
In
molecular genetics
Molecular genetics is a sub-field of biology that addresses how differences in the structures or expression of DNA molecules manifests as variation among organisms. Molecular genetics often applies an "investigative approach" to determine the ...
, 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
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
. DNA adducts in scientific experiments are used as
biomarkers
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
of exposure. They are especially useful in quantifying an organism's exposure to a carcinogen. 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.
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.
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
Replication may refer to:
Science
* Replication (scientific method), one of the main principles of the scientific method, a.k.a. reproducibility
** Replication (statistics), the repetition of a test or complete experiment
** Replication crisi ...
process.
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
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 l ...
. Repeated mutations can lead to
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
– the beginnings of cancer.
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.
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
In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they a ...
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.

Many compounds require enzyme metabolic activation to become
mutagenic
In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer i ...
and cause DNA damage. Furthermore, reactive intermediates can be produced in the body as a result of
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal re ...
, thus harming the DNA. Some chemical carcinogens, metabolites, as well as
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, ...
compounds generated by inflammatory processes cause oxidative stress. This can result in the formation of a
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen ...
(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.
[
]
Chemicals that form DNA adducts
* acetaldehyde
Acetaldehyde (IUPAC systematic name ethanal) is an organic chemical compound with the formula CH3 CHO, sometimes abbreviated by chemists as MeCHO (Me = methyl). It is a colorless liquid or gas, boiling near room temperature. It is one of the ...
, a significant constituent of tobacco smoke
* cisplatin
Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelio ...
, which binds to DNA and causes crosslinking (leading to cell death)
* DMBA ( 7,12-dimethylbenz(a)anthracene)
* malondialdehyde, a naturally-occurring product of lipid peroxidation
* polycyclic aromatic hydrocarbons
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. P ...
(PAHs)
* nitro-PAHs
* Nitrosamines
In organic chemistry, nitrosamines (or more formally ''N''-Nitrosamines) are organic compounds with the chemical structure , where R is usually an alkyl group. They feature a nitroso group () bonded to a deprotonated amine. Most nitrosamines a ...
* Aflatoxins
* Mustards
* aromatic amines
In organic chemistry, an aromatic amine is an organic compound consisting of an aromatic ring attached to an amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amin ...
* heterocyclic aromatic amines (HAAs)
* methylating agents
* other alkylating agents
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecti ...
* Haloalkanes
Testing methods
32P-postlabeling assay:
* 32P-postlabeling assays screen for DNA adducts by transferring 32P-ATP into a carcinogenic labeled nucleotide sequence, with selectivity favoring modified nucleotides.
Liquid chromatography–mass spectrometry (LC–MS):
* Liquid chromatography–mass spectrometry is useful in testing DNA adducts, but does have a different approach than a 32P-postlabeling assay. [
Fluorescence labeling:
* Certain DNA adducts can also be detected by the means of ]fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, ...
because they contain fluorescent chromophores.
Enzyme linked immunosorbent assay (ELISA):
* ELISA
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
contains an antigen in solution that can bind with DNA adducts. Any remaining free antigen will fluoresce. This allows ELISA to quantify DNA adducts as well as map an inverse relationship between DNA damage and the intensity of the samples fluorescence.
DNA adduct as biomarkers of exposure
Beef diet
Human consumption of more than of red meat
In gastronomy, red meat is commonly red when raw and a dark color after it is cooked, in contrast to white meat, which is pale in color before and after cooking. In culinary terms, only flesh from mammals or fowl (not fish) is classified as ...
(beef, lamb or pork) a day increases the risk of colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...
, but eating chicken does not have this risk. 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. These adducts were a type of methyl-cytosine (possibly N3-methyl-cytosine), an adduct of two malondialdehyde molecules with guanine, and carboxyl-adenine.
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
Formaldehyde ( , ) ( systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section ...
and acetaldehyde
Acetaldehyde (IUPAC systematic name ethanal) is an organic chemical compound with the formula CH3 CHO, sometimes abbreviated by chemists as MeCHO (Me = methyl). It is a colorless liquid or gas, boiling near room temperature. It is one of the ...
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.
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
Guanine () (symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is c ...
adducts than white and Native Hawaiian individuals, while there were no differences in outcome by ethnicity among non-smokers. Understanding the epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are " ...
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.
Airborne particulate matter
Particulate matter
Particulates – also known as atmospheric aerosol particles, atmospheric particulate matter, particulate matter (PM) or suspended particulate matter (SPM) – are microscopic particles of solid or liquid matter suspended in the air. The t ...
(PM), broadly known as air pollution, is considered a group 1 carcinogen
A group is a number of persons or things that are located, gathered, or classed together.
Groups of people
* Cultural group, a group whose members share the same cultural identity
* Ethnic group, a group whose members share the same ethnic id ...
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
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal re ...
– creating reactive oxygen species, forming DNA adducts, and inducing double-strand breaks
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
(DSBs). In regards to DNA adduct formation, this analysis was conducted after looking at leukocytes
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mul ...
from residents of heavily-populated cities (e.g. pollution, long-term traffic); a common component of PMs, polycyclic aromatic hydrocarbon
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. ...
(PAH), was one of the many molecules considered to be highly correlated with the presence of DNA bulky lesions
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
in these individuals. These findings support the theory that DNA adduct presence indicates a level of carcinogenic activity.
See also
* Adduct
An adduct (from the Latin ''adductus'', "drawn toward" alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all co ...
* Adductomics
Adductomics is the study of DNA adducts in the context of an entire genome. DNA adducts are compounds that bind to DNA, causing damage and mutations. These mutations can result in cancer and birth defects in multicellular organisms. The scie ...
References
{{DEFAULTSORT:Dna Adduct
Genetics techniques
Oncology