How does toxins cause DNA damage?
Toxins induce their effects by distorting the DNA structure through breakage of hydrogen bonds between two complementary base pairs involved in stabilization of DNA strands. In order to maintain the genome integrity, it is necessary to repair the DNA damage with the help of DNA repair machineries.
How does a carcinogen cause a mutation?
A carcinogen is termed genotoxic if it covalently binds to cellular DNA. If unrepaired, the damaged DNA may cause mutations by inducing the misincorporation of bases during DNA replication.
How does carcinogens affect the body?
Some carcinogens cause cancer by changing a cell's DNA. Others do not affect DNA directly, but lead to cancer in other ways. For example, they may cause cells to divide at a faster than normal rate, which could increase the chances that DNA changes will occur.
Do carcinogens cause mutations in genes?
What specifically causes mutations to happen one after another in these genes is largely unknown. Mutations can be caused by things in the environment known to increase the risk for cancer (carcinogens). The development of mutations is also a natural part of aging.
What causes DNA mutation?
Mutations can result from errors in DNA replication during cell division, exposure to mutagens or a viral infection. Germline mutations (that occur in eggs and sperm) can be passed on to offspring, while somatic mutations (that occur in body cells) are not passed on.
Why are carcinogens harmful to cells?
Carcinogens may increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division, ultimately leading to the formation of tumors.
How do carcinogens affect the cell cycle?
However, when carcinogens are introduced in the body they can affect the genes and cause them to change in a bad way. Theses mutations occur when the DNA makes a copy of itself before mitosis. Therefore, the new cell that has been replicated also has a mutation in its DNA. A cancer cell is born.
How does the body get rid of carcinogens?
Six Ways to Detox Your Life from CarcinogensStay Active. Exercising for as little as 30 minutes will reduce the risk of cancer for a multitude of reasons. ... Choose a Cancer-Fighting Diet. ... One Drink a Day. ... Be Aware of Indoor Toxins. ... Live Tobacco-Free. ... Avoid Sun Damage.
What is the difference between carcinogen and mutation?
Main Difference – Mutagen vs Carcinogen The somatic cell mutations can cause cancers. The main difference between mutagen and carcinogen is that mutagen causes a heritable change in the genetic information of an organism whereas carcinogen causes or promotes cancer in animals and humans.
How do mutagens cause mutations?
Mutagens cause mutations in three different ways: Some act as base analogs and are mistakenly used as substrates when new DNA is synthesized at the replication fork. Some react directly with DNA, causing structural changes that lead to miscopying of the template strand when the DNA is replicated.
What is the damage caused by carcinogens?
Exposure to carcinogens is associated with various forms of DNA damage such as single-stand breaks, double-strand breaks, covalently bound chemical DNA adducts, oxidative-induced lesions and DNA-DNA or DNA-protein cross-links.
Is DNA damage a carcinogen?
Humans are variously and continuously exposed to a wide range of different DNA-damaging agents, some of which are classed as carcinogens. DNA damage can arise from exposure to exogenous agents, but damage from endogenous processes is probably far more prevalent.
Is DNA damage exogenous or endogenous?
DNA damage can arise from exposure to exogenous agents, but damage from endogenous processes is probably far more prevalent. That said, epidemiological studies of migrant populations from regions of low cancer risk to high cancer risk countries point to a role for environmental and/or lifestyle factors playing a pivotal part in cancer aetiology.
How does exposure to carcinogens affect DNA?
Exposure to carcinogens can either directly [ 7] or indirectly [ 1, 8] induce DNA damage. Subsequent repair mechanisms may result in alterations in DNA sequences, i.e. mutations [ 2, 9 ]. Induced mutations may be initiating events in cancer causation, when the damage is fixed within oncogenes or tumour suppressor genes [ 10 ]. Such risk may also be directly influenced by individual susceptibility and genetic instability [ 11 ]. For example, in the inherited genetic disorder Xeroderma Pigmentosum ( XP ), mutations in the XP proteins disrupt DNA repair resulting in the build-up of sunlight-induced lesions in skin DNA and a high rate of skin cancer [ 12 ].
What is the damage caused by carcinogens?
