Lecture 16 Flashcards
(57 cards)
1
Q
Types of mutagens
A
Teratogens- Congenital malformations
Carcinogens- Tumor formation, cancer causing agents
Clastogens- chromosomal abnormalities
Non-specific- DNA damage
2
Q
What is a codon
A
A codon is a DNA or RNA sequence of three nucleotides (a trinucleotide) that forms a unit of genomic information encoding a particular amino acid or signaling the termination of protein synthesis (stop signals).
3
Q
DNA
A
- A nucleotide is the basic building block of nucleic acids.
- RNA and DNA are polymers made of long chains of nucleotides.
- A codon is a trinucleotide sequence of DNA or RNA that corresponds to a specific amino acid.
- Mutagenesis is the process by which an organism’s DNA changes, resulting in a gene mutation, which can result in altered protein function and phenotypic changes.
4
Q
What is translocation
A
A translocation, as related to genetics, occurs when a chromosome breaks and the (typically two) fragmented pieces re-attach to different chromosomes. The detection of chromosomal translocations can be important for the diagnosis of certain genetic diseases and disorders.
5
Q
Single Nucleotide Polymorphism (SNP)
A
DNA sequence variation that occurs when a single nucleotide (adenine,
thymine, cytosine, or guanine) in the genome sequence is altered.
For example, a G nucleotide present at a specific location in a reference genome may be replaced by an A in a minority of individuals. The two possible nucleotide variations of this SNP – G or A – are called alleles.
6
Q
Single Nucleotide Polymorphism (SNP)- three categories…
A
- SYNONYMOUS – Silent
- MISSENSE – Amino acid change
- NONSENSE – Stops transcription
7
Q
Amorphic / Genetic null effect on genes
A
Complete loss of function
8
Q
Hypomorphic effect on genes
A
A reduction in expression and/or function
9
Q
Hypermorphic effect on gene
A
An increase in expression and/or function
10
Q
Antimorphic effect on gene
A
Active, but opposite effect of normal gene
11
Q
Neomorphic effect on gene
A
New function
12
Q
Gene components
A
- The information contained within genes can be divided into several parts.
- The promoter region is located upstream from the coding region of the gene. Within the coding region of a gene are nucleotide sequences referred to as exons and introns. It initiates a particular gene expression.
- Exons contain the code that directs the assembly of amino acids that produce the protein product(s) of the gene.
- The introns, which are interspersed among the exons, do not code for amino acids and are spliced out of the final messenger RNA (mRNA) transcript.
- Research suggests that alternative splicing patterns within the gene give rise to sequences of DNA that may behave as exons or introns, depending on the circumstances.
- The end of the coding region of the gene is signified by a special nucleotide sequence called the terminator sequence.
13
Q
SNP Location
A
- SNPs are single-nucleotide substitutions of one base for another that occur in more than one percent of the general population.
- SNP identification could serve as predictive
markers that inform us about effects of toxins on genes including causing specific diseases,
effectiveness of various medicines/toxins and
adverse reactions to specific drugs. This can save time, money, and discomfort for patients through accurate diagnoses and matching patients with appropriate medicines.
14
Q
What do exonic SNP’s alter
A
Protein functions
15
Q
What do Intronic / promoter SNP’s alter
A
Gene expression
16
Q
Ethyl methanesulfonate (EMS)
A
Ethyl methanesulfonate (EMS) is a chemical mutagen believed to mainly induce G/C to A/T transitions randomly in genomes.
Ethyl methanesulfonate (EMS) mutagenesis of plants is a well-tested approach, which can induce point mutation in DNA of plants altering gene expression and help screen out favorable phenotypic
expression.
17
Q
What is DNA alkylation
A
DNA alkylation refers to the addition of alkyl groups to specific bases, resulting in
alkylation products.
It causes DNA mutations.
18
Q
What is DNA Oxidation
A
Oxidative DNA damage provides direct routes to mutations. While guanine usually pairs with cytosine, 8-oxo-7,8-dihydroguanine (8-oxoG), the most frequent type of oxidative base damage, may cause mispairing with adenine through a conformational change. This is one route to oxidative DNA damage induced mutations.
19
Q
Crosslinking of DNA
A
INTRASTRAND
Adjacent pyrimidines on the same DNA strand form dimers
*Deletion
*SNPs
INTERSTRAND
*Replication blocked
*Transcription blocked
20
Q
What are Intercalating agents
A
Insertion into DNA
*deletions
*insertions
*duplications
Insertion of these agents distorts the DNA
double helix, thereby interfering with DNA
replication, transcription, and repair. Such DNA distortions often result in mutations,
so intercalating agents are also mutagens.
