Mutagens and carcinogen

Here a presentation is given regarding mutagens and carcinogen.

1. Mutagens and Carcinogens
Presented by,
Md. Galib Ishraq Emran.
Department of Environmental Sciences.
2015-16 Sessions.
Registration No: 41778.
Class Roll: 219.
Jahangirnagar University,
Savar, Dhaka-1342.
Email: [email protected]
Contact:01871137168, 01782368136.

2. Mutagens and Carcinogens
•Carcinogen:
Substance that can cause cancer by inhalation, ingestion or
skin contact
•““Cancer is a group of diseases characterized by Cancer is a group of diseases characterized by
uncontrolled growth and spread of abnormal cells that uncontrolled growth and spread of abnormal cells that
can result in death”can result in death” (American Cancer Society, 2006) (American Cancer Society, 2006)
•Mutagen:
Substance that can damage the hereditary material (DNA)
Mutagen may cause cancer, but not always
•Often this word has a negative undertone, but mutation has
made the immense variety of life on earth possible.

3. Mutation
•DNA has 3 unique properties that distinguish it
from other macromolecules:
- self replicating
-mutable
- transmissible
•Mutation means change, mutation is an event
that gives rise to an alteration in the genotype
•It also can be the change itself
•Mutation does not mean “bad”
•Mutations are IMPORTANT for a variety of
reasons

4. Mutations Are Heritable Changes in DNA
•Mutations are the ultimate source of all genetic
variation in humans and other organisms
•Mutation can occur spontaneously as a result of errors
in DNA replication or is induced by exposure to
radiation or chemicals
•An agent that causes a mutation is called a mutagen
•What do mutagens do?
•Mutagens primarily affect DNA by causing a physical
change in the structure, which ultimately alters the
sequence, leading to changes in genes such that the
information is altered. This leads to loss of a protein, a
change in the sequence (and likely structure) of a protein
or a change in the level of proteins found in cells.

5. Types of Mutagens
•Physiclal : UV, Xray
•Chemical: PCB, PAH, Benzene etc.
•Biological: Oncogenic viruses
•A variety of chemicals react directly with DNA.
Alkylating agents are electrophiles that add methyl,
ethyl and more complicated alkyl groups to nucleic
acid bases..
•Electrophilic reactants can also be generated by
cytochrome P450 oxidation of xenochemicals. These
chemicals include benzo[a]pyrene,
acetylaminofluorene and aflatoxin.
•Nitrogen and sulfur mustards (used in chemical
warfare) link bases on opposite DNA strands,
creating cross-links.

6. Two Categories of Mutations
•Somatic Mutations
–Occur in cells of the body that do not form gametes
–Occurs in mitosis
–Is not transmitted to future generations
•Germ-line Mutations
–Occur in cells that produce gametes
–Occurs during meiosis
–Transmitted to future generations - inherited

7. Mutation ‘Levels’
•DNA Level, Chromosomal Level, Genome Level
What Causes Mutations ?
•1) Spontaneous (?????)
•2) Chemically induced
•3) Radiation induced
•Most (if not all) really come down to a chemical level
•No such thing as a “spontaneous” mutation
• Many chemicals are mutagens; many others are promutagens
• Chemicals (just like radiation) can cause point mutations.
• Chemicals (just like radiation) can cause chromosome breakage
(e.g. - LSD, Mercury, Caffeine --- at least in cell culture)
• Mustard gas (adds a methyl group)
• Formaldehyde, Phenol, Nitrous Oxide (replaces NH
2
with O)

8. Mutations Can Be Detected in Several Ways
•How do we know that a mutation in a gene has occurred?
–Change in a phenotype that is passed on
•Mutations that do not cause a change in phenotype would most
likely only be detected by sequencing an individual’s DNA
•Not all mutations cause permanent genetic damage
•Cells have enzyme systems that repair DNA
–Mismatch repair – enzymes detect nucleotides that do not base
pair in newly replicated DNA; the incorrect base is excised and
replaced
–Excision repair - enzymes cut out the 1-30 bases of DNA with
the mistake and resynthesize the small fragment
–End-joining – when both strands of the DNA molecule are cut,
proteins simply take the ends and stick them back together
Mutations and DNA Damage Can Be Repaired

