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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

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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

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 derived, and it is the purpose of this article to provide a
brief introduction to them.2,3

CLASSIFICATION OF PRIMARY CHANGES

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 4,5

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:

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

Figure 1

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Chromatid-type where the breaks and re-joins affect only one of the sister-chromatids at
any one locus (Fig 2).

The distinction is important. For some aberration-inducing agents, like ionizing radiation,
the type of aberration recovered at metaphase reflects the duplication status of the
chromosomes in the treated cell. But, for the majority of chemical agents which can
induce aberrations, for ultra-violet light, and most probably all “spontaneous” (and de
novo aberrations) only primary chromatid-types are recovered. When, at subsequent
interphase, the chromatids duplicate, surviving aberrations (and bits of aberrations) are
converted into apparent chromosome-types, some of which are then transmitted almost
indefinitely to further cell generations. These are the “derived” aberrations, and many are
so modified that it is impossible to deduce their primary origin.

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Thus, following an “acute” treatment with any clastogen, surviving cells in later
generations carry only chromosome-type changes. The presence in such cells of
chromatid-type aberrations is, therefore, an indicator of an ongoing production of primary
structural changes, i.e. of some form of chromosome instability.

Nearly all the aberrations we see with solid staining appear to result from the interaction
(“re-joining”) of two breaks, so we can further classify them on the basis of where these
breaks are situated in relation to the chromosome arms

• 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.

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)

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Many such chromosome-type exchanges are not visible with solid-staining, and their
accurate detection requires special techniques like banding or FISH-painting. In
contrast, most symmetrical chromatid-type exchanges are visible with solid staining
because of the retention of sister-chromatid adherence until metaphase. Because there
is no loss of genetic material, and no mechanical problems at mitosis, most
symmetrical forms are transmissible to future cell generations, hence they constitute
the bulk of the recovered “derived” aberrations encountered in clinical and cancer
cytogenetics.
As mentioned, re-joining can sometimes be (apparently) INCOMPLETE. This is
much more frequent for chromatid-type aberrations (typically 30-50% of interchanges)
than it is for chromosome-type aberrations (difficult to measure accurately, but probably
around 3-5%). Incompleteness leads to genetic loss, and so to increased cell lethality.

The four basic categories discussed above are seen in their simplest forms for
chromosome-type aberrations, as shown in Figure 1. Traditionally, certain forms have
specific names, as indicated. Symmetrical forms are seldom visible with solid staining
(probably less than 20% of reciprocal translocations lead to an obvious change in
chromosome morphology)
Because sister-chromatids tend to adhere, strongly, along their lengths, many chromatid-
type symmetrical forms remain visible without recourse to special staining methods

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

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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.

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 ).

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.

Meaningful quantitative work with chromatid-types is extremely difficult because

observed frequencies fluctuate with time of sample after treatment, and are subject to
dramatic modifications as the result of mitotic perturbation and differential cell selection.

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This makes comparison between different treatments, or the production of sensible dose-
response curves, virtually impossible .

ABERRATION TRANSMISSION AND STABILITY

Although there is an enormous range of primary aberration forms, very few of them are
transmissible to future cell generations long term, so only a handful of secondary ( or
“derived” ) forms are recovered .

The following paragraphs list the kinds most likely to be encountered, together with
comments and a note about probable primary origin.

RECIPROCAL TRANSLOCATION

Involves no mechanical separation problems at anaphase, and usually no genetic loss or

imbalance. Problems can occur at meiosis because of multivalent formation, and degrees
of sterility may arise.

At the molecular level, the re-joining points can disrupt important genetic sequences,
leading to inactivation, mutation or position effects (e.g. the t(9;22) Ph1 chromosome of
CML).

Derived directly from chromosome-type reciprocal translocations or from one segregation

sequence of symmetrical chromatid-type interchanges. (Note that the alternative
interchange segregation leads to imbalance and cell lethality).

PERICENTRIC INVERSION
Very similar properties to those for reciprocal translocations given above. Large
inversions lead to meiotic bridges, sterility and cell death.

Derived directly from chromosome-type or chromatid-type pericentric inversions.