Exposure to carcinogens is associated with various forms of DNA damage such as single-stand breaks, double-strand breaks, covalently bound chemical DNA adducts, oxidative-induced lesions and DNA–DNA or DNA–protein cross-links.
What are indirect-acting carcinogens?
Indirect-acting carcinogens are relatively unreactive parent compounds that include polycyclic aromatic hydrocarbons (PAHs), heterocyclic aromatic amines (HAAs), N -nitrosamines, mycotoxins and aristolochic acid (AA). These typically require bioactivation in host cells to transform them into carcinogenic metabolites or reactive intermediates that are capable of exerting genotoxic effects [ 1, 8, 36 ]. This is often mediated by phase I and/or II metabolic reactions. Phase I reactions include oxidation, reduction or hydrolysis, mainly involving cytochrome P450 (CYP) mixed function oxidase isoforms, commonly referred to as CYPs. These enzymes have the ability to activate carcinogens independently or in conjugation with phase II enzymes such as sulfotransferases and N -acetyltransferase [ 8, 37, 38 ]. A classic example is the bioactivation process of benzo [ a ]pyrene (B [ a ]P), which undergoes a multi-step process involving CYP1A1 and epoxide hydrolase-mediated conversion to r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo [ a ]pyrene (BPDE) ( Figure 1 ). Bulky chemical adducts are commonly seen as a result of the interaction between activated carcinogens and DNA, e.g. reactive nitrenium ions formed through the reduction and hydrolysation of AA, yield bulky purine DNA adducts at the exocyclic amino group of purines [ 39 ]. Nitrosamines encompass a large diverse group of compounds formed by various combinations of amines and nitrogen functional groups. Some nitrosamines are known to be direct-acting carcinogens such as those formed in foodstuffs and are implicated in oesophageal cancer or stomach cancer, while others such as the tobacco-specific lung pro-carcinogen 4- (methylnitrosamino)-1- (3-pyridyl)-1-butanone are bioactivated [ 40 ]. Other work shows that nitrosamines can be locally activated within the urothelium [ 41 ]. In contrast, α-nitrosoamino aldehydes are highly reactive compounds which are direct-acting mutagens [ 42 ]. We see the relevance of this in the high incidence of gastric cancers in certain regions associated with consumption of particular foodstuffs [ 43 ].
How do indirect carcinogens enhance bioactivation?
Although indirect carcinogens are reliant on activation, a few have the ability to enhance bioactivation by inducing changes in gene expression. PAHs such as B [ a ]P increase the expression in members of CYP450 family by acting as exogenous ligands of the cytosolic aryl hydrocarbon receptor (AhR)–aromatic receptor nuclear translocator complex [ 36, 44 ]. Such enzymes are also involved in bioactivation of HAAs, PAHs, AA and aflatoxins, therefore potentially increasing the metabolism and subsequent exposure of DNA to reactive intermediates [ 1 ]. Expression of such enzymes has been investigated in tissues possessing the capability of bioactivating carcinogens to reactive electrophiles [ 45, 46 ].
What are the two types of carcinogens?
Carcinogens may fall into two categories: activation-dependent and activation-independent. Those which do not require metabolic activation or any molecular modification in order to induce DNA damage are termed direct-acting carcinogens and examples include nitrosamines, ultraviolet (UV), IR and alkylating agents [ 5, 7, 26, 35 ]. These agents have the capability to interact directly with DNA and other cellular components due to their electrophilic groups. These electrophilic groups exhibit an inherent reactivity, allowing them to interact with nitrogen and oxygen atoms within negatively charged cellular macromolecules to induce molecular modifications and distortion [ 3 ]. Alteration of DNA bases causes a disarrangement of the genetic material and formation of DNA adducts depending on the type of carcinogen. Failure within DNA repair mechanisms allows DNA lesions to be inherited by daughter cells [ 7 ], eventually leading to the accumulation of DNA damage and potentially the development of cancer.
What is the chemical adduct in DNA?
Bulky chemical DNA adducts are formed when a reactive electrophilic carcinogen, formed by the metabolism of an indirect carcinogen, binds to a particular nucleophilic moiety in DNA. Nucleophilic targets of the reactive carcinogen include nitrogen and oxygen atoms within the bases and phosphodiester backbone of DNA.
