DNA adduct

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A metabolite of benzo[a]pyrene forms an intercalated DNA adduct, at center Benzopyrene DNA adduct 1JDG.png
A metabolite of benzo[a]pyrene forms an intercalated DNA adduct, at center

In molecular genetics, a DNA adduct is a segment of DNA bound to a cancer-causing chemical. This process could lead to the development of cancerous cells, or carcinogenesis. DNA adducts in scientific experiments are used as biomarkers of exposure. They are especially useful in quantifying an organism's exposure to a carcinogen. [1] The presence of such an adduct indicates prior exposure to a potential carcinogen, but it does not necessarily indicate the presence of cancer in the subject animal.

Contents

DNA adducts are researched in laboratory settings. A typical experimental design for studying DNA adducts is to induce them with known carcinogens. A scientific journal will often incorporate the name of the carcinogen with their experimental design. For example, the term "DMBA-DNA adduct" in a scientific journal refers to a piece of DNA that has DMBA (7,12-dimethylbenz(a)anthracene) attached to it.   [2]

Carcinogens' impact

Several diseases, including cancer, develop from mutated DNA. These mutations are caused by carcinogens through external and internal factors. Carcinogens are chemical or physical agents that cause DNA damage, which may later develop into cancer. They can initiate mutagenesis in DNA by interfering with the replication process. [3] These interactions typically cause chemical adducts to form in the cell. This allows for DNA adducts to serve as biomarkers of exposure to carcinogens from the environment. They are attractive biomarkers because they are stable, abundant, and easily characterizable. Exposure to them can directly or indirectly cause DNA damage. In the direct case, a carcinogen can bind to DNA and cause it to distort or become cross-linked. Although DNA repair happens under normal circumstances, sometimes the DNA will not repair itself. This could be the start of a mutation, or mutagenesis. Repeated mutations can lead to carcinogenesis – the beginnings of cancer. [4]

The presence of endogenous carcinogens contributes to levels of DNA adducts in a patient. This can bias the quantification of carcinogens that are from environmental exposure. Ongoing research on DNA adducts seeks to overcome these complications. It is the hope that in future medical practices DNA adducts may serve to guide therapeutic treatments that are more targeted and effective. [5]

Mechanism of DNA damage

Adduct formation is determined by the structures of reactive chemicals, the movement(s) of electrophiles, and the capacity of the compounds to bind with DNA, potentially driving adduct formation to specific nucleophilic sites. The N3 and N7 locations (nucleotide positioning) of guanine and adenine are believed to be the most nucleophilic, and hence, they form adducts selectively over exocyclic oxygen atoms. The generation of DNA adducts is also influenced by certain steric factors. Guanine's N7 position is exposed in the major groove of double-helical DNA, making it more suitable for adduction than when compared to adenine's N3 position, which is orientated in the minor groove. [6]

Figure 2: Reactive Sites of Interest for Nucleic Acids in DNA Adduct Formation Nucleic Acids in DNA Adduct Formation.png
Figure 2: Reactive Sites of Interest for Nucleic Acids in DNA Adduct Formation

Many compounds require enzyme metabolic activation to become mutagenic and cause DNA damage. Furthermore, reactive intermediates can be produced in the body as a result of oxidative stress, thus harming the DNA. Some chemical carcinogens, metabolites, as well as endogenous compounds generated by inflammatory processes cause oxidative stress. This can result in the formation of a reactive oxygen species (ROS) or reactive nitrogen species (RNS). ROS and RNS are known to cause DNA damage via oxidative processes. Figure 2 shows each of the reactive sites for the nucleic acids involved in adduction and damage, with each form of transfer distinguished by arrow color. These positions are of interest to researchers studying DNA adduct formation. Research has indicated that many different chemicals may change human DNA and that lifestyle and host characteristics can impact the extent of DNA damage. Humans are constantly exposed to a diverse combination of potentially dangerous substances that might cause DNA damage. [6]

Chemicals that form DNA adducts

Figure 3: DNA damaged by carcinogenic 2-aminofluorene DNA damaged by carcinogenic 2-aminofluorene AF.jpg
Figure 3: DNA damaged by carcinogenic 2-aminofluorene

