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Review of literature

Toxic chemicals can cause genetic damage. The genetic material of a cell consists of
genes, which exist in chromosomes. Genes and chromosomes contain the information
that tells the cell how to function and how to reproduce (form new cells).

Some chemicals may change or damage the genes or chromosomes. This kind of change,
or damage in a cell is called a mutation. Anything that causes a mutation is called a
mutagen. Mutations may affect the way the cell functions or reproduces. The mutations
can also be passed on to new cells that are formed from the damaged cell. This can lead
to groups of cells that do not function or reproduce the same way the original cell did
before the mutation occurred.

Some kinds of mutation result in cancer. Most chemicals that cause cancer also cause
mutations. However, not all chemicals that cause mutations cause cancer.

Tests for the ability of a chemical to cause a mutation take little time and are relatively
easy to perform. If testing shows a chemical to be a mutagen, additional testing must be
done to determine whether or not the chemical also causes cancer.
Exposure to chemical substances may affect your children or your ability to have
children. Toxic reproductive effects include the inability to conceive children (infertility
or sterility), lowered sex drive, menstrual disturbances, spontaneous abortions
(miscarriages), stillbirths, and defects in children that are apparent at birth or later in the
child’s development.

Teratogens are chemicals which cause malformations or birth defects by directly


damaging tissues in the fetus developing in the mother’s womb. Other chemicals that
harm the fetus are called fetotoxins. If a chemical causes health problems in the pregnant
woman herself, the fetus may also be affected. Certain chemicals can damage the male
reproductive system, resulting in sterility, infertility, or abnormal sperm.

There is not enough information on the reproductive toxicity of most chemicals. Most
chemicals have not been tested for reproductive effects in animals. It is difficult to predict
risk in humans using animal data. There may be “safe” levels of exposure to chemicals
that affect the reproductive system. However, trying to determine a “safe” level is very
difficult, if not impossible. It is even more difficult to study reproductive effects in
humans than it is to study cancer. At this time, only a few industrial chemicals are known
to cause birth defects or other reproductive effects in humans.1
CHROMOSOMAL ABBERATION

INTRODUCTION
Chromosomes are the organized form of DNA found in cells. Chromosomes contain one
very long, continuous piece of DNA, which contains many genes, regulatory elements
and other intervening nucleotide sequences. A broader definition of "chromosome" also
includes the DNA-bound proteins which serve to package and manage the DNA. The
word chromosome comes from the Greek (chroma, color) and (soma, body) due to their
property of being stained very strongly with vital and supravital dyes. 2,3

chromosome abnormality reflects an abnormality of chromosome number or structure.


Chromosome abnormalities usually occur when there is an error in cell division following
meiosis or mitosis. There are many types of chromosome abnormalities.
Visible changes to chromosome structure and morphology have played a very important
part as indicators of genetic damage in both clinical and cancer studies.Most of the
changes encountered in clinical studies are “secondary” or “derived” aberrations. This is
true also in cancer studies, except that here, there is an ongoing production of aberrations,
so that in some cells, a mixture of primary and secondary changes is present, and a
continuously changing karyotype (true chromosomal instability).To appreciate these
observed secondary changes we need to understand the primary changes from which they
are derive.4

CLASSIFICATION OF PRIMARY CHANGES

A chromosome abnormality reflects an abnormality of chromosome number or structure.


There are many types of chromosome abnormalities. However, they can be organized into
two basic groups:
Numerical Abnormalities:

When an individual is missing either a chromosome from a pair (monosomy) or has more
than two chromosomes of a pair (trisomy). An example of a condition caused by
numerical abnormalities is Down Syndrome, also known as Trisomy 21 (an individual
with Down Syndrome has three copies of chromosome 21, rather than two). Turner
Syndrome is an example of monosomy, where the individual - in this case a female - is
born with only one sex chromosome, an X.

Structural Abnormalities:

When the chromosome's structure is altered. This can take several forms:

• Deletions: A portion of the chromosome is missing or deleted.

• Duplications: A portion of the chromosome is duplicated, resulting in extra


genetic material.

• Translocations: When a portion of one chromosome is transferred to another


chromosome. There are two main types of translocations. In a reciprocal
translocation, segments from two different chromosomes have been exchanged. In
a Robertsonian translocation, an entire chromosome has attached to another at the
centromere.

