Download Hereditary Effects of Radiation

CHAPTER 11
HEREDITARY EFFECTS
OF
RADIATION
GERM-CELL PRODUCTION AND
RADIATION EFFECTS ON FERTILITY
In the male, doses as Iowa 0 15 Gy (15 rad) result
in oligospermia (diminished sperm count) after a
latent period of about 6 weeks.
 Doses above 0.5 Gy (50 rad) result in
azoospermia (absence of living spermatozoa) and
therefore temporary sterility.
 Recovery time depends on dose.
 Permanent sterility in the male requires a single
dose in excess of 6 Gy (600 rad)
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GERM-CELL PRODUCTION AND
RADIATION EFFECTS ON FERTILITY
In the male, fractionated doses cause more
gonadal damage than a single dose.
 Permanent sterility can result from a dose of 25
to 3 Gy (250-300 rad) in a fractionated regime
over 2 to 4 weeks
 In the female, radiation is highly effective in
inducing permanent ovarian failure, with a
marked age dependence on the dose required.
 The dose required for permanent sterility in the
female varies from 12 Gy (1,200 rad) prepubertal
to 2 Gy (200 rad) premenopausa I.
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The induction of sterility in males does not
produce significant changes in hormone balance,
libido, or physical capability, but in the female
leads to pronounced hormonal changes
comparable to natural menopause.
 Exposure of a population can cause adverse
health effects in the descendants as a
consequence of mutations induced in germ cells
These used to be called "genetic" effects but are
now more often called "hereditary" effects.
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HEREDITARY
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DISEASES
Hereditary diseases are classified into three
principal categories :
Mendelian
chromosomal
and multifactorial
Radiation does not produce new, unique
mutations but increases the incidence of the
same mutations that occur spontaneously.
HEREDITARY
DISEASES
Exposure of a population to radiation can cause
adverse health effects in the descendants as a
consequence of mutations induced in the germ
cells.
 Hereditary diseases, also known as genetic
diseases,' may result when mutations occurring
in the germ cells of parents are transmitted to
progeny
 most cancers result from mutations in somatic
cells.
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It is a commonly held view that radiation produces bizarre
mutations or monsters that may be recognized readily This
is not true. Radiation increases the incidence of the same
mutations that occur spontaneously in a given population.
The study of radiation-induced hereditary effects is difficult
because the
mutations produced by the radiation must be identified on
a statistical basis in the presence of a high natural
incidence of the same mutations.
MENDELIAN DISEASE
Mendelian diseases are those caused by
mutations in single genes located on either the
autosomes or the sex chromosomes.
 The mutation may be a change in the structure of
DNA, which may involve either the base
composition, the sequence, or both.
 sickle-cell anemia results from the substitution of
only one base.
 the relationship between mutation and
Mendelian disease is simple and predictable.
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MENDELIAN DISEASE
Mendelian diseases are subdivided into:
 autosomal dominant
 autosomal recessive
 and X-linked conditions
depending on which chromosome the mutant genes
are located on and the pattern of transmission.
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DOMINANT
A dominant gene mutation is expressed in the
first generation after its occurrence.
 More than 700 such conditions have been
identified with certainty and an additional 700 or
more are less well established.
 Some examples :
 polydactyl,
 achondroplasia
 Huntington's chorea.
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RECESSIVE MUTATIONS
require that the gene be present in duplicate to
produce the trait, which means that the mutant
gene must be inherited from each parent;
 many generations may pass before it is
expressed.
 If one copy of the gene is mutant and the other is
normal, the individual is not affected.
 Some examples :
 sickle-cell anemia
 cystic fibrosis
 Tay-Sachs disease.
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X-LINKED RECESSIVE DISEASES
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X-linked recessive diseases are caused by mutations
in genes located on the X-chromosome.
The Y chromosome contains far fewer genes than the
X.
Because males have only one X chromosome, all
males having a mutation in the X chromosome show
the effect of mutation: like dominant mutations.
Since females have two X chromosomes, they need
two mutant genes to show the effect of an X-linked
recessive mutation.
The best known examples of sex-linked disorders are
hemophilia, color blindness, and a severe form of
muscular dystrophy,
THE THREE TYPES OF MENDELIAN DISEASES
ARE SUMMARIZED AS FOLLOWS:
Autosomal dominant: The disease is due to a
mutation in a single gene on one chromosome.
 Autosomal recessive: The disease is due to a
defective copy of the same gene from each parent.