21
Q
Mutagenicity Test - Ames Test
A
It is used to detect the mutagenicity of environmental samples such as drugs, dyes, reagents, cosmetics, waste water, pesticides and other substances which are easily solubilized in a liquid suspension.
22
Q
Mutagenicity Test - Ames Test- Principles
A
- Ames test uses several strains of bacteria
(Salmonella, E.coli) that carry a particular
mutation. - Point mutations are made in the histidine
(Salmonella typhimurium) or the tryptophan (Escherichia coli) operon, rendering the bacteria incapable of producing the corresponding amino acid. - These mutations result in his- or trp-
organisms that cannot grow unless histidine or tryptophan is supplied. - But culturing His- Salmonella is in a media
containing certain chemicals, causes
mutation in histidine encoding gene, such
that they regain the ability to synthesize
histidine (His+). This is to say that when a
mutagenic event occurs, base
substitutions or frameshifts within the
gene can cause a reversion to amino acid
prototrophy. This is the reverse mutation. - These reverted bacteria will then grow in
histidine- or tryptophan-deficient media,
respectively.
23
Q
Mutagenicity Test - Ames Test- result interpretation
A
- The mutagenicity of chemicals is proportional to number of colonies observed.
- If there is a large number of colonies on the test plate in comparison to control, then
such chemical are said to be mutagens. - Very few numbers of colonies can be seen on control plate also. This may be due to
spontaneous point mutation on hisidine encoding gene.
24
Q
What are prokaryotes
A
Prokaryotes are organisms made up of cells that lack a cell nucleus or any membrane-encased organelles.
25
What are eukaryotes
Eukaryotes are organisms made up of cells that possess a membrane-bound nucleus that holds genetic material as well as membrane-bound organelles.
26
What are carcinogens
A substance capable of causing cancer in living tissue.
27
Cancer is when...
abnormal cells divide in an uncontrolled way. Some cancers may eventually spread into other tissues.
*There are more than 200 different types of
cancer.
*1 in 2 people in the UK will get cancer in their lifetime.
28
Types of tumours
*Benign
*Premalignant
*Malignant
29
What are benign tumours
Benign tumors are those that stay in
their primary location without invading other sites of the body. They do not spread to local structures or to distant parts of the body. Benign tumors tend to grow slowly and have
distinct borders. Benign tumors are not usually problematic.
30
What are premalignant tumours
Premalignant tumors, which we also
may refer to as precancerous conditions, refer to atypical cells that are not cancer, but have the possibility to develop into cancerous
cells if a patient doesn’t receive treatment. They can potentially become malignant.
31
What are malignant tumours
Malignant tumors are cancerous. Malignant tumors can spread rapidly and require treatment to avoid spread. If they are caught early, treatment is likely to be surgery with possible chemotherapy or radiotherapy. If the cancer has spread, the treatment is likely to be systemic, such as chemotherapy or
immunotherapy. Spread of cancerous cells to distant sites via the bloodstream or the lymphatic system is called metastasis.
32
What is oncogene
Oncogenes is a mutated (changed) form of a type of gene called a proto-oncogene (A gene involved in normal cell growth and division). When a proto-oncogene is changed so that too many copies are made or it becomes more active than normal, it is called an oncogene.
33
What is P53
*P53 is a gene that makes a protein that is found inside the nucleus of cells and plays a key role in controlling cell division and cell death.
* If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.
* Mutations (changes) in the p53 gene itself, may cause cancer cells to grow and spread in the body.
34
Types of Cancer
* Carcinoma – skin / tissues that line internal organs.
E.g. basal / squamous / renal cell carcinoma
* Sarcoma – connective / supportive tissues
E.g. angiosarcoma / osteosarcoma / liposarcoma
* Leukaemia – blood and bone marrow
E.g. chronic/acute myeloid / lymphocytic / lymphoblastic
* Lymphoma – lymph nodes
* Hodgkin / Non-Hodgkin
* Brain, spinal cord – CNS
35
Metastatic meaning
able to establish growth in a new location
36
What are Polycyclic Aromatic Hydrocarbons (PAH)
Polycyclic aromatic hydrocarbons (PAHs) are a class of chemicals that occur naturally in coal, crude oil, and gasoline. They result from burning coal, oil, gas, wood, garbage, and
tobacco. PAHs can bind to or form small particles in the air. High heat when cooking meat and other foods will form PAHs.
e.g. Benzo[a]pyrenes
37
Procarcinogen
a chemical substance that does not itself
cause cancer, but which can be converted by
enzymatic action to another substance that
can cause cancer (the ultimate carcinogen)
38
What can asbestos cause
*Translocation
*DNA oxidation
*Cell proliferation
39
What is asbestos
a highly heat-resistant fibrous silicate mineral that can be woven into fabrics, and is used in brake linings and in fire-resistant and insulating materials
40
Carcinogen Classification
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
41
What is a teratogen and its manifestations
A teratogen is a substance that may lead to birth defects in an embryo or fetus. During pregnancy, exposure to certain chemicals, infections, and drugs may increase the risk that a person will miscarry or that the embryo or fetus could have a developmental abnormality.
