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 11
In 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.