PARACENTRIC INVERSION
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,

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and reverse segments of the reading frame. Large inversions will give problems at
meiosis.

Derived directly from chromosome-type paracentric inversions, or from one form of

chromatid-type intra-chromatid intra-arm interchange.

INTERSTITIAL DELETION
The loss of small segments of a chromosome (usually in only one homologue) is not
uncommon. Many mutations that have been genetically sequenced have been shown to be
actually small deletions.

Very occasionally, the loss of quite large segments appears to be compatible with cell
survival.

Derived directly from chromosome-type interstitial deletions (“double minutes”) and

from the alternative form of chromatid-type intra-chromatid intra-arm intrachange to that
which produces paracentric inversions. Segregation products from some complex
chromatid-type interchanges can also carry deletions.

TERMINAL DELETION :
It is now questionable whether true stable terminal deletions actually exist. All those that
have been investigated using the new fluorescent telomere probes are found to be
“capped” by telomere sequences. This either means that they are disguised interstitial
deletions, where one re-join point was almost terminal, or that survival has been rendered
possible by de novo telomere synthesis. The recent development of end-specific telomere
probes should be able to solve this question .

Derivation, if genuine, from various forms of incomplete chromosome-type or chromatid-

type intrachanges and interchanges, followed by telomerase activity to achieve capping.

INTERSTITIAL DUPLICATION :
Segments of a chromosome repeated in tandem, sometimes in reverse sequence. This
may not necessarily arise from a pre-existing structural aberration, segment amplification
and re-duplication is a well attested phenomenon under certain conditions (e.g. HSR

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regions following chronic methotrexate exposure). Nevertheless, there are primary

aberrations which can survive as segmental duplication.

Most likely derived from one form chromatid-type inter-chromatid intra-arm

intrachanges. Some forms of complex chromatid-type interchanges can segregate to give
surviving chromosomes with duplicated segments.

INTERSTITIAL INSERTION :
Deletion of a segment and its insertion into another chromosome within the same cell is a
fairly common transmitted aberration. Much less common is the insertion of a segment
additional to the two complete homologues within a cell.

All insertions are derived from complex exchanges, since, by definition, their production
requires the interaction of a minimum of 3 lesions. Either chromosome-type or
chromatid-type complex interchanges may be involved, the range of inter-intrachanges in
the latter being particularly productive of insertions.

Occasionally, a surviving dicentric may be found, usually without the related acentric
fragment. Very often, the two centromeres lie very close together, because, under these
circumstances, only one of the centromeres is active, so anaphase bridges do not form.
Likewise, an occasional centric-ring may survive, again usually very small so that “fall-
free” separation always happens. Larger rings are very unstable with respect to size, and
the positive selection pressure towards very small rings soon eliminates the big ones.

Most of the above comments apply to the situation in normal individuals and cells. When
we turn to cancer-derived cells, or to transformed cell lines growing in culture, the
situation is somewhat different. These cells are inherently chromosomally unstable. There
is a continuous production of structural change so that new primary changes are
superimposed on the already existing background of secondary aberrations, and these
new ones, in their turn, become secondary.

Moreover, some of the new changes are being produced in already abnormal
chromosomes, so the observed aberrations are often very complicated and bizarre.

On top of this, it is clear that most cancer cells are very tolerant of chromosomal loss, or
gain, as is evidenced by considerable numerical variations and multiple chromosome

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copies. These facts make cancer cytogenetics a very difficult and uncertain field for
investigation, and considerable credit goes to those workers whose careful and
painstaking efforts have produced meaningful advances.

Mechanisms of chromosomal instability

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 .

In normal cells, DNA lesions are detected and repaired by a sophisticated physiological
machinery. An essential component of this is the BRCA1-associated genome surveillance
complex (BASC), including the BRCA1, BRCA2, MSH2, MSH6, MLH1, ATM, BLM
proteins, as well as the RAD50 - MRE11 - NBS1 complex . So far, germ-line mutations
of BRCA1, BRCA2, MSH2, MLH1, ATM, and BLM have been found to cause inherited
syndromes with an increased tumour incidence . Also, somatic mutations of these genes
occur in sporadic tumours, e.g. MSH2 and MLH1 in colorectal carcinomas . ATM in
lymphomas , and BRCA1 in mammary cancer. Both the Bloom syndrome and ataxia
telangiectasia exhibit an increased level of spontaneous chromosomal aberrations in
somatic cells. Still, the incidence of chromosomal instability far exceeds the frequencies
of somatic ATM and BLM mutations in sporadic cancers, indicating that other
mechanisms are primarily responsible.