Testing methods

32P-postlabeling assay:

Liquid chromatography–mass spectrometry (LC–MS):

Fluorescence labeling:

Enzyme linked immunosorbent assay (ELISA):

DNA adduct as biomarkers of exposure

Beef diet

Human consumption of more than 2.5–3.5 oz (70–100 g) of red meat (beef, lamb or pork) a day increases the risk of colon cancer, but eating chicken does not have this risk. [20] [21] The increased risk of colon cancer from red meat may be due to higher increases in DNA adducts from digestion of red meat. When rats were fed either beef or chicken, three types of DNA adducts in colon tissue were significantly higher after consumption of beef than after consumption of chicken. [22] These adducts were a type of methyl-cytosine (possibly N3-methyl-cytosine), an adduct of two malondialdehyde molecules with guanine, and carboxyl-adenine. [23]

Tobacco use

Human exposure to tobacco smoke has been associated with an increased risk of lung cancer. Tobacco smoke can impose great risk to DNA, with chemicals such as formaldehyde and acetaldehyde reacting directly with DNA to form adducts. In addition, there are other tobacco-specific carcinogens to consider in humans that are activated metabolically, such as nicotine-derived nitrosamine ketone (NNK) and N'-nitrosonornicotine (NNN). These carcinogens end up forming adducts when reacted with DNA, with those being called pyridyl oxobutyl (POB) adducts. [24]

Figure 4: Effects of Tobacco on Healthy Human DNA Effects of Carcinogen Exposure on Healthy DNA.png
Figure 4: Effects of Tobacco on Healthy Human DNA

Further analysis has been conducted on the topic, determining that 1,3-Butadiene (BD) is a human carcinogen that is found in cigarette smoke among other synthetic polymer industries. Tests were conducted to understand the differences in the level of urinary BD-DNA adducts among various ethnic groups – white, Japanese American, and Native Hawaiian. It was determined that Japanese American smokers exhibited heightened levels of urinary BD-induced guanine adducts than white and Native Hawaiian individuals, while there were no differences in outcome by ethnicity among non-smokers. Understanding the epigenetic and genetic factors driving these differences in urinary BD-DNA adduct presence is the next step for this research, serving as a link between sociology and the life sciences. [25]

Airborne particulate matter

Particulate matter (PM), broadly known as air pollution, is considered a group 1 carcinogen by the International Agency for Research on Cancer; while it is unclear if a direct link between cancer and PM exposure exists, it is likely that PM exposure leads to some degree of cell damage. Upon further investigation, it was determined that PM exposure causes oxidative stress – creating reactive oxygen species, forming DNA adducts, and inducing double-strand breaks (DSBs). In regards to DNA adduct formation, this analysis was conducted after looking at leukocytes from residents of heavily-populated cities (e.g. pollution, long-term traffic); a common component of PMs, polycyclic aromatic hydrocarbon (PAH), was one of the many molecules considered to be highly correlated with the presence of DNA bulky lesions in these individuals. These findings support the theory that DNA adduct presence indicates a level of carcinogenic activity. [26]

See also

Related Research Articles

<span class="mw-page-title-main">Carcinogen</span> Substance, radionuclide, or radiation directly involved in causing cancer

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise from both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.

Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic substances are not mutagenic. The alteration can have direct or indirect effects on the DNA: the induction of mutations, mistimed event activation, and direct DNA damage leading to mutations. The permanent, heritable changes can affect either somatic cells of the organism or germ cells to be passed on to future generations. Cells prevent expression of the genotoxic mutation by either DNA repair or apoptosis; however, the damage may not always be fixed leading to mutagenesis.

<span class="mw-page-title-main">Polycyclic aromatic hydrocarbon</span> Hydrocarbon composed of multiple aromatic rings

A polycyclic aromatic hydrocarbon (PAH) is a class of organic compounds that is composed of multiple aromatic rings. The simplest representative is naphthalene, having two aromatic rings, and the three-ring compounds anthracene and phenanthrene. PAHs are uncharged, non-polar and planar. Many are colorless. Many of them are found in coal and in oil deposits, and are also produced by the incomplete combustion of organic matter—for example, in engines and incinerators or when biomass burns in forest fires.