How does nitrosamine affect DNA?
Metabolism of nitrosamines subsequently induces alkylating DNA damage via the formation of DNA adducts such as O 6 -alkylguanine, oxidative stress and production of diazonium ions. Humans are exposed to these agents through various foods and tobacco smoke. [ 25, 26 ] Mycotoxins.
How do environmental carcinogens affect DNA?
Most environmental carcinogens produce DNA damage that leads to mutational events in important cellular genes. Ultimately, the accumulation of mutations in multiple genes leads to loss of growth control and cancer development. Investigations over the past several decades have resulted in the identification of numerous naturally-occurring and synthetic compounds that exhibit the ability to inhibit the development of cancer by a variety of mechanisms. The ability to reduce DNA damage and ensuing mutational events associated with this damage is an important role for these compounds, generally referred to as chemopreventive agents. This chapter discusses mechanisms by which chemopreventive agents reduce DNA damage and adduct formation using specific compounds and vitamins as examples. The principal criteria for selecting these compounds for discussion is the fact that data were available on the mechanisms by which they reduce not only DNA damage but also tumorigenesis in specific organs. Protocols for the identification of agents that reduce DNA damage in animal model systems are given and some results from human clinical trials are presented. It is important to recognize that there may be many naturally-occurring chemopreventive agents that have not as yet been identified and many of them undoubtedly have the ability to reduce DNA damage. Probably the most effective agents are those that have a dual role of reducing DNA damage and mutational events as well as cellular and molecular events associated with tumor promotion/progression.
How do carcinogens cause cancer?
Many cancers caused by chemical carcinogens do so through a mutagenic mechanism initiated by the formation of carcinogen–DNA damage. Some chemical carcinogens can damage DNA with no metabolic intervention, and others must be biotransformed. DNA adduct formation is considered necessary but not sufficient for tumorigenesis, as dosimetry for DNA adducts and tumorigenesis has been amply demonstrated in experimental models. Once methods became available to measure DNA adducts in humans, studies showed widespread distribution of DNA adducts in human tissues, dosimetry for DNA adduct formation in circumstances where exposure was accurately known, and consistent positive associations between DNA adduct formation and human cancer risk. Case–control and nested case–control epidemiological studies, examining DNA adducts in individuals exposed to a single carcinogen or carcinogenic mixtures, have shown, for many cancers, that individuals with the highest DNA adduct levels are also those with the highest cancer risk. The modest nature of these associations (odds ratio or relative risk between 1.25 and 9.10) indicates that, although DNA damage is essential, other events typically contribute to human cancer etiology.
What antibodies detect guanine?
Polyclonal and monoclonal antibodies have been developed that recognize the guanine adducts formed by the reactive intermediates of benzo (a)pyrene, a ubiquitous environmental carcinogen. The antibodies cross-react with the guanine adducts of several other polycyclic aromatic hydrocarbons (PAH) and thus can detect a wide range of PAH diol epoxide guanine adducts. These antibodies have been used in highly sensitive enzyme-linked immunosorbent and immunohistochemical assays to monitor human exposure to PAHs. Occupational, lifestyle, and environmental exposures to PAHs have been detectable by measurement of white blood cell DNA adduct levels. Other studies have used the assays to investigate the role of PAHs in cancer induction. In the last 30 years, data produced using antibody-based methods have been essential for much of the progress in our understanding of the hazards of PAHs.
What is DNA damage?
DNA damage is the critical step linking carcinogen exposure from tobacco products to cancer-causing mutations in important growth control genes. This chapter provides an overview of carcinogens in tobacco products and their conversion to metabolites that react readily with DNA bases producing addition products known as DNA adducts found in smokers’ DNA. DNA adducts can cause errors during DNA replication leading to permanent changes in DNA sequence. When such mutations occur in critical regions of oncogenes such as KRAS and tumor suppressor genes such as p 53, the result can be loss of normal growth control mechanisms and cancer development. This chapter presents evidence for this important biochemical pathway.
What are the effects of DNA adducts on cancer?