9. Exposure to Chemical Mutagens
Aflatoxin – in peanuts
Nitrophenols, anisoles, toluene – hair dyes
Furylfofuramide – food additive
Nitrosamines – pesticides, herbicides cigarette
smoke
Sodium nitrite – smoked meats
Polybrominated diphenyl ether (PBDEs) – flame
retardant

10. Endogenous and exogenous sources of mutagens
Mutagens are any reagent that causes changes in DNA
(often referred to as DNA damage) that can ultimately
lead to a change in the DNA sequence.
There are endogenous and exogenous sources of
mutagens
Examples of endogenous reagents are; free radicals
generated during oxidation reactions, pH changes
that can lead to changes in DNA, errors in DNA
replication and recombination errors.
Examples or exogenous reagents are UV radiation,
ionizing radiation, chemicals such as benzopyrene
and and natural compounds such as aflatoxin.

11. Endogenous DNA damage
•Replication errors
–Polymerase misincorporation
•Recombination errors
–Unequal crossing over, etc.
•Spontaneous base damage
–Deaminations, depurinations
•Byproducts of metabolism
–Oxygen radicals

12. Sources of exogenous DNA damage
•Chemicals
–Natural
•In foods, e.g. aflatoxin
–Man-made/man-increased
•Nitrogen Mustard - WWI nerve gas
•Benzopyrene - smoke from coal, autos, cigs
•Ultraviolet (UV) Radiation (from sun)
•Ionizing radiation
–Natural: radon gas, cosmic rays
–Man-made: x-rays, nuclear tests

13. What Is Cancer?
•Cancer is not a single disease but rather a name applied to
a great variety of malignant tumor that are formed by the
same basic process of uncontrolled growth. i.e. Cancer is a
large group of diseases characterized by the uncontrolled
growth and spread of abnormal cells
•Neoplasm – new growth of tissue that serves no
physiological function. Tumor – clumping of neoplasmic
cells
•Malignant - cancerous
•Benign - noncancerous
•Biopsy – microscopic examination of cell development
•Metastasis – malignant tumors that are not enclosed in a
protective capsule have the ability to spread to other
organs

14. What causes cancer?
•Cancer arises from the mutation of a normal gene.
•Mutated genes that cause cancer are called oncogenes.
•It is thought that several mutations need to occur to give rise to
cancer
•Cells that are old or not functioning properly normally self
destruct and are replaced by new cells.
•However, cancerous cells do not self destruct and continue to
divide rapidly producing millions of new cancerous cells.
•A factor which brings about a mutation is called a mutagen.
•A mutagen is mutagenic.
•Any agent that causes cancer is called a carcinogen and is
described as carcinogenic.
•So some mutagens are carcinogenic.

15. How do mutations cause cancer?
•Mutation is the Permanent change in the DNA sequence of a gene
•It is Inherited or acquired during lifetime
•Single mutations are often harmless but multiple mutations can
results in cancer
• Cancer is a multi-stage, multiple event disease
• Mutation is involved in the etiology of cancer
• Cancer is a disease of mutation and cell division
• Increased mutations can occur by the induction of new mutations or
by increasing the “spontaneous” mutation rate
•DNA RNA protein
• Genes contain the instructions necessary for a cell to work. If some of
the instructions to the cell are wrong, then the cell may not know what
to do!
•Mutated DNA mutated RNA mutated protein
•Many mutations accumulated over time can result in harmful changes
in the cells instructions, These mutations in genes result in mutations
in proteins that control the cell cycle

16. Mechanism
Cancer = unrestrained cellular proliferation
Cancer development is a multistep process:
-For the growth of a cancer several factors must
work together
-Several influencing factors play an additional large
role if a cancer will develop: food, age, hormones,
-For this different steps are necessary:
1. Initiation
2. Promotion
3. Progression
•The begin of cancer generally needs many years
•Different carcinogens have different working
mechanism

17. Mechanisms of Action of Carcinogens

18. Metastasis
•The most fearsome aspects of cancer is the spread of
maglignant cells from the primary site to another parts of the
body, a process known as matastasis.
• metastasis is the primary reason for the failure of treatment
of cancer patients.
• The extent of the dissemination of the malignant cells is
determined by the physiological condition of the host.
• During metastasis continuous changes take place in tumor
cells and function and behaviour of the tumor cells in the late
stage is quite different from those of the early stage.
• The late stage of the disease is characterize by invasive
activity and apperance of a variety cancer cell types.
• Some of the cells which have the inherent ability to detach
from the primary site, will eventually travel via blood/lymph
to start a secondary tumor in another sites.