<span class="mw-page-title-main">Molecular lesion</span> Damage to the structure of a biological molecule

A molecular lesion or point lesion is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in DNA may consist of breaks or other changes in chemical structure of the helix, ultimately preventing transcription. Meanwhile, lesions in proteins consist of both broken bonds and improper folding of the amino acid chain. While many nucleic acid lesions are general across DNA and RNA, some are specific to one, such as thymine dimers being found exclusively in DNA. Several cellular repair mechanisms exist, ranging from global to specific, in order to prevent lasting damage resulting from lesions.

Benzo(<i>a</i>)pyrene Carcinogenic compound found in smoke and soot

Benzo[a]pyrene (BaP or B[a]P) is a polycyclic aromatic hydrocarbon and the result of incomplete combustion of organic matter at temperatures between 300 °C (572 °F) and 600 °C (1,112 °F). The ubiquitous compound can be found in coal tar, tobacco smoke and many foods, especially grilled meats. The substance with the formula C20H12 is one of the benzopyrenes, formed by a benzene ring fused to pyrene. Its diol epoxide metabolites (more commonly known as BPDE) react with and bind to DNA, resulting in mutations and eventually cancer. It is listed as a Group 1 carcinogen by the IARC. In the 18th century a scrotal cancer of chimney sweepers, the chimney sweeps' carcinoma, was already known to be connected to soot.

<span class="mw-page-title-main">4-Nitroquinoline 1-oxide</span> Chemical compound

4-Nitroquinoline 1-oxide is a quinoline derivative and a tumorigenic compound used in the assessment of the efficacy of diets, drugs, and procedures in the prevention and treatment of cancer in animal models. It induces DNA lesions usually corrected by nucleotide excision repair.

<span class="mw-page-title-main">Sudan I</span> Chemical compound

Sudan I is an organic compound, typically classified as an azo dye. It is an intensely orange-red solid that is added to colourise waxes, oils, petrol, solvents, and polishes. Sudan I has also been adopted for colouring various foodstuffs, especially curry powder and chili powder, although the use of Sudan I in foods is now banned in many countries, because Sudan I, Sudan III, and Sudan IV have been classified as category 3 carcinogens by the International Agency for Research on Cancer. Sudan I is still used in some orange-coloured smoke formulations and as a colouring for cotton refuse used in chemistry experiments.

The International Agency for Research on Cancer is an intergovernmental agency forming part of the World Health Organization of the United Nations. Its role is to conduct and coordinate research into the causes of cancer. It also collects and publishes surveillance data regarding the occurrence of cancer worldwide.

<i>N</i>-Nitrosonornicotine Chemical compound

N-Nitrosonornicotine (NNN) is a tobacco-specific nitrosamine produced during the curing and processing of tobacco.

4-Aminobiphenyl (4-APB) is an organic compound with the formula C6H5C6H4NH2. It is an amine derivative of biphenyl. It is a colorless solid, although aged samples can appear colored. 4-Aminobiphenyl was commonly used in the past as a rubber antioxidant and an intermediate for dyes. Exposure to this aryl-amine can happen through contact with chemical dyes and from inhalation of cigarette smoke. Researches showed that 4-aminobiphenyl is responsible for bladder cancer in humans and dogs by damaging DNA. Due to its carcinogenic effects, commercial production of 4-aminobiphenyl ceased in the United States in the 1950s.

<i>o</i>-Toluidine Aryl amine

o-Toluidine (ortho-toluidine) is an organic compound with the chemical formula CH3C6H4NH2. It is the most important of the three isomeric toluidines. It is a colorless liquid although commercial samples are often yellowish. It is a precursor to the herbicides metolachlor and acetochlor.

<i>N</i>-Nitrosodiethylamine Chemical compound

N-Nitrosodiethylamine (NDEA) is an organic compound with the formula Et2NNO (Et = C2H5). A member of the nitrosamines, it is a light-sensitive, volatile, clear yellow oil that is soluble in water, lipids, and other organic solvents. It has an amine or aromatic odor. It is used as gasoline and lubricant additive, antioxidant, and stabilizer for industry materials. When heated to decomposition, N-nitrosodiethylamine emits toxic fumes of nitrogen oxides. N-Nitrosodiethylamine affects DNA integrity, probably by alkylation, and is used in experimental research to induce liver tumorigenesis. It is carcinogenic and mutagenic. NDEA has also been found to perturb amino acid biosynthesis including arginine, as well as DNA damage repair and mitochondrial genome maintenance in yeast.

