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

Figure 1 Schematic diagram representing the structure of DNA bases. A, adenine; C, cytosine; G, guanine; T, thymine.

(PAHs). Figure 2b, 2, is a schematic representation of a benzo[^]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.

Oxidative damage

Oxidative damage occurs as a result of interaction of free radicals or singlet oxygen (molecular oxygen in an excited state) with DNA. The most common oxyradicals include hydroxide radicals (OH ) and the superoxide anion O^. Oxyradicals and singlet oxygen are potential mutagenic chemicals known as reactive oxygen species (ROSs). These ROSs are produced to some extent by endogenous metabolic processes, for example, during mitochondrial respiration, metabolism of natural and man-made hydrocarbons, and metabolism of fats. However, some chemicals may stimulate cells to overproduce ROSs metabolically. Besides metabolic processes, some hydrocarbons and heavy metals may convert molecular oxygen to superoxide.

ROSs can damage DNA in two ways. First, the ROSs themselves can form chemical bonds to nucleotide bases (Figure 2b, 3 and 4). Second, the oxyradicals may cause internal rearrangement of the DNA to form fragmented bases or open-ring structures (Figure 2b, 6). These ROSs may also react with cellular lipids or phospholipids, which leads to formation of lipid adducts (Figure 2b, 6). Finally, oxyradicals may oxidize proteins, creating protein radicals, which can form covalent attachments to DNA in the form of DNA-protein cross-links (Figure 2b, 8).

Base loss, sugar damage, and strand breakage

Base loss, sugar damage, and strand breakage may occur in several ways. For example, a base may be hydrolyzed from the deoxyribose sugar (Figure 2 c, 9) enzymatically - during DNA repair (see below) - as a result of oxyradical attack, or as a result of bulky adducts or oxidized bases. This site is called an abasic site. Base loss can also occur as a result of free radical attack on the sugar, resulting in sugar damage (Figure 2c, 10). In addition, sugar damage may result in DNA strand breakage (Figure 2c, 11). Strand breaks may also be formed by hydrolysis of the sugar-phosphate bond (Figure 2c, 12). These types of strand breaks may be produced transiently during the DNA repair process. However, some chemicals might inhibit repair enzymes, resulting in persistent strand breaks.

Because DNA is a double-stranded molecule, strand breaks may occur in one (single-strand breaks, SSBs) or both of the DNA strands (double-strand breaks, DSBs; Figure 3). DSBs are less easily repaired and more persistent than SSBs, and are more effective in producing deleterious cellular effects. There are basically three ways in which DSBs may be formed. First, there may be two SSBs directly across from each other or in close proximity (Figure 3). Second, if an SSB is unrepaired and the cell tries to replicate a DNA molecule with an SSB, this may result in a DSB. Third, some types of enzymes can produce DSBs. If left unrepaired, DSBs can lead to chromosomal mutations, as discussed below, or may lead to cell death.

DNA cross-links

An additional class of chemically induced DNA lesions includes DNA cross-links. These are formed when some chemical agents such as ¿/'j-platinum (a chemotherapeutic agent), arsenic, or chromate can form adducts to two or more bases simultaneously. DNA cross-linking agents may covalently cross-link adjacent nucleotide bases on the same strand (intrastrand cross-links; Figure 2c, 15) or on opposite strands bases or (interstrand cross-links; Figure 2c, 16). Alternatively, cross-linking agents may link proteins to the DNA bases (DNA-protein cross-links).

Radiation-induced DNA damage

Chemicals are not the only environmental agents that can cause mutations. Radiation, a type of electromagnetic energy, may also be mutagenic. In general, there are two primary categories of mutagenic ionizing radiation and ultraviolet (UV) radiation. Although there have been claims that other types of electromagnetic energy - such as magnetic fields, microwaves, and radiowaves - are mutagenic or carcinogenic, to date, the evidence for this remains equivocal.