• Inversions: A portion of the chromosome has broken off, turned upside down and
reattached, therefore the genetic material is inverted.

• Rings: A portion of a chromosome has broken off and formed a circle or ring.
This can happen with or without loss of genetic material.

Most chromosome abnormalities occur as an accident in the egg or sperm. Therefore, the
abnormality is present in every cell of the body. Some abnormalities, however, can
happen after conception, resulting in mosaicism, where some cells have the abnormality
and some do not.

Chromosome abnormalities can be inherited from a parent (such as a translocation) or be


"de novo" (new to the individual). This is why chromosome studies are often performed
on parents when a child is found to have an abnormality.5

For purely pragmatic and diagrammatic purposes, we can regard the chromosomal
changes we see down the microscope as being the result of “breaks” followed by “re-
joins” of the chromosome thread. However, we must always remember that, in reality,
their origin is much more complicated
Since the chromosome we see and score at metaphase has two (sister-) chromatids, it is
convenient (and conventional) to divide all aberrations into two broad types:

Chromosome-type where the breaks and re-joins always affect both sister-chromatids at
any one locus. Examples in Figure 1.

Chromatid-type where the breaks and re-joins affect only one of the sister-chromatids at
any one locus (Fig 2
• If the breaks are situated in the arms of different (non-homologous or homologous)
chromosomes we have the category of INTERCHANGES.
• If the breaks are in the opposite arms of the same chromosome, we have the category
of INTER-ARM INTRACHANGES.
• If the two breaks are both in the same arm of a chromosome, we have the category of
INTRA-ARM INTRACHANGES.
These three categories are often referred to collectively as EXCHANGES.

• Finally, some aberrations appear to arise from a single, open break in just one arm.
This category we term “BREAKS” or “DISCONTINUITIES”. Many (perhaps all) of
them are, in reality, intra-arm intrachanges where one end has failed to join up
properly, though the limitations of microscopical resolution do not permit us to be
certain that the re-joining is really incomplete.5,6

Interaction between the four ends of two breaks can obviously take place in three
ways :

 Join back to re-form the original chromosomes (“RESTITUTION”) so that no


aberration is produced
 Re-join in such a way that an acentric fragment is always formed
(ASYMMETRICAL RE-JOINING)
 Re-join in a way that never leads to an acentric fragment unless one of the re-joins
is incomplete (SYMMETRICAL RE-JOINING)6

RELEATIONSHIP WITH CELL CYCLE

Conventionally, the period between successive mitoses (“INTERPHASE”) is sub-divided


into three phases G1, S and G2 . For critical work, further sub-division of S is possible.
G1 is the pre-duplication period, when the cell begins to prepare for DNA synthesis and
the next mitosis. If the cell is not going to divide again, it passes out of cycle during this
phase into another phase termed G0. From this phase it may, or may not, be possible to
call it back into a division cycle. Usually, however, cells pass on to irreversible
differentiation with their chromosomes unduplicated.

S-phase is a discrete period of interphase of a few hours duration during which the
chromosomal DNA and protein is duplicated, and the new chromatin segregated into the
sister-chromatids. Each chromosome has a precise programme of replication, closely
associated with its G-band pattern.

Pale G-bands always replicate early in S-phase, dark G-bands later, and constitutive
heterochromatin tends to be among the very last regions to replicate.

During G2 , the newly replicated chromosomes undergo a rapid programme of


condensation, packing and coiling to produce the familiar metaphase chromosomes
where we normally identify and score aberrations. These condensed chromosomes
facilitate transport of the genetic material to the daughter cells at mitosis. This
condensation and packing readily obscures, modifies and disguises aberrations which are
produced during interphase - a point that should always be borne in mind when
interpreting what we see down the microscope.7,8,9

Most aberration-inducing agents can introduce lesions into the chromatin at all stages of
the cell cycle, but relatively few of them can produce actual structural changes in G1,(
and therefore give rise to primary chromosome-type changes) or in S and G2 (producing
primary chromatid-types,cobalt60 causes chromosome types of changes 10

Ionising radiation, restriction endonucleases, and a few chemicals like bleomycin and
some antibiotics are amongst those that can.

