for the individuals' susceptibility to the disease. Metabolic polymorphisms in the CYP1A1 and glutathione S-transferase (GST) have been shown to be associated with lung and bladder cancer risk, in the latter case of Japanese populations. CYP1A1 metabolizes PAHs to reactive electrophilic epoxide compounds that can form DNA adducts (carcinogenic metabolites bound to DNA), usually at guanine or adenine. If DNA adducts escape cellular repair mechanisms and persist, they lead to miscoding resulting in permanent mutation. If the mutation occurs in the critical region of an oncogene or tumor suppressor gene, it can cause activation or deactivation of these genes. This can lead to aberrant loss of the normal regulatory function of cell growth.

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Geochemistry of Estuaries and Coasts

J.A. Hagger, ... D. Copplestone, in Treatise on Estuarine and Coastal Science, 2011

4.12.2.1.2 Micronucleus assay

Ionizing radiation and numerous chemical mutagens cause structural chromosomal aberrations, many of which are visible using a light microscope. Micronuclei are also known as Howell–Jolly bodies by hematologists; because they are caused by chromosomal aberrations (Countryman and Heddle, 1976), micronuclei are considered to be a sensitive indicator of genotoxic risk of exposure to mutagenic agents (Rodgers and Baker, 2000). Evans et al. (1959) were the first authors to suggest counting cells with micronuclei as a method evaluating cytogenetic damage. Schmid (1975) and Heddle (1973) both independently proposed the micronucleus test as an alternative to the laborious, and sometimes complex, counting of aberrations in metaphases. The micronucleus assay was initially developed in dividing mammalian cells, and its use in bone marrow and peripheral blood erythrocytes is now one of the best-established in vivo cytogenetic assays in the field of genetic toxicology (Mavournin et al., 1990). Micronuclei are only expressed in dividing cells that contain chromosome breaks lacking centromeres (acentric fragments) and/or whole chromosomes that are unable to travel to the spindle poles during mitosis. At telophase, a nuclear envelope forms around the lagging chromosomes and fragments, which then uncoil and gradually assume the morphology of an interphase nucleus with the exception that they are smaller than the main nuclei in the cell, hence the term 'micronucleus'. In mammalian systems, the cytokinesis-blocked micronucleus assay has been developed to block cells that have completed one nuclear division from performing cytokinesis, using cytochalasin-B. Consequently, cells will have a bi-nucleated appearance and the accumulation of virtually all dividing cells will occur regardless of their degree of synchrony and proportions of dividing cells. Micronuclei are then scored in bi-nucleated cells only, which enable reliable comparisons of chromosome damage between cell populations that may differ in their cell division kinetics. Figure 2 represents the mechanisms involved in the formation of micronuclei.

Figure 2. Formation of micronuclei during cell division.

The micronucleus assay has several advantages over other cytogenetic assays. Heddle (1973) showed that the scoring micronuclei were more than 10 times faster than scoring chromosomal aberrations at metaphase. Other advantages of the micronucleus assay are that the number of scorable cells is virtually unlimited; little formal training is needed as the endpoint is easily recognizable and a suitable karyotype is not required. Problems associated with the interpretation of other cytogenetic tests such as the significance of chromosomal gaps or sister chromatid exchanges are avoided with the micronucleus test. One limitation of the micronucleus assay is when agents cause neither chromosomal breakage nor lagging chromosomes, for example, aberrations that involve chromosomal rearrangement without the occurrence of an acentric fragment such as translocation or inversion, and these will not be detected (Heddle et al., 1983).

As with many other mammalian-based assays, the micronucleus test has been successfully adapted to aquatic organisms (Figure 3). Induction of micronuclei in fish has been widely used due to advantages over other cytogenetic assays such as chromosomal aberrations and sister chromatid exchanges. As these later-mentioned techniques, besides being time-consuming, are not very effective due to the relatively large number of very small chromosomes which makes the analysis of aberrations and sister chromatid exchanges virtually impossible (Ayllon and Garcia-Vazquez, 2000) and, as in cold water fish, the cells have a low mitotic activity which results in fewer scorable metaphase spreads (Hooftman and De Raat, 1982).