19. Global Causes of Cancer

20. Types Of Cancers
•Classification of cancers
–Carcinomas: cancer arise in the epithelium tissue
line of the skin/ internal organs
–Sarcomas: cancer of the connective tissues
–Lymphomas: cancer of the lympnodes/ lymp
glands
–Leukemias: cancer of the blood- bone marrow or
blood foriming tissues

21. Carcinogens
•Ionising radiation – X Rays, UV light
•Chemicals – tar from cigarettes
•Virus infection – papilloma virus can be responsible
for cervical cancer.
•Hereditary predisposition – Some families are more
susceptible to getting certain cancers. Remember
you can’t inherit cancer its just that you maybe more
susceptible to getting it.

22. Tumor
Benign Tumors
Self-limited in
their growth.
Usually do not
invade or
metastasize
Malignant Neoplasm or Tumors
Group of cells display
Excessive growth and division
without respect to normal limit,
Invasive, invade and destroy
adjacent tissues, and sometime,
Distant metastasis spread to other
locations in the body.

23. Age: Cells are more likely to become damaged as the body ages.
Family history of cancer (Genetic susceptibility): People with a family
history of a particular cancer are more likely to develop it themselves.
•Environmental factors, defined broadly to include tobacco use, diet,
sunlight and infectious diseases, alcohol, radiation are some lifestyle factors
which may influence the risk of developing some cancers.
•Hormones: The risk of some cancers is linked to levels of certain hormones
in the body.
•Infection: Certain cancers are linked to viral infection.
• Unhealthy lifestyle : Poor diet, lack of physical activity, or being
overweight.
• Occupational carcinogens
• Radiation, Chemicals and other substance like medical complication
Risk Factors
A risk factor is anything that increases a person's chance of
getting a disease.
Some risk factors can be changed, and others cannot.
Different cancers have different risk factors

24. Risk Factors of Cancer

25. Microorganism Cancer
Human papilloma virus Cervical cancer
Helicobacter pylori Stomach cancer
Hepatitis B and hepatitis C viruses Liver cancer
Human T-cell leukemia/lymphoma virus Lymphoma and leukemia
Human immunodeficiency virus Lymphoma and a rare cancer called
Kaposi's sarcoma
Epstein-Barr virus Lymphoma
Human herpes virus 8 Kaposi's sarcoma
Certain viruses/bacteria may increase the risk of developing cancer

26. Biological Factors
•Some cancers such as breast, stomach, colon, prostate,
uterus, ovaries and lung appear to run in families
•Certain leukemia's show similar patterns
•Some study suggests that a gene for breast cancer exists
•A rare form of eye cancer appears to be transmitted
genetically from mother to child
Reproductive And Hormonal Risks For Cancer
•Pregnancy and oral contraceptives increase a woman’s
chances of breast cancer
•Yearly first childbirth, having many children have been shown
to reduce risk of breast cancer

27. Occupational and Environmental Factors
•Asbestos
•Nickel
•Chromate
•Benzene
•Arsenic
•Radioactive substances
•Cool tars
•Herbicides/pesticides

28. Social And Psychological Factors
•Stress has been implicated in increased susceptibility
to several types of cancers
•Sleep disturbances, diet, or a combination of factors
may weaken the body’s immune system
Chemicals In Foods
•Sodium nitrate when ingested forms a potential
carcinogen, nitrosamine
•Sodium nitrate is still used because it is effective in
preventing botulism
•Pesticide and herbicide residues

29. Medical Factors
•Some medical treatments actually increase a
person’s risk for cancer
•Diethylstilbestrol (DES) used 1940 to 1960 to
control bleeding during pregnancy, the daughters
of mothers that used DES were found to have an
increased risk for cancers of the reproductive
organs
•Estrogen supplementation
•Chemotherapy used to treat one form of cancer
may increase risk for another type of cancer

