Riview Of Litarature

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 “rejoins” 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 A chromosomal inversion that does not include the centromere.

15

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.