Ionizing radiation includes alpha particles (two protons and two neutrons, that is, a helium nucleus), beta particles (high-energy electrons), and gamma particles (high-energy photons). The sources of ionizing radiation in the environment may be natural or man-made. Natural sources include cosmic radiation - originating from the sun, stars, or other celestial bodies - and naturally occurring radioisotopes. Man-made sources are listed in Table 1. Ionizing radiation could produce base or sugar radicals, which are unstable and rapidly react with other

Figure 2 Diagram of the types of DNA damage that can occur as a result of exposure to genotoxic agents. (a) Undamaged DNA; (b) 1 - Methylated guanine, 2 - benzo[a]pyrene adduct, 3 and 4 - oxidized bases, 5 - DNA cross-link, 6 - two examples of lipid aldehyde adducts, 7 - open ring base, 8 - DNA-protein cross-link; (c) 9 - abasic site (hydrolysis of glycosidic linkage), 10 - sugar damage leading to base loss, 11 - sugar damage leading to strand break, 12 - hydrolysis of sugar-phosphate bond, 13 - thymine dimer, 14 - cytosine 6-4 photoproduct, 15 -DNA-DNA cross-link (interstrand), in this case mediated by c/'s-platinum (complete structure of c/'s-platinum not shown), 16 - DNA-DNA cross-link (interstrand), in this case mediated by chromate.

Figure 2 Diagram of the types of DNA damage that can occur as a result of exposure to genotoxic agents. (a) Undamaged DNA; (b) 1 - Methylated guanine, 2 - benzo[a]pyrene adduct, 3 and 4 - oxidized bases, 5 - DNA cross-link, 6 - two examples of lipid aldehyde adducts, 7 - open ring base, 8 - DNA-protein cross-link; (c) 9 - abasic site (hydrolysis of glycosidic linkage), 10 - sugar damage leading to base loss, 11 - sugar damage leading to strand break, 12 - hydrolysis of sugar-phosphate bond, 13 - thymine dimer, 14 - cytosine 6-4 photoproduct, 15 -DNA-DNA cross-link (interstrand), in this case mediated by c/'s-platinum (complete structure of c/'s-platinum not shown), 16 - DNA-DNA cross-link (interstrand), in this case mediated by chromate.

Undamaged DNA

Single-strand break

Double-strand breaks

Single-strand break

Double-strand breaks

Figure 3 Schematic representation of DNA with single- and double-strand breaks.

Figure 3 Schematic representation of DNA with single- and double-strand breaks.

macromolecules or undergo internal molecular rearrangements. This results in strand breakage, base loss, fragmented bases, DNA-DNA cross-links (Figure 2b, 5), or DNA-protein cross-links (Figure 2b, 8). Alternatively, the radioactive particles can interact with water or oxygen, which produces ROSs and singlet oxygen, which leads to oxidative DNA damage.

Another type of radiation is UV radiation. Because the source of UV radiation is the sun, environmental sources of UV radiation are entirely natural. However, anthropogenic activities may result in increased exposure or susceptibility to UV-induced mutagenesis. For example, chlorofluorocarbons (CFCs) may react with ozone in the upper atmosphere to convert it to molecular oxygen. Because ozone strongly absorbs solar UV light, this may result in increased UV reaching the Earth. Also, changes in climate (e.g., due to buildup of atmospheric CO2) or draining of wetlands may lower water levels and expose aquatic organisms to more UV. Furthermore, some chemicals may inhibit an organism's natural ability to repair or prevent UV-induced DNA damage, or may react with UV to produce ROS.

UV can cause DNA damage in two mechanisms. First, UV can convert molecular oxygen into singlet oxygen (an energized, highly reactive form ofoxygen). This may lead to increase oxidative DNA damage. Second, UV radiation can directly interact with DNA bases to produce so-called dimers and photoproducts (Figure 2c, 13 and 14, respectively).

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