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Chemistry LibreTexts

22.6: Carcinogens and Teratogens

  • Page ID
    152300
  • Learning Objectives

    • Explain the process of cancer development.
    • List the factors that may increase and lower the risk of cancer.
    • Define teratogens and describe the birth defects that result from them.

    A carcinogen is any agent that directly increases the incidence of cancer. Most, but not all carcinogens are mutagens. Carcinogens that do not directly damage DNA include substances that accelerate cell division, thereby leaving less opportunity for cell to repair induced mutations, or errors in replication. Carcinogens that act as mutagens may be biological, physical, or chemical in nature, although the term is most often used in relation to chemical substances.

     

    Defining Cancer

    Cancer is actually a group of more than 100 diseases, all of which involve abnormal cell growth with the potential to invade or spread to other parts of the body. In general terms, cancer occurs when the cell cycle is no longer regulated due to DNA damage. The number of potential underlying causes of this DNA damage is great, so there are many different risk factors for cancer. Any cells that become cancerous divide more quickly than normal cells. They may form a mass of abnormal cells called a tumor. The rapidly dividing cells take up nutrients and space, damaging the normal cells around them. If the cancer cells spread to other parts of the body, they invade and damage other tissues and organs. They may eventually lead to death.

     

    clipboard_e8b565471c8f8aa74ea044c5a7240b204.png

    Figure \(\PageIndex{1}\) A dividing breast cancer cell.

    Source: National Cancer Institute/Univ. of Pittsburgh Cancer Institute

     

     

    By far, the most common of the 100-plus types of human cancer is basal cell carcinoma, the type of skin cancer Bernie Sanders had removed in 2016. Basal cell carcinoma makes up 40 percent of all new cancers each year in the United States. Other common types of cancer include lung, colorectal, prostate (in males), and breast (in females) cancers. These cancers are not as common as skin cancer, but they cause the majority of cancer deaths.

    How Cancer Develops

    Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells.  The transformation of a normal cell into a cancer cell is a multi-step process that involves initiation, promotion, progression and finally malignancy (see Figure \(\PageIndex{2}\)). This process takes years and starts with a single cell in which the right genes are mutated so the cell does not appropriately die and begins to proliferate abnormally. Then, additional mutations occur that select for more rapidly growing cells within this population leading to a tumor with rapid growth and malignancy. By the time the cells are cancerous, proto-oncogenes have been activated and tumor suppressor genes inactivated. Even within the same tumor type, like colon cancer, the specific genes mutated can vary from person to person making cancer a unique disease for each individual. 

    22A5.jpg

    Figure \(\PageIndex{2}\): Multistep process involved in carcinogenesis that transforms a normal cell into a malignant tumor.

    How Cancer Spreads

    Once a normal cell transforms into a cancer cell and starts dividing out of control, cancer cells can spread from the original site (called the primary tumor) to other tissues. This can occur in three different ways. One way is local spread, in which aggressively dividing cancer cells directly invade nearby tissues. Another way involves the lymphatic system. Cancer cells can spread to regional lymph nodes through lymph vessels that pass by the primary tumor.

    The third way cancer cells can spread is through the blood to distant sites. This is called metastasis, and the new cancers that form are called metastases. Although the blood can carry cancer cells to tissues everywhere in the body, cancer cells generally grow only in certain sites (Figure \(\PageIndex{3}\)). Different types of cancers tend to metastasize to particular organs. The most common places for metastases to occur are the brain, lungs, bones, and liver. Almost all cancers can metastasize, especially during the late stages of the disease. Cancer that has metastasized generally has the worst prognosis and is associated with most cancer deaths.

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    Figure \(\PageIndex{3}\): Cancer cells that originate in one organ may metastasize by traveling in the blood to distant sites (metastases). Metastasized lung cancer grows in the brain, bone, and adrenal gland. Metastasized pancreas cancer grows in the liver and lungs. Metastasized breast cancer can grow in the bone, brain, and liver. Metastasized Colon and Ovarian cancer grow in the liver.