Almost all remaining aberration producing agents are “S-dependent”; surviving


unrepaired lesions from G1 or G2 have to pass through a scheduled S-phase to convert
them into exclusively chromatid-type aberrations.

Any interference with or abnormality in the processes of chromatin replication also leads
to chromatid-type aberrations visible at next mitosis. It is almost certain that the vast
majority of “spontaneous” and de novo aberrations arise in this way. Chromosome
instability syndromes also probably produce aberrations via defective S-phase pathways.
However they are produced, the resulting chromatid-type aberrations are qualitatively
(but not quantitatively) identical

RECIPROCAL TRANSLOCATION
Reciprocal translocations (rcp) are among the most common constitutional chromosomal
aberrations in man. 11In a reciprocal translocation there is a mutual exchange of
chromosomal segments between two different chromosomes. This exchange can take
place between any two chromosomes and at various sites along the length of the
chromosome.12

PERICENTRIC INVERSION
An inversion in which the breakpoints occur on both arms of a chromosome. The inverted
segment spans the centromere.13 Pericentric inversion in chromosome 7 may play a role
in the etiology of the family's miscarriages 14

PARACENTRIC INVERSION
15
A chromosomal inversion that does not include the centromere. Very difficult to detect
at the chromosome level unless they are very large (many megabases of DNA). Again the
re-joining points can disrupt important genetic sequences, and reverse segments of the
reading frame. Large inversions will give problems at meiosis.

INTERSTITIAL DELETION
Deletion that does not involve the terminal parts of a chromosome called interstitial
deletion.16 A case of autism with an interstitial deletion on 4q leading to hemizygosity for
genes encoding for glutamine and glycine neurotransmitter receptor sub-units and
neuropeptide receptors 17

TERMINAL DELETION

Deletion is the loss of genetic material. . Terminal Deletion - a deletion that occurs
towards the end of a chromosome. Cryptic terminal deletion of chromosome 9q34 a novel
cause of syndromic obesity in childhood 18
Structural chromosome instability
An elevated frequency of structural chromosome aberrations could be directly caused by
an abnormally high incidence of DNA double-strand breaks. Chromosomal breakage can
result in a number of different structural rearrangements, some of which give rise to
abnormalities of chromosomal segregation at mitosis. For example, terminal deletions
due to a break of a single chromatid will result in a centric derivate chromosome plus an
acentric fragment. Because of its failure to bind the mitotic spindle, the fragment may be
permanently lost in the subsequent cell division, and may be seen as a lagging chromatin
body at metaphase or anaphase. Such lagging is a common finding in cell populations
exposed to ionising radiation .It has also been described in a number of solid tumours,
such as head and neck, and breast carcinomas .

Chromosomal instability is a common feature of cancer cells. Several cellular


mechanisms lead to numerical and structural chromosomal instability in cancer cells,
including defects in chromosomal segregation, cellular checkpoints that guard against
reproduction of abnormal cells, telomere stability, and the DNA damage response.
Human papillomavirus interferes with these processes, causing chromosomal instability
and tumor formation in some of the epithelial cells which it infects. The rate of
discoveries about the mechanisms leading to chromosomal instability in cancer cells is
increasing rapidly. Although these mechanisms were thought to be unrelated, they are
intimately intertwined, connecting the complex network of cellular pathways. Since
chromosomal instability is undoubtedly a major cause of tumor evasion of therapy,
understanding the mechanisms leading to chromosomal instability has major translational
significance. 19