Genomic integrity is also under surveillance from a system of cell cycle checkpoints,
preventing cells that have sustained DNA damage from proliferating further. For instance,
double-strand DNA breaks induced by clastogenic agents, such as radiation or reactive

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oxygen species, may lead either to cell cycle arrest or apoptosis by a mechanism
including activation of the TP53 and p21 proteins. Factors involved in this cell cycle
checkpoint system are frequently deregulated or inactivated in tumour cells. Mutations of
TP53 are responsible for the Li-Fraumeni tumour syndrome and also occur at a frequency
of approximately 50% in sporadic malignant tumours. The gene for the TP53-inhibitor
MDM2 is amplified in another 10%-20% of bone and soft tissue tumours. Inactivation of
TP53 in immortalised cells results in a marked instability of chromosome structure,
including translocations, deletions, telomeric associations, and ring chromosomes . A
similar pattern of aberrations is typically seen in pancreatic carcinomas and poorly
differentiated sarcomas with mutations in TP53 or genomic amplification of MDM2.

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.

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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.

Numerical instability
Already at the end of the 19th century, Hansemann observed aberrations of the mitotic
apparatus in malignant tumours, including abnormal mitotic polarity and an unequal
segregation of chromosomes at anaphase. A few decades later, Boveri suggested that
abnormalities in mitotic polarity could be caused by an abnormal number of centrosomes
— the organelles responsible for organisation of the mitotic spindle. Today it is well

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established that many epithelial tumours exhibit an asymmetrical segregation of

chromosomes at the metaphase-anaphase transition, resulting in an aberrant distribution
of the genetic material to the daughter cells .Also, abnormalities in the number and
structure of centrosomes have been observed in malignancies with aneuploid
chromosome numbers, including cancers of the breast, colon, and the head and neck
region. These changes in centrosomal configuration have been correlated with a number
of molecular genetic abnormalities, including amplification of STK15, mutations in TP53,
and inactivation of BRCA1, BRCA2, and GADD45. Abnormal centrosomal function may
also be induced in vitro by expression of the papilloma virus genes E6 and E7, inhibiting
normal TP53 and RB1 activity, respectively. This is particularly interesting since
multipolar mitoses and other manifestations of chromosomal instability are hallmarks of
malignant progression in HPV-related cervical carcinomas. It has also been suggested
that inactivation of genes that control the timing of mitotic chromosome segregation may
contribute to numerical instability. However, only rare examples of such aberrations have
so far been identified.

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 (beyond the Hayflick limit) 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

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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

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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.

GENETIC DISORDER

A genetic disorder is a condition caused by abnormalities in genes or chromosomes.

While some diseases, such as cancer, are due to genetic abnormalities acquired in a few
cells during life, the term “genetic disease” most commonly refers to diseases present in
all cells of the body and present since conception. Some genetic disorders are caused by
chromosomal abnormalities due to errors in meiosis, the process which produces

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reproductive cells such as sperm and eggs. Examples include Down syndrome (extra
chromosome 21), Turner Syndrome (45X0) and Klinefelter’s syndrome (a male with 2 X
chromosomes). Other genetic changes may occur during the production of germ cells by
the parent. One example is the triplet expansion repeat mutations which can cause fragile
X syndrome or Huntington’s disease. Defective genes may also be inherited intact from
the parents. In this case, the genetic disorder is known as a hereditary disease. This can
often happen unexpectedly when two healthy carriers of a defective recessive gene
reproduce, but can also happen when the defective gene is dominant.

Currently around 4,000 genetic disorders are known, with more being discovered. Most
disorders are quite rare and affect one person in every several thousands or millions.
Cystic fibrosis is one of the most common genetic disorders; around 5% of the population
of the United States carry at least one copy of the defective gene. Some types of recessive
gene disorder confer an advantage in the heterozygous state in certain environments.