    Chemical Carcinogens

    Chemical carcinogens (Table \(\PageIndex{1}\)) can be either natural or synthetic compounds that, based on animal feeding trials or epidemiological (i.e. human population) studies, increase the incidence of cancer. The definition of a chemical as a carcinogen is problematic for several reasons. Some chemicals become carcinogenic only after they are metabolized into another compound in the body; not all species or individuals may metabolize chemicals in the same way. Also, the carcinogenic properties of a compound are usually dependent on its dose. It can be difficult to define a relevant dose for both lab animals and humans. Nevertheless, when a correlation between cancer incidence and chemical exposure is observed, it is usually possible to find ways to reduce exposure to that chemical.

    Table \(\PageIndex{1}\): Some Classes of Chemical Carcinogens.

    Class Examples and/or Sources
    PAHs (polycyclic aromatic hydrocarbons)  benzo[a]pyrene and several other components of the smoke of cigarettes, wood, and fossil fuels
    Aromatic amines compounds formed in food when meat (including fish, poultry) are cooked at high temperature
    Nitrosamines and nitrosamides found in tobacco and in some smoked meat and fish
    Azo dyes various dyes and pigments used in textiles, leather, paints.
    Carbamates ethyl carbamate (urethane) found in some distilled beverages and fermented foods
    Halogenated compounds e.g. pentachlorophenol used in some wood preservatives and pesticides.
    Inorganic compounds asbestos; may induce chronic inflammation and reactive oxygen species
    Miscellaneous compounds e.g. alkylating agents, phenolics

     

    WEB LINK

    A detailed list of occupational carcinogens can be found on the link below

    https://bio.libretexts.org/Bookshelves/Human_Biology/Book:_Human_Biology_(Wakim_and_Grewal)/21:_Disease/21.7:_Cancer

    The carcinogens implicated as the main causative agents of the four most common cancers worldwide are given in the table below. These four cancers are lung, breast, colon, and stomach cancers. Together they account for about 41% of worldwide cancer incidence and 42% of cancer deaths. 

     

    Table \(\PageIndex{2}\): Major Carcinogens Implicated In The Four Most Common Cancers Worldwide.

    Type of Cancer Carcinogen
    Lung Cancer Tobacco smoke
    Breast Cancer Estrogen
    Colon Cancer Tobacco smoke and bile acids: deoxycholic acid (DCA) or lithocholic acid (LCA)
    Stomach Cancer Heliobacter pylori

    WEB LINK

    Note:  A more detailed description for each major carcinogen listed in Table \(\PageIndex{2}\) can be found on the link below

    https://en.wikipedia.org/wiki/Carcinogen#Major_carcinogens_implicated_in_the_four_most_common_cancers_worldwide

    Anticarcinogens

    Dietary fiber and calorie restriction are two anti-carcinogen or anti-promoters that decrease the risk of tumor formation. Dietary fiber is both and is inversely associated with cancer, particularly colon cancer. So the more fiber you eat, the less risk you have of developing colon cancer. One mechanism by which fiber acts is hastening bile acid excretion. Fiber also increases the rate of passage of materials through the colon resulting in decreased production and exposure of the colon to cancer-causing agents, ie dilutes the concentration of carcinogens.

    Animal studies have shown that restricting caloric intake by 30% reduces tumor growth and increases life span. The mechanism is not known but may be due to less oxidation thus damage to DNA.

    Antioxidants can help block the action of initiators or promoters if their mode of action is to damage DNA by oxidation. Vitamin A, C, E, beta-carotene, and selenium are antioxidant nutrients. Some work locally, like vitamin E in the colon, while other work more globally like selenium and vitamin C. Vitamin A appears to work by keeping cells differentiated which slows the growth rate.