A number of important cancer chemotherapeutic drugs, best represented by those belonging to the groups of platinum drugs, nitrogen mustards, nitrosoureas and methylating agents, bring about their therapeutic effects by forming with the DNA of cancer cells covalent complexes (DNA adducts) which block cell replication and thus lead to cell death. The amount of such adducts accumulating in the cells of a given patient represents the biologically relevant dose of drug reaching the patient’s tissues and, as such, may constitute a marker susceptibility to the drug’s therapeutic effects at the individual level. Based on this anticipation, extensive efforts have been made to develop analytical methodologies for measuring drug-DNA adducts and to apply them in studies aimed at the evaluation of the relationship between DNA adduct accumulation and patient therapeutic response.
What are DNA and protein adducts?
DNA and protein adducts are validated biomarkers of human exposure to carcinogens and, in some instances, of risk of developing cancer. As derivatives of reactive chemicals, adducts may also provide unique mechanistic insights. Until recently studies have adopted a “bottom-up” approach, whereby exposure to known or suspected agents is monitored. The advent of the “exposome (see Glossary)” concept, which seeks to define the totality of the influence of the environment on disease susceptibility, has led to a more untargeted top-down “adductomics” approach to identifying multiple modifications to DNA or protein (hemoglobin and albumin), attempting to capture entire populations of adducts. Although still in its infancy, the approach offers the prospect, particularly when combined with other omic approaches, such as proteomics, transcriptomics and metabolomics, all of which have potential for highthroughput screening of populations, of capturing snapshots of human exposure to genotoxicants and the resultant biological consequences at multiple stages throughout life. This should shed significant light on the causes and courses of chronic diseases afflicting humans and provide new opportunities for early interventions for disease prevention.
Is chromium a carcinogen?
Occupational and environmental exposure to metals are risk factors for both workers and the general population. However, mechanisms for metal induced carcinogene sis are poorly understood. Metals can act as mimics for essential elements, increase free radicals or disrupt protein structure and folding. The physical and chemical properties of metals can also affect their potency and bioavailability. Here we use chromium as a model metal carcinogen to address the potential mechanisms of its carcinogenicity. We discuss the cellular uptake and intracellular reduction of hexavalent chromium, its effect on DNA repair, its effect on cell cycle and mitosis, and epigenetic alterations including methylation, histone modification and microRNAs.
What can we do once we have identified carcinogens?
Importantly, once we have identified carcinogens, we can then go on to take specific measures to limit our exposure and so reduce the incidence of specific cancers associated with carcinogens, for example, limiting asbestos exposure. Daphne W. Bell, Ph.D.
What is the name of the agent that causes cancer?
Carcinogen. A carcinogen is an agent with the capacity to cause cancer in humans. Carcinogens may be natural, such as aflatoxin, which is produced by a fungus and sometimes found on stored grains, or manmade, such as asbestos or tobacco smoke.
Is asbestos a carcinogen?
Interestingly, some carcinogenic agents are associated with increasing the risk of developing specific types of cancer. One good example is the carcinogen asbestos. Asbestos exposure, particularly to workers in industrial settings, has actually been strongly linked to the development of a specific type of lung cancer called mesothelioma.
How does DNA damage cells?
By directly damaging the DNA in cells leading to mutations (disrupting the normal process of cells) By not affecting the DNA directly, but instead causing cells to divide at a faster rate than normal, which can increase the chances that DNA changes and mutations will occur.
What is a carcinogen?
Douglas A. Nelson, MD. Updated on April 22, 2020. A carcinogen is any substance or agent that causes cancer. It does so by altering the cellular metabolism or by damaging DNA in our cells, interfering with normal cellular processes. The identification of substances in the environment that cause people to become ill with cancer helps in prevention ...
How many substances are considered carcinogenic to humans?
Therefore researchers have only been able to classify a little over 100 substances as “carcinogenic to humans.”
What are the most common substances that are carcinogenic to humans?
Some of the most common substances and exposures known as being carcinogenic to humans include (there are many more): Alcoholic beverages. Arsenic and inorganic arsenic compounds.
What are the causes of cancer?