Genetic diseases are typically diagnosed and treated by geneticists. Genetic counselors
assist the physicians and directly counsel patients. The study of genetic diseases is a
scientific discipline whose theoretical underpinning is based on population genetics.

Single gene disorders

Where genetic disorders are the result of a single mutated gene they can be passed on to
subsequent generations in the ways outlined in the table below. Genomic imprinting and
uniparental disomy, however, may affect inheritance patterns. The divisions between
recessive and dominant are not “hard and fast” although the divisions between autosomal
and X-linked are (related to the position of the gene). For example, achondroplasia is
typically considered a dominant disorder, but young goats or children with two genes for
achondroplasia have a severe skeletal disorder that achondroplasics could be viewed as
carriers of. Sickle-cell anemia is also considered a recessive condition, but carriers that
have it by half along with the normal gene have increased immunity to malaria in early
childhood, which could be described as a related dominant condition.

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Inheritance
Description Examples
pattern
Only one mutated copy of the gene is
needed for a person to be affected by an
autosomal dominant disorder. Each Huntingtons disease,
affected person usually has one affected Neurofibromatosis 1, Marfan
parent. There is a 50% chance that a child Syndrome, Hereditary
Autosomal will inherit the mutated gene. Conditions nonpolyposis colorectal cancer
dominant that are autosomal dominant have low
penetrance, which means that, although Hereditary multiple
only one mutated copy is needed, a exostosesis high penetrance
relatively small proportion of those who autosomal dominant disorder
inherit that mutation go on to develop the
disease, often later in life.
Two copies of the gene must be mutated
for a person to be affected by an
autosomal recessive disorder. An affected
Cystic fibrosis, Sickle cell
person usually has unaffected parents who
anemia, Tay-Sachs disease,
Autosomal each carry a single copy of the mutated
Spinal muscular atrophy, Dry
recessive gene (and are referred to as carriers). Two
(otherwise known as “rice-
unaffected people who each carry one
brand”) earwax[2]
copy of the mutated gene have a 25%
chance with each pregnancy of having a
child affected by the disorder.
X-linked X-linked dominant disorders are caused by Hypophosphatemia, Aicardi
dominant trait mutations in genes on the X chromosome. Syndrome, Chokenflok
Only a few disorders have this inheritance Syndrome
pattern. Males are more frequently
affected than females, and the chance of
passing on an X-linked dominant disorder
differs between men and women. The sons
of a man with an X-linked dominant
disorder will not be affected, and his
daughters will all inherit the condition. A
woman with an X-linked dominant
disorder has a 50% chance of having an
affected daughter or son with each
pregnancy. Some X-linked dominant
conditions, such as Aicardi Syndrome, are
fatal to boys, therefore only girls have
them (and boys with Klinefelter

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Syndrome).
X-linked recessive disorders are also
caused by mutations in genes on the X
chromosome. Males are more frequently
affected than females, and the chance of
passing on the disorder differs between
men and women. The sons of a man with Hemophilia A, Duchenne
X-linked an X-linked recessive disorder will not be muscular dystrophy, Color
recessive affected, and his daughters will carry one blindness, Muscular dystrophy
copy of the mutated gene. With each Androgenetic alopecia
pregnancy, a woman who carries an X-
linked recessive disorder has a 50%
chance of having sons who are affected
and a 50% chance of having daughters
who carry one copy of the mutated gene.
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
Y-linked Male Infertility
chromosome is very small, Y-linked
disorders only cause infertility, and may
be circumvented with the help of some
fertility treatments.
This type of inheritance, also known as
maternal inheritance, applies to genes in
mitochondrial DNA. Because only egg
cells contribute mitochondria to the
Leber’s Hereditary Optic
Mitochondrial developing embryo, only females can pass
Neuropathy (LHON)
on mitochondrial conditions to their
children.

See Human mitochondrial genetics

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

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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

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.

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.

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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.

Antioxidants have a central role in the microevolutionary model of cancer development.