Figure 3. Micronuclei (→) in hemocytes of Mytilus edulis stained with Giemsa.

In addition to fish species, the micronucleus assay has been extensively used in hemocytes and gill cells of many molluska species, including the freshwater zebra mussel Dreissena polymorpha (Mersch and Beauvais, 1997; Pavlica et al., 2000), the oyster Crassostrea gigas (Burgeot et al., 1995), the Mediterranean mussel Mytilus galloprovinciallis (Majone et al., 1987, 1988; Scarpato et al., 1990; Venier et al., 1997), and the common blue mussel Mytilus edulis (Wrisberg and Rhemrev, 1992; Dopp et al., 1996; Bolognesi et al., 1999). Many micronuclei studies have been carried out on mollusks in laboratory conditions, but due to the sedentary nature of mollusks the micronucleus test has also been proposed as a potential biomarker of pollutant exposure in field studies (Mersch and Beauvais, 1997). The incidence of micronuclei has also been linked to the induction of leukemia cells in the clam Mya arenaria, suggesting that the micronucleus test is a very good indicator of the potentially life-threatening consequences of genotoxic exposure (Dopp et al., 1996). Detailed method of how to perform the micronucleus assay is available in the appendix.

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Airborne Polycyclic Aromatic Hydrocarbons and Their Derivatives

Barbara J. Finlayson-Pitts, James N. PittsJr., in Chemistry of the Upper and Lower Atmosphere, 2000

3. The Salmonella TM677 "Forward Mutation" Assay

In the late 1970s, a forward mutagen assay using a different strain of Salmonella was introduced by Skopek et al. (1978a). The "genetic marker" is resistance to 8-azaguanine. This is produced when the "normal" strain TM677—which cannot survive in the presence of this purine analog—is mutated (e.g., by an airborne mutagen) to forms that can survive (Skopek et al., 1978a, 1978b; Kaden et al., 1979; Hannigan et al., 1994, 1996, and references therein).

As with the Salmonella reversion assay, this short-term test is conducted both without (-PMS) and with metabolic activation produced by addition of "postmitochondrial supernatant" containing rat liver enzymes (+PMS). These terms are equivalent to −S9 and +S9 in the Ames reversion assay; we use the latter designation for both types of bacterial assays. A more sensitive micro-forward mutation bioassay using this TM677 strain to determine the mutagenicity of indoor air particles, including ETS and wood smoke, is described by Lewtas et al. (1987).

For a comparison of the two techniques, reverse vs forward mutation Salmonella assays, see Skopek et al. (1978b) and Lewtas et al. (1990b). Examples of its use in atmospheric chemistry/air pollution research include the following: application to the mutagenicity of soot and 70 PAHs (Kaden et al., 1979), indoor air particles, using a modification that increased assay sensitivity (Lewtas et al., 1987), urban aerosol sources compared to atmospheric samples (Hannigan et al., 1994), mutagenicities of mono- and dinitropyrenes in Salmonella typhimurium strain TM677 (Busby et al., 1994a), and seasonal and spatial trends in the mutagenicity of fine organic aerosols in southern California (Hannigan et al., 1996) (vide infra).

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Polycyclic Aromatic Hydrocarbons

J.P. Meador, in Encyclopedia of Ecology, 2008

Mutagenicity and neoplasia

There is overwhelming evidence that certain PAHs are well-known mutagens that can cause genetic damage, toxicopathic lesions, and tumor formation. Most of the studies describe the mutagenic properties of PAHs in mammals, which has been directed at human health. Several review articles describe many of the relevant studies for ecotoxicologists concerning PAH-induced abnormalities.

Potential mutagens are those PAHs containing four to six rings (HPAHs). Additionally, the alkyl moiety often increases the mutagenic potential. Based on the diverse sources of PAHs in the environment and urban areas, there is ample opportunity for both humans and other species to be exposed. Much of the mammalian literature is directly applicable to wildlife, including most vertebrates. Because metabolic activation of PAHs is necessary for the expression of mutagenic properties, well-developed biotransformation capabilities are needed. For that reason, many invertebrate species do not exhibit alterations to DNA from exposure to PAHs.