THE BFB CYCLE — A CHAIN REACTION OF CHROMOSOMAL BREAKAGE


Concurrent breaks in two different chromosomes may either give rise to translocations or
dicentrics. Whereas translocation derivatives are stably transmitted through cell division,
the dicentric chromosomes may be stretched out between the spindle poles to form
bridges at anaphase (Figure 1A). These bridges may subsequently break, and the
chromosomes are transmitted to the daughter cells with broken ends that may recombine
further during the subsequent interphase. Similarly, ring chromosomes having undergone
sister chromatid exchange, may be stretched out at anaphase, break, and then be
transmitted to the daughter cells as broken chromosomes (Figure 1B; ) The broken
chromosome ends may fuse into novel dicentrics and rings, which may again break at the
next cell division. Thus, chromosomal damage may not only result in static aberrations,
such as translocations, inversions, deletions, and duplications; it may also result in
mitotically unstable chromosomes, which may trigger a series of breakage-fusion-bridge
(BFB) events. Such BFB cycles have been shown to occur in many malignant solid
tumours with complex chromosome abnormalities, including head and neck, pancreatic,
and ovarian carcinomas, as well as leiomyosarcoma, osteosarcoma, malignant fibrous
histiocytoma, and atypical lipomatous tumours.Data from in vitro and animal studies
indicate that the BFB cycles may be initiated by shortening of telomeric repeat
sequences, leading to impaired integrity of chromosome termini and telomeric
associations between chromosomes . It is probable that similar mechanisms are
responsible for the high frequency of BFB instability in human.

Figure 1 Chromosome breakage-fusion-bridge (BFB) cycles: Dicentric (A) and ring (B)
chromosomes may form bridges at anaphase and the broken ends of the two chromatids
(red and white) may fuse into novel dicentric and ring-shaped structures in the daughter
cells.
Different mechanisms or steps in a single process

In most tumours exhibiting chromosomal instability, BFB events and centrosomal


abnormalities occur together. In analogy, most malignant tumours exhibit both structural
and numerical chromosome abnormalities. However, in many low-grade mesenchymal
and neuroglial tumours, BFB events involving telomeric associations and ring
chromosomes are seen at mitosis, in the absence of major numerical. However, at
progression of these tumours towards higher malignancy, numerical aberrations as well as
highly complex structural aberrations become more frequent. This implies a sequence of
parallel cytogenetic and molecular steps, where telomeric dysfunction and BFB events
occur at an early stage, and numerical instability develops later. First, a continued
proliferation of cells with reduced telomere length requires an inhibition of cell cycle
control mechanisms. In vitro, this may be induced by partial inhibition of normal TP53
and RB1 function, for instance by SV40 transfection. The corresponding in vivo changes
remain to be elucidated, although recent findings indicate that some cell types, such as
human mammary epithelial cells, may spontaneously proliferate beyond the normal
telomere length and acquire chromosomal changes such as dicentrics and rings. Further
survival of cell populations with disrupted telomeric integrity, resulting in frequent BFB
events, would require additional impairment or total abrogation of the systems normally
causing arrest or apoptosis in cells with double-strand DNA breaks. This step appears to
be associated with inactivating mutations in TP53 or high-level amplification of MDM2.
Also, the numerical chromosome instability associated with abnormal centrosome
function indicates that highly malignant cells have acquired some tolerance to massive
genomic imbalances
Figure2

Hypothetical scenario of progressive mitotic instability: Telomere shortening, seen as


absence of detectable TTAGGG repeats (top image) may compromise the integrity of
chromosome ends, leading to the formation of rings and dicentrics. These may form
bridges at anaphase, which either breaks and initiate a series of BFB-events, or induce
cytokinetic failure leading to the formation of binucleate cells with supernumerary
centrosomes. Cells with an abnormal centrosome number may form multipolar mitoses at
the next cell division. Thus, telomeric dysfunction may result both in structural and
numerical chromosome instability.

The common concurrence of BFB instability and centrosome abnormalities suggests that
these phenomena are mechanistically linked. Although it is true that both these
instabilities may be associated with similar molecular genetic lesions, such as TP53
mutation, their causal relationship, if any, remains unclear. There may be one rather
straightforward relationship, however. It is well established that anaphase bridging may
cause collapse of the cytokinetic process, leading to formation of cells with a duplicated
genome . Tumours with BFB events show a high frequency of binucleated cells . These
cells would not only carry the double amount of genetic material, but also twice the
normal number of centrosomes. After the next round of replication, such cells may thus
enter mitosis with abnormal centrosome configurations, leading to either tri- or tetrapolar
cell divisions (Figure 2). Incomplete cytokinesis could then easily explain the connection
between telomere shortening and BFB events, on one hand, and mitotic multipolarity, on
the other hand. 20

GENETIC DISORDER

A genetic disorder is a disease that is caused by an abnormality in an individual's DNA.