    Other compounds in food, particularly fruits and vegetables, have been shown to slow tumor formation. Cruciferous vegetables (eg broccoli, cauliflower, cabbage, and Brussel sprouts to name a few) are rich in nutrients, fiber, glucosinolates which are sulfur-containing chemicals, indoles, and isothiocyanates. Animal studies have found these substances inhibit the development of cancer in several organs in rats and mice (Hecht SS. Inhibition of carcinogenesis by isothiocyanates. Drug Metabolism Reviews 2000;32(3-4):395-411; Murillo G, Mehta RG. Cruciferous vegetables and cancer prevention. Nutrition and Cancer 2001;41(1-2):17-28). Indoles and isothiocyanates help protect cells from DNA damage; help inactivate carcinogens; have antiviral and antibacterial effects; have anti-inflammatory effects; induce cell death (apoptosis); and inhibit tumor blood vessel formation (angiogenesis) and tumor cell migration (needed for metastasis) (National Cancer Institute, Cruciferous Vegetables and Cancer Prevention, 2012, https://www.cancer.gov/about-cancer/...les-fact-sheet). Studies in humans, however, have shown mixed results.

    Test for Carcinogens

    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, such mutagens are therefore carcinogens, although not all necessarily are.  Many different systems for detecting mutagen have been developed.[54][55] Animal systems may more accurately reflect the metabolism of human, however, they are expensive and time-consuming (may take around three years to complete), they are therefore not used as a first screen for mutagenicity or carcinogenicity.

    The Ames test is a widely employed method that uses bacteria to test whether a given chemical can cause mutations in the DNA of the test organism. More formally, it is a biological assay to assess the mutagenic potential of chemical compounds.[1] A positive test indicates that the chemical is mutagenic and therefore may act as a carcinogen, because cancer is often linked to mutation. The test serves as a quick and convenient assay to estimate the carcinogenic potential of a compound because standard carcinogen assays on mice and rats are time-consuming (taking two to three years to complete) and expensive. However, false-positives and false-negatives are known.  Other tests, similar to the Ames tests have also been developed using yeast and other bacteria.

    Drosophila, plants, and cell cultures have been used in various test assays for mutagenecity of chemicals.

    In animal test systems, rodents are usually used in animal test. The chemicals under test are usually administered in the food and in the drinking water, but sometimes by dermal application, by gavage, or by inhalation, and carried out over the major part of the life span for rodents.  Transgenic mouse assay using a mouse strain infected with a viral shuttle vector is another method for testing mutagens. Animals are first treated with suspected mutagen, the mouse DNA is then isolated and the phage segment recovered and used to infect E. coli

     

    Did You Know?

    Video \(\PageIndex{1}\) Risk factors for cancer.

     

    Birth Defects:Teratogens

    A teratogen is a compound that permanently deforms the function or structure of a developing embryo or fetus in utero. In general, the degree of teratogenicity depends on:

    • The potency of the drug as a mutagen.
    • The susceptibility of the fetus to teratogenesis.
    • The dose of the teratogen.
    • The duration of teratogen exposure.
    • The time of exposure.
    • The degree of transfer from maternal to fetal circulation.

    The global average of all live births complicated by malformation is 6% (Environmental Health Perspectives, (NIH), October 2009). The majority of these complications are due to unknown factors. The vast majority of recognized etiologies are genetic, with only 10% being attributed to environmental etiologies such as maternal health, infection, and toxicants. In general, the central nervous and skeletal systems are the most affected.

    Thalidomide (a sedative previously marketed in Europe to prevent morning sickness) see Figure \(\PageIndex{4}\)is a classic teratogen that caused limb defects in babies born to women who took this drug in the 1960s (see Figure \(\PageIndex{5}\)). Thalidomide was first marketed in 1957 in West Germany, where it was available over the counter.[5][6] When first released, thalidomide was promoted for anxiety, trouble sleeping, "tension", and morning sickness.[6][7] While initially deemed to be safe in pregnancy, concerns regarding birth defects were noted in 1961 and the medication was removed from the market in Europe that year.[6][5] The total number of people affected by use during pregnancy is estimated at 10,000, of which about 40% died around the time of birth.[6][3] Those who survived had limb, eye, urinary tract, and heart problems.[5]

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    Figure \(\PageIndex{4}\). Chemical structure of Thalidomide.

    Its initial entry into the US market was prevented by Frances Kelsey at the FDA.[7] The birth defects of thalidomide led to the development of greater drug regulation and monitoring in many countries. in 2006 the U.S. Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients.

    A photograph of the limbs of baby born to a mother who took thalidomide while pregnant. The feet are curved inwards and have seven misshaped toes.

