Vol 43 # 2 June 2011 - Kma.org.kw

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The Knowledge of Teratogenicity in the Prevention of Congenital Anomalies
June 2011
were most severely affected by cyclophosphamide as
in the case of the forelimb on day 13 of gestation. In
contrast, the hind limb that rapidly proliferates was
less severely affected. These authors suggested that
cyclophosphamide exerts teratogenic effect on its
target by disturbing the RNA metabolism, which varies
according to the state of differentiation of the cell [61-63] .
Pharmaco-kinetics and metabolic factors in general
do not appear to play an important role in target organ
specificity of teratogens. During the organogenesis
period in rodents the embryo has little capacity to
activate drugs via mixed function oxidase metabolism.
The amount of cytotoxic agents reaching the cell,
differential drug distribution, permeability of cells to
the agent and amount of intra-cellar binding do not
appear to be important factors in determining which
embryonic organ systems are damaged, but rather
intrinsic cell differences related to rate of proliferation
and differentiative state appear to determine which
cells are susceptible to teratogenesis [61] .
So far as the depression in DNA synthesis and
cell death is concerned in embryonic as well as adult
tissues treated with teratogenic agents, cytotoxicity
can be assumed to be a common biological property of
these agents. Whether or not birth defects results from
the cytotoxic response of the embryos, teratogenesis
depends upon gestational time of treatment
(proliferative and differentiative state of the target
organ), and the extent of cell death [62] .
MUTATION IN TERATOGENESIS
Mutagen is an agent - toxin, radiation, virus - capable
of causing mutation, that is, a relatively permanent
change in DNA, the hereditary material. The amount
of damage caused by a mutagen depends on three
factors: (1) chemical reactivity between DNA and the
mutagen, (2) the concentration or dose of the mutagen,
and (3) length of exposure time of DNA to mutagen.
Damage and repair to DNA are constantly occurring;
but when the damage is not repaired the result can
be cancer or cell death. Also, genetic diseases such as
cystic fibrosis and sickle cell disease can be caused by a
single DNA mutation in one gene [65] .
Mutation is a permanent alteration in DNA
produced by base-pair substitutions, frame-shift
mutations, aneuploidy / polyploidy (gain or loss of
chromosomes), or chromosome aberrations (deletion,
translocation, duplication). If mutations occur in germ
cells, they can lead to teratogenic effects. For example,
acrylamide found in some pre-cooked and processed
foods can cause reduced fertility in males [38] . The role
played by mutation as a fundamental mechanism in
teratogenesis has been receiving little experimental
attention, even though somatic mutation is postulated
to be one of the underlying causes of birth defects.
Mutagenic lesions are believed to be distinguishable
from teratogenic responses in that the former are
transmissible to future generations, whereas the
latter are confined to a single generation. The lack of
experimental examination of mutagenesis could be
due to the prominence of teratogenic damage. Dead
cells cannot transmit genetic defects to progeny cells.
The belief that teratogenesis occurs when more cells are
removed from a population of cells destined to form
an organ rudiment that can be replaced by restorative
hyperplasia within the critical period needs to be reexamined.
Cell death invariably accompanies chemical
induced heritable mutation and transformations, but it
is not believed to be causative factor in these genetic
alterations. It seems logical that DNA damaging lesions
could be the initial event to cell death [66-70] .
REPARATIVE GROWTH FOLLOWING
TERATOGENESIS
The importance of reparative processes in the final
expression of malformation after teratogenic insults
has not been given adequate consideration in the field
of teratology. For most teratogenic agents, a threshold
dose exists below which abnormal development cannot
be detected [43] . This ‘threshold’ changes throughout
gestation and there are developmental stages, that is,
during organogenesis period, during which embryo
is highly resistant to teratogenic insults. Implicit in
this concept of a threshold dose is that the embryo
possesses a varying capacity at different developmental
stages to repair teratogenic damage [43] . Repairs of
teratogenic insults during the organogenesis period
which hitherto had traditionally been viewed in terms
of tissue regeneration or of restorative hyperplasia of
the surviving cells to replace dead cells undergoing
necrosis from teratogenic insults would be interesting
to investigate. Study of the differential capacity of cells
surviving teratogenic insults versus those that die may
contribute to an understanding to the process of cell
death. Correlation of the time dependent insults with
the rate of repair of DNA damage may help elucidate
the target organ specificity of certain teratogens. For
example, the question may be asked: are embryonic
limbs susceptible to teratogenic insults on day 11 of
gestation but not on day 14 due to a depressed capacity
of the day 11 bud to repair DNA damage Such
questions yet need to be addressed as earlier workers
in this field had pointed out [43] .
The processes whereby embryos cope with
teratogenic assaults are fundamental to understanding
the mechanisms of teratology. A deleterious response
may occur only after the defense mechanisms are
overwhelmed. Embryonic repairs had traditionally
been regarded in term of tissues regeneration. The
critical lesions, however, involve injury to individual
cells. Detailed analyses of the capacity of the embryonic
cells to repair lesions in DNA during the organogenesis