Pollution: outdoor air pollution or even secondhand tobacco smoke. Some carcinogens do not directly cause cancer but can lead to cancer.
What are the different groups of carcinogens?
Carcinogens are classified into one of the following groups: Group 1: Carcinogenic to humans. Group 2A: Probably carcinogenic to humans. Group 2B: Possibly carcinogenic to humans. Group 3: Unclassifiable as to carcinogenicity in humans. Group 4: Probably not carcinogenic to humans.
What are the causes of DNA damage?
The cell’s DNA can be damaged by a wide range of substances and exposures, including: 1 Lifestyle: what you eat, if you smoke, lack of physical activity 2 Natural exposure: to ultraviolet light, radon gas, infectious agents 3 Medical treatment: radiation and chemotherapy, hormones, immunosuppressants 4 Workplace exposure: some jobs have increased exposure to industrial chemicals or products 5 Household exposure: cleaning products, paints, herbicides, and pesticides, etc. 6 Pollution: outdoor air pollution or even secondhand tobacco smoke
What is a carcinogen?
A carcinogen is defined as an agent that increases the incidence of neoplasms compared with the incidence in appropriate controls in a defined test organism. From: Comprehensive Toxicology, 2010. Download as PDF. About this page.
How does DNA damage cause mutations?
If unrepaired, the damaged DNA may cause mutations by inducing the misincorporation of bases during DNA replication. Genotoxic carcinogens may either be direct-acting (ultimately reactive toward DNA from the outset) or require metabolic activation to become reactive toward DNA (indirect-acting carcinogens).
How does the EPA assess cancer risk?
Estimating cancer risk helps investigators determine when and if behavior modifications should be enforced. This process of predicting cancer risk in a given exposure scenario is referred to as risk assessment, whereas the response to predicted risk is referred to as risk management. The EPA is responsible for risk assessment in areas of known or suspected exposure of the population to carcinogens and makes recommendations for risk management to minimize health consequences due to environmental contamination.
What are the carcinogens that do not require metabolic activation or modification to induce cancer?
Several carcinogens exist that do not require metabolic activation or modification to induce cancer and are termed direct-acting or activation-independent carcinogens. These chemicals function as ultimate carcinogens (Table 4). Usually existing as highly reactive electrophilic molecules, direct-acting carcinogens directly interact with and bind to cellular macromolecules, including DNA. Due to this high reactivity, direct-acting carcinogens frequently result in tumor formation at the site of chemical exposure. Direct-acting carcinogens include β-propriolactone, epoxides, imines, alkyl and sulfate esters, halogen derivatives such as mustard gasses, halo ethers (bis (chloromethyl)ether), nitrosamides, and nitrosoureas (N -methylnitrosourea and N -methyl- N ′-nitro- N-nitrosoguanidine). Direct-acting electrophilic chemicals typically test positive in the Ames mutagenesis bioassay without additional metabolic activation. The relative potency of direct-acting carcinogens for inducing cancer depends in part on the relative rates of interaction between the chemical and DNA, and competing reactions with the chemical and other cellular nucleophiles. Thus, the relative activity of direct-acting carcinogens will be dependent upon such competing reactions and also on enzymatic detoxification reactions. Direct-acting carcinogens are typically carcinogenic at multiple sites and in all species examined (Fox and Scott 1980; Sontag 1981 ).
What is the relative potency of direct-acting carcinogens for inducing cancer?
The relative potency of direct-acting carcinogens for inducing cancer depends in part on the relative rates of interaction between the chemical and DNA, and competing reactions with the chemical and other cellular nucleophiles.
What are direct-acting carcinogens?
Usually existing as highly reactive electrophilic molecules, direct-acting carcinogens directly interact with and bind to cellular macromolecules, including DNA. Due to this high reactivity, direct-acting carcinogens frequently result in tumor formation at the site of chemical exposure.
How do BAF carcinogens inhibit cell growth?
BAF carcinogens may thus inhibit cellular growth by activating the mitotic checkpoint, and consequently constitute a selection pressure that favors breakdown of this control mechanism. In other words, BAF carcinogens may promote CIN in a manner similar to that whereby methylating agents promote the MIN phenotype.
