Chemical mutagens
Chemical mutagens are substances that can induce mutations, or changes in DNA, which may lead to serious health issues such as birth defects and cancer. These mutagens can be either naturally occurring or synthetic, and their impact on genetic material has been a significant area of study since the first documented case in 1946, when nitrogen mustard was shown to cause mutations in fruit flies. They operate primarily through two mechanisms: direct interaction with DNA or by tricking cellular processes into creating mutations.
Direct-acting mutagens, such as base analogs and alkylating agents, alter the structure of DNA bases or introduce chemical groups that can disrupt the normal pairing during DNA replication. Indirect mutagens, like aromatic amines and certain oxidizing agents, often require metabolic activation and can lead to errors in DNA repair mechanisms. The Ames test is a common method used to screen for mutagenic properties in chemicals, helping to identify potential risks to human health.
Understanding chemical mutagens is crucial for assessing environmental and dietary exposures, as well as developing strategies to mitigate their effects. By recognizing the sources and actions of these mutagens, researchers aim to reduce the risk of related diseases and improve public health outcomes.
Chemical mutagens
SIGNIFICANCE: Mutagens are naturally occurring or human-made chemicals that can directly or indirectly create mutations or changes in the information carried by the DNA. Mutations may cause birth defects or lead to the development of cancer.
The Discovery of Chemical Mutagens
The first report of mutagenic action of a chemical occurred in 1946, when Charlotte Auerbach showed that nitrogen mustard (a component of the poisonous “mustard” gas widely used in World War I) could cause mutations in fruit flies (Drosophila melanogaster). Since that time, it has been discovered that many other chemicals are also able to induce mutations in a variety of organisms. This led to the birth of genetic toxicology during the last half of the twentieth century, dedicated to identifying potentially mutagenic chemicals in food, water, air, and consumer products. Continued research has identified two modes by which mutagens cause mutations in DNA: (1) by interacting directly with DNA and (2) indirectly, by tricking the cell into mutating its own DNA.
Chemical Mutagens with Direct Action on DNA
Base analogs are chemicals that structurally resemble the organic bases and and may be incorporated into DNA in place of the normal bases during DNA replication. An example is bromouracil, an artificially created compound extensively used in research. It resembles the normal base thymine and differs only by having a bromine atom instead of a methyl (CH3) group. Bromouracil is incorporated into DNA by DNA polymerase, which pairs it with an adenine base just as it would thymine. However, bromouracil is more unstable than thymine and is more likely to change its structure slightly in a process called tautomerization. After the tautomerization process, the new form of bromouracil pairs better with guanine rather than adenine. If this happens to a DNA molecule being replicated, will insert guanine opposite bromouracil, thus changing an adenine-thymine pair to guanine-cytosine by way of the two intermediates involving bromouracil. This type of mutation is referred to as a transition, in which a purine is replaced by another purine and a pyrimidine is replaced by another pyrimidine.
Another class of are those that alter the structure and the pairing properties of bases by reacting chemically with them. An example is nitrous acid, which is formed by digestion of nitrite preservatives found in some foods. Nitrous acid removes an amino (NH3) group from the bases cytosine and adenine. When cytosine is deaminated, it becomes the base uracil, which is not a normal component of DNA but is found in RNA. It is able to pair with adenine. Therefore, the action of nitrous acid on DNA will convert what was a cytosine-guanine base pair to uracil-guanine, which, if replicated, will give rise to a thymine-adenine pair. This is also a transition type of mutation.
Alkylating agents are a large class of chemical mutagens that act by causing an alkyl group (which may be methyl, ethyl, or a larger hydrocarbon group) to be added to the bases of DNA. Some types of alkylation cause the base to become unstable, resulting in a single-strand break in the DNA; this type of event can cause a mutation if the DNA is replicated with no base present or can lead to more serious breaks in the DNA strand. Other alkylation products will change the pairing specificity of the base and create mutations when the DNA is replicated.