Redox mechanisms occur throughout nature, being widely used for the control of cell
division, differentiation and growth. Their involvement in cancer is not surprising, since
they are of fundamental importance to the basic chemistry of all living organisms.
Numerous genes, enzymes and small molecules are used in controlling the cell, signalling
growth, proliferation and death.

Redox mechanisms play an integral part in all aspects of cancer development. Free
radicals are involved from the start of the process. Throughout its progress, increased free
radical damage and internal oxidation drives the growth of cancer cells. Raised levels of
oxidants initiate cell proliferation and growth. Later, lack of oxygen restricts growth, until
the cancer cells evolve mechanisms to stimulate the formation of blood vessels. The
resulting blood supply allows the tumour to expand rapidly and spread to distant sites in
the body.

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Dietary advice to prevent cancer and slow its early development can be stated succinctly.
A diet to prevent cancer is low in carbohydrates, with a high proportion of antioxidants.
The consumption of a variety of coloured vegetables and fruit in the diet will reduce the
incidence of cancer, because of the antioxidants they contain. Supplementation with a
range of antioxidant vitamins and minerals will also hinder the initiation and
microevolutionary development of cancer.

Naturally occuring antioxident

Vitamins

Vitamin A (Retinol), also synthesized by the body from beta-carotene, protects dark
green, yellow and orange vegetables and fruits from solar radiation damage, and is
thought to play a similar role in the human body. Carrots, squash, broccoli, sweet
potatoes, tomatoes (which gain their color from the compound lycopene), kale,
seabuckthorn, collards, cantaloupe, peaches and apricots are particularly rich sources of
beta-carotene.

Vitamin C (Ascorbic acid) is a water-soluble compound that fulfills several roles in living
systems. Important sources include citrus fruits (such as oranges, sweet lime, etc.), green
peppers, broccoli, green leafy vegetables, black currants, strawberries, blueberries,
seabuckthorn, raw cabbage and tomatoes. Linus Pauling was a major advocate for its use.

Vitamin E, including Tocotrienol and Tocopherol, is fat soluble and protects lipids.
Sources include wheat germ, seabuckthorn, nuts, seeds, whole grains, green leafy
vegetables, vegetable oil, and fish-liver oil. Recent studies showed that some tocotrienol
isomers have significant anti-oxidant properties.

Vitamin cofactors and minerals

Coenzyme Q10

Manganese, particularly when in its +2 valence state as part of the enzyme called
superoxide dismutase (SOD).

Hormones

Melatonin

Carotenoid terpenoids

Lycopene - found in high concentration in ripe red tomatoes.

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Lutein - found in high concentration in spinach and red peppers.

Alpha-carotene

Beta-carotene - found in high concentrations in butternut squash, carrots, orange bell

peppers, pumpkins, and sweet potatoes.

Zeaxanthin - the main pigment found in yellow corn.

Astaxanthin - found naturally in red algae and animals higher in the marine food chain. It
is a red pigment familiarly recognized in crustacean shells and salmon flesh/roe.

Canthaxanthin

Flavonoid polyphenolics

Flavonoids, a subset of polyphenol antioxidants, are present in many berries, as well as in

coffee and tea.

Flavones:

Luteolin

Apigenin

Tangeritin

Flavonols:

Quercetin and related, such as rutin

Kaempferol

Myricetin - walnuts are a rich source

Isorhamnetin

Proanthocyanidins, or condensed tannins

Flavanones:

Hesperetin (metabolizes to hesperidin)

Naringenin (metabolized from naringin)

Eriodictyol

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Flavanols and their polymers:

Catechin, Gallocatechin and their coresponding gallate esters

Epicatechin, Epigallocatechin and their coresponding gallate esters

Theaflavin its gallate esters

Thearubigins

Isoflavone phytoestrogens - found primarily in soy, peanuts, and other members of the
Fabaceae family.

Genistein

Daidzein

Glycitein

Stilbenoids:

Resveratrol - found in the skins of dark-colored grapes, and concentrated in red wine.

Pterostilbene - methoxylated analogue of resveratrol, abundant in Vaccinium berries

Anthocyanins

Cyanidin

Delphinidin

Malvidin

Pelargonidin

Peonidin

Petunidin

Phenolic acids and their esters

Ellagic acid - found in high concentration in raspberry and strawberry, and in ester form
in red wine tannins.