30. Having a healthy diet, being physically
active, and maintaining a healthy weight may
help reduce cancer risk.
Eat well: A healthy diet includes plenty of foods that
are high in fiber, vitamins, and minerals. This includes
whole-grain breads and cereals and 5 to 9 servings of
fruits and vegetables every day. Also, a healthy diet
means limiting foods high in fat (such as butter, whole
milk, fried foods, and red meat).
Be active and maintain a healthy weight: Physical
activity can help control your weight and reduce body
fat. Moderate physical activity, walking for at least 30
minutes daily is recommended.
Avoidable Cancer Risk

31. Energy Intake, Body Weight, Obesity, and Physical Activity
•Energy restriction inhibits cancer and extends life span
in animals
•Positive associations between overweight and cancers
of the breast, endometrium (mucous membrane that
lines the inside of the uterus), kidney, colon, prostate,
and others
•Overweight increases risk of cancer recurrence and
decreases survival
•Physical activity is inversely associated with cancer, I e
Physical activity may have a protective effect
•Women who spent an average 3.8 hours per week in
physical activities had lower risk of colon, reproductive
cancers

32. Etiology of Cancer/Carcinogenic Agents
The etiology of cancer is multifactorial, with
genetic, environmental, medical, and lifestyle
factors interacting to produce a given
malignancy.
Most cancer is caused by genetic mutations
often, by a series of mutations.
•Chemical carcinogens.
•Physical/ Radiation carcinogenesis.
•Viral & microbial oncogenesis.

33. Nutrition and Cancer Etiology
•Fat
•Protein
•Soy and phytoestrogens
•Carbohydrates: fiber,
sugars, and glycemic
index
•Fruits and vegetables
•Nonnutritive sweeteners
•Alcohol
•Coffee and tea
•Methods of food preparation
and preservation
•Cancer chemoprevention
•Cancer prevention
recommendations: nutrition
and physical activity

34. Fat
•High intake of total and saturated fat is associated
with increased risk of breast, colon, lung and prostate
cancers
•High fat diets are associated with obesity, which is
linked with cancer of the colon, rectum, esophagus,
gall bladder, breast, endometrium, pancreas, and
kidney
•Animal fat (from meat and dairy) was associated with
increased risk of breast cancer
•Higher omega-3 vs. omega 6 may reduce risk of breast
cancer
•Low fat diet (<20% fat) may reduce risk of recurrence
of breast cancer

35. Obesity is a Risk Factor for:
•Breast cancer
(among
postmenopausal
women)
•Colon
•Endometrium
•Esophagus
•Gallbladder
•Pancreas
•Kidney
•Is also a risk
factor for cancer
recurrence

36. Protein
•Difficult to isolate effects of protein, since ↑
protein diets are ↑ in fat and ↓ in fiber
•Low protein diets seem to reduce the risk of
cancer, while risk is increased by very high
protein intakes
•Increased meat intake is associated with
increased risk of colon cancer and advanced
prostate cancer

37. Fiber
•Observational studies and case control studies
indicate that fiber-rich diets are associated
with a protective effect in colon cancer
•Higher intakes of vegetables were inversely
associated with colon cancer risk in one study
•But high fiber diets also tend to be lower in
meat, fat, and refined carbohydrates
•Recommendation is to eat high fiber foods
despite lack of conclusive evidence re cancer

38. Carbohydrate and Glycemic Index
•High glycemic-index diet associated with
increased risk of cancers including ovarian,
endometrial, breast, colorectal, pancreas, and
lung
•Limit processed foods and refined sugars and
emphasize whole grains and low GI foods
Not all Carbohydrate foods are equal. The Glycemic Index (GI) is a
relative ranking of carbohydrate in foods according to how they
affect blood glucose levels. Carbohydrates with a low GI value
(55 or less) are more slowly digested, absorbed and metabolised
and cause a lower and slower rise in blood glucose

39. Fruits, Vegetables and Plant based foods
•Increased consumption of fruits and vegetables is associated
with lower risk of cancers of the oral cavity, esophagus,
stomach, colon, rectum, and bladder
•Low in energy, good sources of fiber, vitamins, minerals
•Good sources of antioxidants (vitamins C, E, selenium,
phytochemicals such as carotenoids, flavonoids, plant sterols,
allium compounds, indoles, phenols, terpenes
People who develop cancer tend to have low intakes of
¨Raw and fresh vegetables
¨Leafy green vegetables
¨Lettuce, carrots, raw and fresh fruit
¨Cruciferous (cabbage family) vegetables
¨Flavenoids and lignans (soy, grains, vegetables) are associated
with lower risk of sex hormone-related cancers