Intercalating agents such as acridine orange, proflavin, and (which are used in labs as dyes and mutagens) have a unique mode of action. These are flat, multiple-ring molecules that interact with bases of DNA and insert themselves between them. This insertion causes a “stretching” of the DNA duplex, and the DNA polymerase is “fooled” into inserting an extra base opposite an intercalated molecule. The result is that intercalating agents cause frame-shift mutations in which the “sense” of the DNA message is lost, just as if an extra letter were inserted into the phrase “the fat cat ate the hat” to make it “the ffa tca tat eth eha t.” This occurs because genes are read in groups of three bases during the process of translation. This type of mutation always results in production of a nonfunctional protein.
Chemical Mutagens with Indirect Action
Aromatic amines are large molecules that bind to bases in DNA and cause them to be unrecognizable to DNA polymerase or RNA polymerase. An example is N-2-acetyl-2-aminofluorine (AAF), which was originally used as an insecticide. This compound and other aromatic amines are relatively inactive on DNA until they react with certain cellular enzymes, after which they react readily with guanine. Mutagens of this type and all others with indirect action work by triggering cells to induce mutagenic DNA repair pathways, which results in a loss of accuracy in DNA replication.
One of the oldest known environmental carcinogens is the chemical benzo(α)pyrene, a hydrocarbon found in coal tar, cigarette smoke, and automobile exhaust. An English surgeon, Percivall Pott, observed that chimney sweeps had a high incidence of cancer of the scrotum. The reason for this was later found to be their exposure to benzo(α)pyrene in the coal tar and soot of the chimneys. Like the aromatic amines, benzo(α)pyrene is activated by cellular enzymes and causes mutations indirectly.
Another important class of chemical mutagens with indirect action are agents causing cross-links between the strands of DNA. Such cross-links prevent DNA from being separated into individual strands as is needed during DNA replication and transcription. Examples of cross-linking agents are psoralens (compounds found in some vegetables and used in treatments of skin conditions such as psoriasis) and cis-platinum (a chemotherapeutic agent used to fight cancer).
Another important class of chemical mutagens are those that result in the formation of active species of oxygen (oxidizing agents). Some of these are actually created in the body by oxidative respiration (endogenous mutagens), while others are the result of the action of chemicals such as peroxides and radiation. Reactive oxygen species cause a wide variety of damage to the bases and the backbone of DNA and may have both direct and indirect effects.
Detection of Chemical Mutagens
The Ames test, developed by biochemistry professor Bruce Ames and his colleagues, is one of the most widely used screening methods for chemical mutagens. It employs particular strains of the bacterium Salmonella typhimurium that require the amino acid histidine because of mutations in one of the genes controlling histidine production. The bacteria are exposed to the potential mutagen and then spread on an agar medium lacking histidine. The strains can grow only if they develop a mutation restoring function to the mutated gene required for histidine synthesis. The degree of growth indicates the strength of the mutagen; mutagens of different types are detected by using bacterial strains with different mutations. Mutagens requiring metabolic activation are detected by adding extracts of rat liver cells (capable of mutagen activation) to the tested substance prior to exposure of the bacteria. The and others like it involving microorganisms are rapid, safe, and relatively inexpensive ways to detect mutagenic chemicals, but it is not always clear how the results of the Ames test should be interpreted when determining the degree of mutagenicity predicted in humans.
Impact and Applications
Mutations can have serious consequences for cells of all types. If they occur in gametes, they can cause genetic diseases or birth defects. If they occur in somatic (body) cells of multicellular organisms, they may alter a growth-controlling gene in such a way that the mutated cell begins to grow out of control and forms a cancer. DNA is subject to a variety of types of damage by interaction with a wide array of chemical agents, some of which are ubiquitous in the environment, while others are the result of human intervention. Methods of detection of chemicals with mutagenic ability have made it possible to reduce the exposure of humans to some of these mutagenic and potentially carcinogenic chemicals.
Key Terms
- deaminationthe removal of an amino group from an organic molecule
- tautomerizationa spontaneous internal rearrangement of atoms in a complex biological molecule, which often causes the molecule to change its shape or its chemical properties
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