Gallic acid - found in gallnuts, sumac, witch hazel, tea leaves, oak bark, and many other
plants.

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Salicylic acid - found in most vegetables, fruits, and herbs; but most abundantly in the
bark of willow trees, from where it was extracted for use in the early manufacture of
aspirin.

Rosmarinic acid - found in high concentration in rosemary, oregano, lemon balm, sage,
and marjoram.

Cinnamic acid and its derivatives, such as ferulic acid - found in seeds of plants such as
in brown rice, whole wheat and oats, as well as in coffee, apple, artichoke, peanut, orange
and pineapple.

Chlorogenic acid - found in high concentration in coffee (more concentrated in robusta

than arabica beans), blueberries and tomatoes. Produced from esterification of caffeic
acid.

Chicoric acid - another caffeic acid derivative, is found only in the popular medicinal
herb Echinacea purpurea.

Gallotannins - hydrolyzable tannin polymer formed when gallic acid, a polyphenol

monomer, esterifies and binds with the hydroxyl group of a polyol carbohydrate such as
glucose.

Ellagitannins - hydrolyzable tannin polymer formed when ellagic acid, a polyphenol

monomer, esterifies and binds with the hydroxyl group of a polyol carbohydrate such as
glucose.

Emblicanin-antioxidant - tannin from Emblica Officinalis

] Other nonflavonoid phenolics

Curcumin

Xanthones

Silymarin - mixture of flavonolignans extracted from milk thistle.

Eugenol

Other organic antioxidants

Citric acid, oxalic acid, and phytic acid

Lignan - antioxidant and phytoestrogen found in oats, flax seeds, pumpkin seeds, sesame
seeds, rye, soybeans, broccoli, beans, and some berries.

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Bilirubin, a breakdown product of blood, has been identified as a possibly significant

antioxidant.

Uric acid In humans accounts for roughly half the antioxidant ability of plasme.

R-α-Lipoic acid - fat and water soluble

N-Acetylcysteine – water
Plant profile of Coriander sativum:
General description
Name: Coraindrum sativum

Part used: fresh juice of Coraindrum sativum

Synonyms: - Coriandrum majus, Coraindrum diversifolium , Coraindrum testiculatum,
Coraindrum globosum Salisb
Biological Source:
Kingdom: Plantae
Division: Magnoliophyta
Class: Magnoliopsida
Order: Apiales
Family: Umbelliferae
Genus: Criandrum
Species: sativum
Vernacular names95:
Hindi : Dhania or Dhanya
Bengali : Dhana, Dhania

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Gujarati : Kothmiri, Libdhaba

Kannada : Kothambri, Kothamiri bija
Kashmiri : Deaniwal, Kothambalari
Malayalam : Kothumpalari bija
Marathi : Dhana
Oriya : Dhania
Punjabi : Dhania
Sanskrit : Dhanyaka
Tamil : Kothamalli
: Dhaniyalu
Telugu

Distribution and Habitat:

It is a native of Mediterranean and commercially produced in India, Morocco, Russia,
East European countries, France, Central America, Mexico, and USA. Coriander is a
tropical crop and can be successfully cultivated as a Rabi season crop in an area free from
severe frost during February when the crop flowers and sets its seeds.

Morphological Description96, 97:

• Follicles: Coriander, the adromonoecious plant is a delicately rigid, strong-
smelling annual with pronounced taproot, and slender branching stems , reaches a
height of 2-3 ft (0.6-0.9 m) with a spread of 1-2 ft (0.3-0.6 m). It often becomes
top heavy and falls over, sprawling along the ground and sending up branches like
so many new plants.
• Leaves: The plant has ferny, pinnately or ternately decompound leaves. The lower
leaves of coriander are lobed, about 1-2 in (2.5-5.1 cm) across, and look a little
like Italian parsley (Petroselinum crispum). The upper leaves are finely dissected
into linear segments and almost fernlike.
• Flowers: The white or pink flowers are tiny and borne in numerous compound
umbels (flat-topped clusters in which the flower stems arise from a single point).
The flower clusters are only about 1-2 (2.5-5.1 cm) across, but are so abundant
that the whole plant is quite showy.