40. Calcium and Cancer Risk
•Several studies suggest that foods high in calcium may
reduce the risk for colorectal cancer and that calcium
supplements may reduce the formation of colorectal
polyps
•However, there is evidence that high calcium intake,
especially supplements, is associated with increased risk of
prostate cancer
•Bottom line: get calcium through food sources
Lycopene and Cancer Risk
•Lycopene is a red-orange carotenoid found in tomatoes and
tomato-based foods
•Several studies show that consuming tomato products reduces
the risk of some cancers,
•Absorption of lycopene is enhanced when lycopene-containing
vegetables are cooked and eaten with fat
•No evidence that supplements are safe and effective in cancer
prevention.

41. Cancer Risk with Preserved Meats and Cooked Meat
•Some studies link eating large amounts of
preserved meat to increased risk of colorectal and
stomach cancers
•Nitrites can be converted in the stomach to
carcinogenic nitrosamines, which may increase the
risk of stomach cancer
•Vegetables and fruit retard the conversion of
nitrites to nitrosamines
•Frying, broiling, and grilling meats at high
temperatures creates chemicals that might
increase cancer risk (cause cancer in animals)

42. Soy and Cancer Risk
•Soy contains several phytochemicals
(phytoestrogens) which have weak estrogen activity
and appear to protect against hormone-dependent
cancers in animal studies
•High doses of soy may increase the risk of estrogen-
responsive cancers, such as breast or endometrial
cancers in certain women
•Breast cancer survivors should consume only
moderate amounts

43. Alcohol and Cancer risk
•Alcohol associated with cancers of the mouth,
pharynx, larynx, esophagus, lung, colon, rectum,
liver and breast
•Appears to act synergistically with tobacco
• Malnutrition associated with alcoholism may also
be implicated
Cancer risk: Coffee and Tea
•Coffee has been investigated as a possible risk factor for a
variety of cancers, but does not appear to be associated with
increased cancer
•Regular drinking of green tea and other sources of
polyphenols may reduce the risk of stomach cancer
•Consumption of very hot drinks may increase the risk of
esophageal cancer

44. Artificial Sweeteners and cancer
•Cyclamate banned as food additive in US in 1969 and
saccharine in 1977 after being associated with bladder
cancer in mice
•Under public pressure, saccharine returned to the market;
it was reviewed and taken off the list of potential
carcinogens in 2000
•Aspartame: no evidence implicating it in increased cancer
risk
Hyperinsulinemia and Cancer
•Increased body mass index may promote hyperinsulinemia
and metabolic syndrome
•Insulin resistance/hyperinsulinemia, higher estrogen levels,
and insulin-like growth factor may act synergistically to
promote tumor growth, particularly mammary tumors.

45. Food Safety and Cancer
•Naturally occurring carcinogens (aflatoxins in peanuts, safrol in
plant oils, tannins in grains and grapes, benzopyrene formed by
smoking meat and fish)
•Naturally found in plant foods like celery, parsley, figs, mustard,
pepper etc.
•Pesticides
•Choose in-season, locally grown produce
•Rinse fruits and vegetables and remove outer leaves before
eating
•Use proper food storage to prevent growth of fungal
carcinogens
•Marinate protein foods to decrease cooking time
•Use cooking methods to avoid contact of foods and food
drippings with flames
•Use lower cooking temperatures with protein foods

46. How to prevent cancer
Primary prevention: avoidance of exposure to
cancer-causing agents (e.g. tobacco, industrial
carcinogens, etc.
Early detection of cancer: education to promote
early diagnosis and screening (Imaging diagnosis
and laboratory tests,…)
Genetic testing: these tests can check for certain
inherited gene changes that increase the chance of
developing cancer.
•Avoid tobacco, Eat healthy, Avoid alcohol, Avoid tobacco, Eat healthy, Avoid alcohol,
Exercise, Protect yourself from the sun, Exercise, Protect yourself from the sun,
Vaccinate, Avoid pollutionVaccinate, Avoid pollution

47. 8 prevention strategies for cancer
1.Be as lean as possible within the normal range of
body weight.
2.Be physically active as part of everyday life.
3.Limit consumption of energy dense foods.
4.Eat mostly foods of plant origin.
5.Limit intake of red meat and avoid processed
meat.
6.Limit alcoholic drinks.
7.Limit consumption of salt.
8.Aim to meet nutritional needs through diet
alone.