1) Functional defects
2) Growth retardation
3) Malformation
4) Death
42
Teratogens – Mechanism of Action
* Oxygen / nutrient supply depletion
* Oxidative stress
* Protein synthesis inhibition
* Chromosomal injury
43
Nicotine
Smoking during pregnancy can cause tissue damage in the unborn baby, particularly in the lung and brain, and some studies suggests a link between maternal smoking
and cleft lip. Studies also suggest relationship between tobacco and miscarriage.
Constricts uterine blood vessels - decreases uterine blood flow- Oxygen / nutrient depletion
Effect:
Reduced foetal growth
Premature babies
44
Illicit drug effects on babies
Drugs can exert major effects on the developing central nervous system (CNS). In the broadest sense, drugs may disturb specific developmental events in the brain and, in turn, produce teratogenic effects. In addition, maternal ingestion of certain drugs
can result in passive addiction of the fetus, and postnatally lead to a neonatal withdrawal or abstinence syndrome.
Evidence suggests that prenatal exposure to both licit and illicit drugs can have short-term and long-lasting effects on the structure and function of the developing CNS. These effects vary in severity, from profound effects on morphological structure to more subtle, but nonetheless clinically significant, neurological effects. Some of the latter may include a striking neonatal abstinence syndrome (NAS) or include a range of neonatal neurobehavioral difficulties. Multiple systems are often affected spanning cognition, motor function, language, and behavior.
45
The effects of opioids on babies
* From opiates and heroin to methadone, hydrocodone and oxycodone
* Neonatal Abstinence Syndrome (NAS) is a group of conditions caused when a baby withdraws from certain drugs he's exposed to in the womb before birth. NAS is most often caused when a woman takes opioids during pregnancy.
* CDC and March of Dimes, reported that children born with NAS were more likely to have educational disability, developmental delay or speech or language impairment in
early childhood, compared to children born without NAS.
46
Foetal Alcohol Syndrome
* Reduced foetal growth
* Microcephaly
* Mental retardation
Head grows because the brain grows. Microcephaly (smaller head size) can occur because a brain has not developed properly during pregnancy or after birth.
47
Methotrexate
Methotrexate is in a class of medications called antimetabolites. It treats cancer by slowing the growth of cancer cells. It also treats psoriasis (a skin condition) by slowing the growth of skin cells to stop scales from forming.
Methotrexate use results in a decreased supply of folates. Folic acid is usually co-administered to minimize the adverse effects of folate deficiency.
Methotrexate prescribing errors can be fatal; if an error occurs and it is taken as a daily dose rather than a once weekly dose it can be fatal.
Methotrexate used in early pregnancy can cause miscarriage and/or serious birth
defects in the baby, and can affect the baby's growth in the womb. The risk of poor pregnancy outcomes is greater with high doses of methotrexate.
48
Phenytoin
Phenytoin is a medicine used to treat epilepsy. Seizures are bursts of electrical activity in the brain that temporarily affect how it works. Phenytoin slows down these electrical signals to stop seizures
Fetal hydantoin syndrome is a characteristic pattern of mental and physical birth defects that results from maternal use of the anti-seizure drug phenytoin during pregnancy.
* Growth and mental retardation
* Microcephaly
* Craniofacial abnormalities (deformities that affect a child's head and facial bones)
49
Tetracycline
Tetracyclines (tetracycline, doxycycline, minocycline, tigecycline) are a class of medication used to manage and treat various
bacterial infections.
Tetracyclines are contraindicated in pregnancy because of the risk of hepatotoxicity in the mother, the potential for permanent discoloration of teeth in the fetus (yellow or brown in appearance), as well as impairment of fetal long bone growth.
* Diminished growth of long bones
* Permanent teeth staining
50
Thalidomide
In the 1950s and 1960s, thalidomide was used to treat morning sickness during pregnancy. But it was found to cause disabilities in the babies born to those taking the drug. Now, decades later, thalidomide (Thalomid) is being used to treat a skin condition and cancer.