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• Seeds: The seeds are contained in spherical yellowish brown pods that are ribbed
and rough textured, and about an eighth inch in diameter.
• Flowering: It is in flower from June to July, and the seeds ripen from August to
September.

Cultivation
Climates : Coriander grows best in dry climates, with well drained soil, but
appreciates regular watering. It suffers during humid, rainy weather.
Hardiness: Coriander is an annual that can tolerate light frosts, but suffers under high
temperatures and humidity. It is planted in spring in USDA hardiness zones 3-8 and in
fall or winter in zones 9-11.
Soil: The plant prefers light (sandy) and medium (loamy) soils and requires well-
drained soil. The plant prefers acid, neutral and basic (alkaline) soils and can grow in
very alkaline soil. It can grow in semi-shade (light woodland) or no shade. It requires
dry or moist soil.
Light: Coriander does well in full sun to partial shade.
Propagation: Sow seeds where the plants are to be grown after the last expected
frost.

Chemical constituent
Coriander sativum consist of following chemical constituent-
Component Content (%)
 Water 11.37
 Crude protein 11.49
 Fat 19.15
 Crude fibre 28.43
 Starch 10.53
 Pentosans 10.29
 Sugar 1.92
 Mineral constituents 4.98

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 Essential oil 0.84

The most important constituents of coriander sativum are the essential oil and the fatty
oil. The essential oil content of the weight of ripe and dried fruits of coriander varies
between 0.03 and 2.6%, and the content of fatty oil varies between 9.9 and 27.7%.
Essential oil: chief components D-(+)-linalool (coriandrol), including among others
borneol, p-cymene, camphor, geraniol, limonene, alpha-pinenes, the unusual smell is
caused by the trans-tridec-2-enale content.
Composition of the essential oil in coriander
Main components % of total essential oil Minor components (all with less than 2%)*
linalool 67.7
pinene 10.5 camphene
terpinene 9.0 myrcene
geranylacetate 4.0 limonene
camphor 3.0 p-cymol
geraniol 1.9 dipentene
terpinene
n-decylaldehyde
borenol
acetic acid esters
Fatty oil: chief fatty acids petroselic acid, oleic acid, linolenic acid.
Composition of the fatty oil in coriander
Main components % of all fatty acids Minor components
petroselinic acid 68.8 stearic acid
linoleic acid 16.6 vaccenic acid
oleic acid 7.5 myristic acid
palmitic acid 3.8
• Hydroxycoumarins: including umbelliferone, scopoletine

Traditional medicinal uses:

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Coriander has been used in medicine for thousands of years.

• On Digestive System- Anorexia, Colic, Dyspepsia, Diarrhoea, Flatulence,
Nausea, Spasm:Coriander has been used as a folk medicine for the relief of
anxiety and insomnia in Iranian folk medicine. Experiments in mice support its
use as an anxiolytic.103 Coriander seeds are also used in traditional Indian
medicine as a diuretic by boiling equal amounts of coriander seeds and cumin
seeds, then cooling and consuming the resulting liquid. It is a commonly used
domestic remedy, valued especially for its effect on the digestive system, treating
flatulence, diarrhoea and colic dyspeptic complaints, loss of appetite, and
complaints of the upper abdomen104. Chinese herbalists use coriander seeds to
treat indigestion and stomachache104.
• On Circulation105- Accumulation of fluids or toxins, poor circulation,
haemorrhoids
• On Muscles and Joints105- Arthritis, Gout, Muscular Aches and Pains,
Rheumatism, Stiffness, Neuralgia: Externally the seeds have been used as a lotion
or have been bruised and used as a poultice to treat rheumatism and painful
joints.
• Aphrodisiac activity: At one time it was believed to have aphrodisiac effects.
• Immune System- Colds, Influenza, Infectious Diseases, Measles: Coriander is
also used traditionally for coughs, chest pains, bladder complaints, leprosy rash,
fever, dysentery, externally for headaches, oral and pharyngeal disorders,
halitosis, and post- partal complications. Chinese herbalists suggests that
coriander herb can be used to treat influenza in which there is no sweating.
• Nervous System- Debility, Migraine and Headaches, Nervous Exhaustion,
Neuralgia
• Antihalitosis; Aromatherapy; Aromatic; Carminative; Expectorant; Narcotic;
Stimulant106: The seed is aromatic, carminative, expectorant, narcotic, and
stimulant. Some caution is advised, however, because if used too freely the seeds
become narcotic.Chinese Folk medicine uses coriander leaves and seeds to help
remove unpleasant odors occurring in the genital areas of men and women, as