48. Early signs and symptoms of cancer
 Bleeding
 A lump or hard area
 raised birth mark/mole
 A hard base chronic sore that does not heal
 Constipation or alternately loose motion
 pain and tender swelling of bone and tissues
 loss of weight
 diminished appetite
 feeling tiredness
 painless or painful swelling
 low grade fever

49. Detecting Cancer
•Investigation required for cancer check-up: History
taking, physical examination and laboratory
investigation
•The earlier the diagnosis the better the prospect for
survival
•Magnetic resonance imaging (MRI)
•Computerized axial tomography scan (CAT scan)
•Prostatic ultrasound
•Regular self-exams, and check ups
• Confirmation by Alpha fetoprotein a cancer marker

50. Assays that detect
mutagenecity/Carcinogenecity
Epidemiology
Animal bioassay
Ames Test
Mouse Lymphoma Assay (MLA): The Mouse Lymphoma Assay
(MLA), also called the in vitro mammalian cell gene mutation
test, can be used to detect gene mutations induced by
chemical substances and their metabolites. In this assay,
thymidine kinase (TK) proficient cells are exposed to the
pyrimidine analogue 
HPRT mutation in various cell lines or in vivo
lymphocytes : The hypoxanthine phosphorybosyl transferase
(HPRT) gene is on the X chromosome of mammalian cells,
and it is used as a model gene to investigate gene mutations in
mammalian cell lines. The assay can detect a wide range of
chemicals capable of causing DNA damage that leads to gene
mutation.

51. Detecting environmental mutations: Ames Test (after Bruce Ames)
•Ames Test is an inexpensive method used to screen
possible carcinogens and mutagens.
•Histidine auxotroph Salmonella typhimurium (requires
Histidine to grow) are mixed with rat liver enzymes and
plated on media lacking histidine.
•Liver enzymes are required to detect mutagens that are
converted to carcinogenic forms by the liver (e.g.,
procarcinogens).
•Test chemical is then added to medium.
•Control plates show only a small # of revertants
(bacteria cells growing without histidine).
•Plates innocculated with mutagens or procarcinogens
show a larger # of revertants.
•Auxotroph will not grow without Histidine unless a
mutation has occurred.

52. Ames test
Bruce Ames (1975(
- measured the ability
of carcinogens to
mutate the bacteria

53. Treatments of Cancers
•Surgery
•Chemotherapy
•Radiation Therapy
•Combine surgery with radiation or chemotherapy
•Immunotherapy
•Cancer-fighting vaccines
•Gene therapy
•Hormone therapy for breast, prostate, uterus,
thyroid
What are their side effects ?

54. Surgery
•Inability to swallow
•Constipation
•Increased metabolic
requirements
- Changes in taste, food aversions, sensitivity to
odors
–Mouth sores
–Nausea, vomiting
–Diarrhea, constipation
–Decreased appetite, anorexia
Chemotherapy
•Side effects dependent on
the dose and site radiated
•Late Side effects
Radiation Therapy

55. Combined Modality Treatment
•Both chemotherapy and radiation therapy at the
same time
•Chemo acts as a radiation sensitizer
•Side effects are frequently worse
•Require diligent follow up
•Most challenging patients
–Head and neck
–Lung
–Esophagus
–Pancreatic
–Colorectal

56. Common Nutrition Related Side Effects
•Nausea: A disorder characterized by a queasy sensation and/or the
urge to vomit.
• Vomitimg: A disorder characterized by the reflexive act of ejecting the
contents of the stomach through the mouth.
•Oral Mucositis: A disorder characterized by inflammation of the oral
mucosal
• Constipation: A disorder characterized by irregular and infrequent or
difficult evacuation of the bowels.
•Diarrhea: A disorder characterized by frequent and watery bowel
movements.
•Esophagitis: A disorder characterized by inflammation of the
esophageal wall.
•Alterations of Taste and Smell
•Dysphagia: Difficulty of swallowing
•Anorexia, Fatigue, dry mouth, heartburn

58. Thanks for being
Patience.