A co-carcinogen is a chemical that promotes the effects of a carcinogen in the production of cancer. Usually, the term is used to refer to chemicals that are not carcinogenic on their own, such that an equivalent amount of the chemical is insufficient to initiate carcinogenesis. A chemical can be co-carcinogenic with other chemicals or with nonchemical carcinogens, such as UV radiation.

Benzo(<i>j</i>)fluoranthene Chemical compound

Benzo[j]fluoranthene (BjF) is an organic compound with the chemical formula C20H12. Classified as a polycyclic aromatic hydrocarbon (PAH), it is a colourless solid that is poorly soluble in most solvents. Impure samples can appear off white. Closely related isomeric compounds include benzo[a]fluoranthene (BaF), bendo[b]fluoranthene (BbF), benzo[e]fluoranthene (BeF), and benzo[k]fluoranthene (BkF). BjF is present in fossil fuels and is released during incomplete combustion of organic matter. It has been traced in the smoke of cigarettes, exhaust from gasoline engines, emissions from the combustion of various types of coal and emissions from oil heating, as well as an impurity in some oils such as soybean oil.

<span class="mw-page-title-main">Chlornaphazine</span> Chemical compound

Chlornaphazine, a derivative of 2-naphthylamine, is a nitrogen mustard that was developed in the 1950s for the treatment of polycythemia and Hodgkin's disease. However, a high incidence of bladder cancers in patients receiving treatment with chlornaphthazine led to use of the drug being discontinued.

<span class="mw-page-title-main">2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine</span> Chemical compound


PhIP (2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is one of the most abundant heterocyclic amines (HCAs) in cooked meat. PhIP is formed at high temperatures from the reaction between creatine or creatinine, amino acids, and sugar. PhIP formation increases with the temperature and duration of cooking and also depends on the method of cooking and the variety of meat being cooked. The U.S. Department of Health and Human Services National Toxicology Program has declared PhIP as "reasonably anticipated to be a human carcinogen". International Agency for Research on Cancer (IARC), part of World Health Organization, has classified PhIP as IARC Group 2B carcinogen. There is sufficient evidence in experimental animals, as well as in vitro models, for the carcinogenicity of PhIP.

Benzo(<i>c</i>)fluorene Chemical compound

Benzo[c]fluorene is a polycyclic aromatic hydrocarbon (PAH) with mutagenic activity. It is a component of coal tar, cigarette smoke and smog and thought to be a major contributor to its carcinogenic properties. The mutagenicity of benzo[c]fluorene is mainly attributed to formation of metabolites that are reactive and capable of forming DNA adducts. According to the KEGG it is a group 3 carcinogen. Other names for benzo[c]fluorene are 7H-benzo[c]fluorene, 3,4-benzofluorene, and NSC 89264.

<span class="mw-page-title-main">Glycidamide</span> Chemical compound

Glycidamide is an organic compound with the formula H2NC(O)C2H3O. It is a colorless, oil. Structurally, it contains adjacent amides and epoxide functional groups. It is a bioactive, potentially toxic or even carcinogenic metabolite of acrylonitrile and acrylamide. It is a chiral molecule.

(+)-Benzo(<i>a</i>)pyrene-7,8-dihydrodiol-9,10-epoxide Cancer-causing agent derived from tobacco smoke

(+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide is an organic compound with molecular formula C20H14O3. It is a metabolite and derivative of benzo[a]pyrene (found in tobacco smoke) as a result of oxidation to include hydroxyl and epoxide functionalities. (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide binds to the N2 atom of a guanine nucleobase in DNA, distorting the double helix structure by intercalation of the pyrene moiety between base pairs through π-stacking. The carcinogenic properties of tobacco smoking are attributed in part to this compound binding and inactivating the tumor suppression ability of certain genes, leading to genetic mutations and potentially to cancer.

References

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