* Phocomelia / Amelia
It is capable of inducing oxidative stress to
reactive oxygen species (ROS) dependent
signaling pathways in the apical ectodermal
ridge (AER), responsible for limb bud growth,
as well as in the zone of polarizing activity
(ZPA), responsible for the establishment of
the anterior-posterior axis in the limb bud.
51
viruses
Many viruses can be transmitted to the
fetus and cause infection and tissue
damage.
Five viruses are known to be teratogenic
in humans: cytomegalovirus, rubella,
herpes simplex, Venezuelan equine
encephalitis, and varicella viruses.
Rubella is one of the more teratogenic
viruses.
52
Bacterial infections
* Bacterial infections can affect pregnant
women from implantation of the fertilized
ovum through the time of delivery and
peripartum period. They may also affect the
fetus and newborn. Many women with these
infections are asymptomatic, necessitating
both a high degree of clinical awareness and
adequate screening.
* Syphilis and Tuberculosi
Approximately 40% of babies born to women with untreated syphilis can be stillborn or die from the infection as a newborn. Babies born with congenital syphilis can have bone
damage, severe anemia, enlarged liver and spleen, jaundice, nerve problems causing blindness or deafness, meningitis, or
skin rashes.
53
Toxoplasmosis
* Toxoplasmosis is an infection with a parasite called Toxoplasma gondii. People often get the infection from eating undercooked meat. You can also get it from contact with cat
feces. The parasite can pass to a baby during pregnancy. Most people infected with the parasite do not have symptoms.
* People are also likely to get toxoplasmosis from eating raw meat or from gardening.
* Infection is more common in pets that go outside, hunt, or are fed raw meat.15-40% of cats have been infected with Toxoplasma at some point.
* In the UK it is thought that 20-30% of the UK population may have antibodies (markers in the blood which show exposure to a specific infection) to toxoplasma in their blood. Only if you get toxoplasmosis for the first time while you're pregnant, or a few months before you conceive, it will be risky.
Fever, hydrocephalus or microcephaly, hepatosplenomegaly, jaundice, convulsions,
chorioretinitis (often bilateral), cerebral calcifications, and abnormal cerebrospinal
fluid are the classic features of severe congenital toxoplasmosis.
If you have had toxoplasmosis in in the past, the parasite remains in your body in an inactive state. As long as it is inactive, and your immune system is healthy, you will not be at risk of passing the infection on to your baby in a future pregnancy.
54
Toxic Metals
Teratogenicity of many metal compounds
such as aluminum, cadmium, chromium,
indium, nickel, platinum, tellurium, thallium, ytterbium and zinc salts has been confirmed in experimental animals.
Some metalloids (e.g., arsenic, selenium
and lithium) appear to have teratogenic
potential for humans.
Lead
* Spontaneous abortion
* Stillbirth
* Minor malformations
* Haemangiomas
* Lymphangiomas
Mercury
* Severe brain damage
If a pregnant woman is exposed to lead, the
lead in her blood can easily cross the placenta
to the fetus. High lead blood levels during
pregnancy increase the risk of miscarriage and can make the baby be born early or at a low birth weight. Even low levels of lead in a child can cause behavior and learning problems.
55
Chemical Exposures
Polychlorinated Biphenyls (PCBs)
* Their use in production has been illegal and banned in the US
in 1979, in the UK in 1981 and in the rest of the EU in 1987.
* PCBs are known to have a teratogenic
effect on animals and humans.
* Discolouration
* Low birthweight
Toluene
* A number of case reports describe
neonatal effects that have been
attributed to toluene abuse during
pregnancy.
* Growth deficiency
* Microcephaly
(head is much smaller than expected)
* Anencephaly
(born without parts of the brain and skull)
* Cardiac / limb defects
* Craniofacial abnormalities similar to FAS
56
Ionising Radiation
Radiation is a common and a well-known physical teratogen. It was only after the Hiroshima and Nagasaki disasters that the fetal effects of radiation drew attention. The effect on the fetus is often based on
animal studies and the data from survivors of the atomic bombings. The commonly teratogenic effects of exposure to high dose radiation are the central nervous system changes. The risk of microcephaly and
the severe mental retardation with high exposure begins at 10 weeks of gestation.
* Loss of organ / tissue functioning
* Pregnancy loss
* Congenital malformations
* Neurobehavioral abnormalities
* Foetal growth restriction
* Development of malignant cells - carcinogens
57
False Hellebore
Veratrum californicum, commonly known as false hellebore, contains a teratogenic alkaloid (cyclopamine) that is responsible for a number of congenital defects in lambs,
depending on the stage of gestation at which they are consumed.
Ovine Cyclopia (one eye)
Jervanine alkaloids
* Cyclopamine
* Cycloposine
* Jervine