    Figure \(\PageIndex{5}\). Thalidomide effects: A photograph of the limbs ofbaby born to a mother who took thalidomide while pregnant.

    Women may encounter a number of other teratogens. Smoking is most likely to cause growth retardation, but has also been implicated in the prelabor rupture of the membranes, preterm labor, abruption of the placenta, spontaneous abortion, perinatal morbidity and mortality, and sudden infant death syndrome. Smoking may exert its effects through competitive binding of carbon monoxide with hemoglobin and/or through the various other components found in cigarettes that cause adverse biological effects.

    Alcohol use in pregnancy may result in fetal alcohol syndrome (FAS) see Figure \(\PageIndex{6}\), which occurs in approximately 1% of all births. Children with FAS present with a flattened and thin upper lip, small palpebral fissures, epicanthal folds, flattened nasal bridge, and a short nose. They may also exhibit microcephaly, mental retardation, and have learning disabilities. It is not clear if there is any safe amount of alcohol consumption in pregnancy.

    This is a photo of a baby with fetal alcohol syndrome Alcohol is a teratogen. When consumed in pregnancy, it can result in mothers giving birth to children with fetal alcohol syndrome. The facial characteristics highlighted in the photograph are a small eye opening, a smooth philtrum, and a thin upper lip.

    Figure \(\PageIndex{6}\). Fetal alcohol syndrome: Alcohol is a teratogen. When consumed in pregnancy, it can result in mothers giving birth to children with fetal alcohol syndrome. The facial characteristics highlighted in the photograph are small eye opening, smooth philtrum, and a thin upper lip.

    Cocaine generally produces growth restriction, preterm delivery, microcephaly, spontaneous abortion, placental abruption, limb anomalies, and central nervous system abnormalities. Cocaine appear to exert a number of its effects through peripheral vasoconstriction that leads to fetal hypoxia.

    Women with indications for warfarin therapy should either abstain from pregnancy or switch to low molecular weight heparins. Warfarin typically produces mental retardation, growth restriction, nasal hypoplasia, and opthalmic abnormalities.

    Angiotensin converting enzyme (ACE) inhibitors will cause fetal renal failure and oligohydramnios that lead to pulmonary hypoplasia and limb contracture. Fetal cranial bone abnormalities are also common.

    Isotretinoin (Accutane), used to treat acne, may cause cardiac, oral, otological, thymic, and central nervous system abnormalities. In one quarter of cases, it causes mental retardation.

    Other teratogenic substance classes and conditions include

    • Various prescription drugs and nutrient deficiencies (e.g., insufficient folic acid).
    • Chemical compounds such as methyl iodide (used in pesticides) and bisphenol A (used in plastics) are suspected teratogens.

    Summary

    • A carcinogen is any agent that directly increases the incidence of cancer.
    • Cancer is caused by changes to the DNA which could be inherited or acquired.
    • Various tests have been developed to test for carcinogens.
    • The American Cancer Society provides an extensive list of probable chemical carcinogens including those found in processed foods and beverages, various household products, pesticides etc.
    • The effects of a teratogen on the fetus depend on several factors: the potency of the teratogen, the susceptibility of the fetus to the teratogen, the dose and duration of teratogen exposure, the degree of transfer from maternal to fetal circulation, and when during development the exposure occurs.
    • Approximately 10% of congenital malformations are attributed to environmental factors, and 20% are due to genetic or hereditary factors. The rest have unknown causes or are due to a mix of different factors.
    • Cigarette components, alcohol, cocaine, warfarin, ACE inhibitors, and Accutane are all teratogens that affect fetal development.

    Contributors and Attributions

    Libretexts: Online Open Genetics (Nickle,T. & Barrette-Ng,I.)

    Libretexts: Human Biology (Wakim and Grewal)

    Libretexts: An Introduction to Nutrition (Byerley)

    Libretexts: Anatomy and Physiology (Boundless)

    Template:ContribOOG

    Wikipedia

    American Cancer Society

    NIH-MedlinePlus

    NIH- National Cancer Institute

    Marisa Alviar-Agnew (Sacramento City College)

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