Abnormalities can range from a small mutation in a single gene to the addition or
subtraction of an entire chromosome or set of chromosomes.21
SINGLE GENE DISORDER

Over 10 000 human diseases are caused by defects in single genes. These single gene
disorders, which are also described as unifactorial or monogenic diseases, are
individually very rare but they affect about 1 per cent of the population as a whole. Since
only a single gene is involved in each case, these diseases generally have simple
inheritance patterns in family pedigrees. This means they can be traced through families
and their occurrence in later generations can be predicted (see Genetic counselling ). The
defective version of the gene responsible for the disease is known as a mutant allele or a
disease allele. Single gene disorders can be divided into a number of different categories
according to how they are transmitted from generation to generation. Some are described
as dominant diseases because only one mutant allele is required, and such diseases tend
to crop up in every generation. Other diseases are described as recessive because both
copies of the gene must be defective in order for the disease to occur. These recessive
diseases often skip generations because mutant alleles can be carried without any effect if
a normal allele is also present. Many single gene disorders affect both sexes equally.
However, where the relevant gene is present on the X-chromosome, the associated
disease tends to be more common in males 22

AUTOSOMAL DOMINANT

Only one mutated copy of the gene is needed for a person to be affected by an autosomal
dominant disorder. Each affected person usually has one affected parent. There is a 50%
chance that a child will inherit the mutated gene. Common example of autosomal
dominant disorders includes Huntingtons disease, Neurofibromatosis 1, Marfan
Syndrome. Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal
dominant disease, characterized by the occurrence of predominantly colon and
endometrial cancer and, less frequently, cancer of the small bowel, stomach,
hepatobiliary tract, ureter, renal pelvis, ovaries and brain23
AUTOSOMAL RECESSIVE

Two copies of the gene must be mutated for a person to be affected by an autosomal
recessive disorder. An affected person usually has unaffected parents who each carry a
single copy of the mutated gene (and are referred to as carriers) common autosomal
recessive disorder includes Cystic fibrosis, Sickle cell anemia(Also Partial Sickle Cell
Anemia), Tay-Sachs disease, Spinal muscular atrophy. A recent study proved that
Parkinson's disease (PD) is a movement disorder of high prevalence in the elderly. It is
characte-rized by a loss of dopaminergic neurons and the presence of intracytoplasmic
inclusions named Lewy bodies. To date six familial PD-associated proteins have been
identified so far. Some of them are implicated in the development of either autosomal
dominant (alpha-synuclein and LRRK2 (leucine-rich repeat kinase 2/dardarin) or early-
onset recessive (parkin, DJ-1, PINK1 (PTEN-induced kinase-1) and ATP13A2) PD
forms. A number of genetic studies have shown that 50% of the recessive forms are
linked to mutations on parkin gene,24

X-LINKED DOMINANT TRAIT

X-linked dominant disorders are caused by mutations in genes on the X chromosome.


Only a few disorders have this inheritance pattern. Males are more frequently affected
than females. Eg Hypophosphatemia, Aicardi Syndrome, Chokenflok Syndrome

Y-LINKED

Y-linked disorders are caused by mutations on the Y chromosome. Only males can get
them, and all of the sons of an affected father are affected. Since the Y chromosome is
very small, Y-linked disorders only cause infertility, and may be circumvented with the
help of some fertility treatments. E.g. male infertilty

Multifactorial and polygenic disorders

Genetic disorders may also be complex, multifactorial or polygenic, this means that they
are likely associated with the effects of multiple genes in combination with lifestyle and
environmental factors. Multifactoral disorders include heart disease and diabetes.
Although complex disorders often cluster in families, they do not have a clear-cut pattern
of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing
on these disorders. Complex disorders are also difficult to study and treat because the
specific factors that cause most of these disorders have not yet been identified.

On a pedigree, polygenic diseases do tend to “run in families”, but the inheritance does
not fit simple patterns as with Mendelian diseases. But this does not mean that the genes
cannot eventually be located and studied. There is also a strong environmental component
to many of them (e.g., blood pressure).