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well as halitosis or bad breath. The raw seed is chewed to stimulate the flow of
gastric juices and to cure foul breath and will sweeten the breath after garlic has
been eaten.
Other Uses
• Essential; Fuel; Fungicide; Insecticide; Oil; Repellent: An essential oil from the
seed is used as a food flavouring, in perfumery, soap making etc. It is also
fungicidal and bactericidal. The growing plant repels aphids. A spray made by
boiling of one part coriander leaves and one part anise seeds in two parts of water
is very effective against red spider mites and woolly aphids.An oil from the seed
is used for making soap. The report does not make it clear if the essential oil or
the fixed oil is used.
The seed contains about 20% fixed oil, this has potential for industrial use in
Britain, it could become an alternative to oilseed rape though the oil content is a
bit on the low side at present (1995). The oil can be split into two basic types; one
is used in making soaps etc, whilst the other can be used in making plastics.

Screened Pharmacological uses

• Anxiolytic effect
Among medicinal plants, Coriandrum sativum L. has been recommended for relief of
anxiety and insomnia in Iranian folk medicine. Additionally, its effect on spontaneous
activity and neuromuscular coordination were evaluated. The anxiolytic effect of aqueous
extract (10, 25, 50, 100 mg/kg, i.p.) was examined in male albino mice using elevated
plus-maze as an animal model of anxiety. The effects of the extract on spontaneous
activity and neuromuscular coordination were assessed using Animex Activity Meter and
rotarod, respectively. In the elevated plus-maze, aqueous extract at 100 mg/kg showed an
anxiolytic effect by increasing the time spent on open arms and the percentage of open
arm entries, compared to control group. Aqueous extract at 50, 100 and 500 mg/kg
significantly reduced spontaneous activity and neuromuscular coordination, compared to
control group. These results suggest that the aqueous extract of Coriandrum sativum seed
has anxiolytic effect and may have potential sedative and muscle relaxant effects.
Anthelmintic activity

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In vitro anthelmintic activities of crude aqueous and hydro-alcoholic extracts of the seeds
of Coriandrum sativum (Apiaceae) were investigated on the egg and adult nematode
parasite Haemonchus contortus. The aqueous extract of Coriandrum sativum was also
investigated for in vivo anthelmintic activity in sheep infected with Haemonchus
contortus. Both extract types of Coriandrum sativum inhibited hatching of eggs
completely at a concentration less than 0.5 mg/ml. ED50 of aqueous extract of
Coriandrum sativum was 0.12 mg/ml while that of hydro-alcoholic extract was
0.18 mg/ml. For the in vivo study, 24 sheep artificially infected with Haemonchus
contortus .Efficacy was tested by faecal egg count reduction (FECR) and total worm
count reduction (TWCR).
Sedative-Hypnotic activity: The aqueous or hydro-alcoholic extracts or essential oil of
coriander seeds were intraperitoneally administered to male albino mice, 30 minutes
before pentobarbital injection (40 mg/kg). Aqueous extract and hydro-alcoholic extract
prolonged pentobarbital-induced sleeping time. The extracts and essential oil of coriander
seeds possess sedative-hypnotic activity. However, it is strongly suggested that the major
active component(s) responsible for the hypnotic effect is mainly present in the aqueous
extract.
Insulin-releasing and insulin like activity
Coriandrum sativum has been documented as a traditional treatment of iadetis,coriander
incorporated into diet(62.5g/kg)and drinking water(2.5g/l)reduced hyperglycaemia of
stretozotocin –diabetic mice.

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