Several field studies have observed histopathological changes and tumor formation in fish associated with sites contaminated with PAHs. Also, one recent study examined cancer in beluga whales and concluded that PAHs were the likely cause. As noted by one author, several factors relating to PAH exposure and toxicity, such as specificity of response, dose–response relationships, experimental evidence, and others, strongly support the conclusion of PAH-induced neoplasia for fish from contaminated sites. This is one of the few examples where a specific (or group of) contaminant(s) can be associated with adverse effects in organisms collected in the field, which is likely applicable for other species.

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Molecular and Genetic Tools for Study of Plant Development

Lalit M. Srivastava, in Plant Growth and Development: Hormones and Environment, 2002

a. Map-based cloning.

Map-based cloning is often used for mutations caused by chemical mutagens, which result in small changes in nucleotide sequences. To clone the gene, the mutation is genetically mapped relative to molecular markers (and to morphological markers if convenient). For mapping, a cross is made with a strain that carries nucleotide differences due to normal polymorphism between strains. The progeny can be allowed to self fertilize to produce the F2 mapping population, which contains meiotic recombination between the chromosomes of the two parents. The gene of intrest can be mapped by virtue of the fact that the mutation lies on a chromosomal segment derived from just one of the original parents. The position of the locus can be mapped on the basis of segregation with DNA markers. The DNA markers are slight sequence deviations between homologous chromosomes that can be easily visualized by techniques, such as polymerase chain reaction (PCR). Given a genetic map of molecular markers and a large segregating population, a mutation can be mapped to a chromosome interval encoding only one or a few mRNAs (Fig. A1-14).

FIGURE A1-14. Map-based cloning. Lines/rectangles with black dots symbolize pairs of homologous chromosomes. The distance between a gene of interest (X) and a molecular marker (1) is determined by meiotic mapping. Briefly, an F1 plant is generated by crossing parents a and b, where parent a has the the mutant allele of gene X (Xm) and parent b has the wild type allele XWT. Because there is abundant sequence divergence between the two parents, numerous molecular markers can be visualized, which identify two different sequences at fixed chromosomal positions, for example, by generating PCR products of distinguishable length. Meiosis in the F1 individual will produce gametes that will either contain one of the parental marker combinations (Xm 1a or XWT, 1b) or, by crossing over, new recombinant marker combinations (e.g., Xm, 1b; XWT, 1a) that will give rise to the F2 mapping population. If a molecular marker (1) is very close to gene X, hardly any recombinant meiotic products will be produced. By contrast, if the marker is away from the gene of interest, or on another chromosome, parental and recombinant marker combinations will be produced at random frequencies. Using the frequency, standard calculations for meiotic mapping can be applied. Thus, given a sufficiently large segregating population, molecular markers extremely closely linked to a mutation-defined gene can be identified.

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TROPOSPHERIC CHEMISTRY AND COMPOSITION | Peroxyacetyl Nitrate

H.B. Singh, in Encyclopedia of Atmospheric Sciences (Second Edition), 2015

Biological/Toxic Effects

PANs are known to be eye irritants (lachrymators), phytotoxins, and bacterial mutagens. Potential phytotoxic episodes in which visible injury to susceptible plants occurs (e.g., pinto beans) are likely only when PAN concentration in excess of 15 ppb is sustained for several hours. Both the eye irritation potential and phytotoxicity of higher PAN homologues (e.g., PPN, PBzN) are substantially greater than that of PAN but their atmospheric concentrations are also much lower. A number of studies have been done on mice to assess the toxic affects of PAN. These studies used PAN concentrations that were often 102–103 times larger than what is typically encountered in polluted air. Based on existing data, it appears that the concentrations of PAN observed in urban atmospheres around the globe are too low to cause injury to human health. Long-term studies on the health effects of exposure to low concentrations of PAN and its homologues have not been performed. The most serious biological effects of PANs are of a phytotoxic nature resulting in injury to plants and vegetation.

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