• autism
• heart disease
• hypertension
• diabetes
• obesity
• cancers
• cleft palate
• Mental retardation 25

MUTAGEN

mutagen is a substance or agent that causes an increase in the rate of change in genes
(subsections of the DNA of the body's cells). These mutations (changes) can be passed
along as the cell reproduces, sometimes leading to defective cells or cancer.
Examples of mutagens include certain biological and chemical agents as well exposure to
ultraviolet light or ionizing radiation.Mutagenesis is the formation of mutations.
There are many types of mutations, some of which are harmful and others which have
little or no effect on the body's function..

The problem of medication safety came to public attention largely through a


chemotherapy error and the high toxicity and low therapeutic index of anticancer
medications make safety in their prescription and administration critical. The anti cancer
drugs are known to be mutagenic, teratogenic and carcinogenic therefore all efforts must
be done to reduce accidents from cancer chemotherapy and to implement safe
chemotherapy practices.26
ANTIMUTAGENIC HERBS

Terminalia arjuna is an important medicinal plants widely used in the preparation of


Ayurvedic formulations proved to have antimutagenic potential 27

Curcumin (diferuloymethane), a yellow colouring agent present in the rhizome of


Curcuma longa Linn (Zingiberaceae), has been reported to possess anti-inflammatory,
antioxidant, antimutagenic and anticarcinogenic activities. Curcumin exerts its
chemoprotective and chemopreventive effects via multiple mechanisms 28

Mutagenic and antimutagenic properties of essential oil (EO) of basil and its major
constituent Linalool, reported to possess antioxidative properties 29

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a major pungent ingredient of red


pepper, is reported to have antimutagenic and anticarcinogenic properties.30

Mucuna collettii Lace is a Thai herb with a long record of consumption among mature
Thai males for the promotion of sexual potency proved to have antimutagenic potential.31

Anacardium occidentale L. species, popularly known as the cashew, which has several
therapeutic indications, such as cicatrizing, antihypertensive, hypoglycemic and
antitumoral properties proved to have antimutagenic activity.32

The major food items of Indian cuisine include rice, wheat, diary products, and abundant
fruits and vegetables. Beside these, there are several kinds of herbs and spices as
important ingredients, containing many phytochemicals with medicinal properties, adding
taste to Indian cuisine. An impressive body of data exists in support of the concept that
Indian food ingredients can be used in preventive strategies aimed at reducing the
incidence and mortality of different types of cancers because of their antioxidative,
antimutagenic and anticarcinogenic properties 33

Antioxidant

An Antioxidant is a molecule capable of slowing or preventing the oxidation of other


molecules. Oxidation is a chemical reaction that transfers electrons from a substance to
an oxidizing agent. Oxidation reactions can produce free radicals, which start chain
reactions that damage cells. Antioxidants terminate these chain reactions by removing
free radical intermediates, and inhibit other oxidation reactions by being oxidized
themselves. As a result, antioxidants are often reducing agents such as thiols or
polyphenols.34

Although oxidation reactions are crucial for life, they can also be damaging; hence, plants
and animals maintain complex systems of multiple types of antioxidants, such as
glutathione, vitamin C, and vitamin E as well as enzymes such as catalase, superoxide
dismutase and various peroxidases. Low levels of antioxidants, or inhibition of the
antioxidant enzymes, causes oxidative stress and may damage or kill cells.

As oxidative stress has been associated with the pathogenesis of many human diseases,
the use of antioxidants in pharmacology is intensively studied, particularly as treatments
for stroke and neurodegenerative diseases. However, it is unknown whether oxidative
stress is the cause or the consequence of such diseases. Antioxidants are also widely used
as ingredients in dietary supplements in the hope of maintaining health and preventing
diseases such as cancer and coronary heart disease. Although some studies have
suggested antioxidant supplements have health benefits, other large clinical trials did not
detect any benefit for the formulations tested, and excess supplementation may
occasionally be harmful. In addition to these uses in medicine, antioxidants have many
industrial uses, such as preservatives in food and cosmetics and preventing the
degradation of rubber and gasoline

Reduced levels of antioxidants such as carotenoids and vitamins A and E can increase
DNA damage caused by free radicals. Exposure to radiation has been proposed to reduce
levels of antioxidants that are used for DNA repair and this reduction may be responsible
for increased levels of mutation in radioactively contaminated areas.