 Sex-linked: Males have one X chromosome, so one
mutation can cause the disease; females have two
Xs, so two mutant genes are needed to cause the
disease.
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MULTIFACTORIAL
Characteristics of multifactorial diseases include
the following:
 Known to have a genetic component
 Transmission pattern not simple Mendelian
 Congenital abnormalities: cleft lip with or without cleft palate; neural tube defects
 Adult onset: diabetes, essential hypertension,
coronary heart disease
 Interaction with environmental factors
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RADIATION-INDUCED HEREDITARY
EFFECTS IN FRUIT FLIES
As early as 1927, Muller reported that exposure to
x-rays could cause readily observable mutations in
the fruit fly, Drosophila melaliogaster.
 These included a change of eye color from red to
white, the ebony mutant with its jet-black color,the
"vestigial wing" mutant, and the easiest of all to
observe, the recessive lethal mutation.
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In the 1950s, hereditary changes were considered the
principal hazard of exposure to ionizing radiation.
 There were three reasons for this:
I.
A low doubling dose (5-150 R) for mutations was
estimated from fruit fly experiments.
(The doubling dose is the dose required to double
the spontaneous mutation rate.)
I.
Based again in the fruit fly, it was thought that
hereditary effects were cumulative; that is, a little
radiation now, some next week, and some next year
all added up and contributed to the genetic load
carried by the human race.
II.
In the 1950s, little was known of the carcinogenic
potential of low doses of radiation. An excess
incidence of leukemia was evident in the Japanese
survivors of the A-bomb attacks, but the much
larger number of solid cancers did not appear until
many years later.
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RADIATION-INDUCED HEREDITARY
EFFECTS IN MICE
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The extensive studies included the irradiation of both
male and female mice with a range of doses, dose rates,
and fractionation patterns.
Five major conclusions are pertinent to the radiologist:
The radiosensitivity of different mutations varies by a
significant factor of about 35, so that it is only possible to
speak in terms of average mutation rates.
In the mouse, there is a substantial dose-rate effect, so
that spreading the radiation dose over a period of time
results in fewer mutations for a given dose than in an
acute exposure.
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Essentially all of the radiation-induced hereditary data
come from experiments with male mice.
The hereditary consequences of a given dose can be
reduced greatly if a time interval is allowed between
irradiation and conception.
The estimate of the doubling dose favored by the
Committee on the Biological Effects of Ionizing
Radiation (BEIR V) and the United Nations Scientific
Committee on the Effects of Atomic Radiation
(UNSCEAR 88) is I Gy (100 rad) based on low dose-rate
exposure.
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In the megamouse project, seven specific locus
mutations were used to study radiation-induced
hereditary effects. This photo shows three of the
mutations, which involve changes of coat color.
(Courtesy of Dr William L. Russell, Oak Ridge
National Laboratory.)
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Mutation in mice as a function of dose ,delivered at high and low
dose rate
RADIATION-INDUCED HEREDITARY
EFFECTS IN HUMANS
To estimate the risk of hereditary effects in the
human population due to exposure to radiation,
two basic pieces of data are needed:
 first, the baseline spontaneous mutation rate,
which is known for humans,
 second, the doubling dose, which can only come
from mouse experiments (1 Gy, or 100 rad).
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Two correction factors are needed:
(1) to allow that not all mutations lead to a diseasethis is the mutation component (MC), which
varies for different classes of hereditary diseases;
(2) to allow for the fact that the seven specific locus
mutations used in the mouse experiments are not
representative of inducible hereditary diseases in
the human because they are all nonessential for
the survival of the animal or cell.
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TABLE 11.4
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The UNSCEAR 2001 estimates of hereditary
risks for the first generation and first two generations of an irradiated population are listed in
Table 11.4.
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The risk of autosomal dominant and X-linked
diseases for the first generation after irradiation is on
the order of 750 to 1,500 cases progeny per gray of
chronic low-LET radiation (compared to the baseline
of 16,500 cases per million).
The risk of autosomal recessive diseases is essentially
zero (compared to the baseline of7,500 per million).
The risk of chronic diseases is on the order of 250 to
1,200 cases per million (compared to the baseline of
650,000 per million).
The risk of multisystem developmental or congenital
abnormalities may be of the order of about 2,000
cases per million.
Note that the total risk per gray is only about 0. 41 to
0.64% of the baseline risk of 738,000 per million live
births-that is, a relatively small proportion.
MUTATIONS IN THE CHILDREN OF
THE A-BOMB SURVIVORS
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Children of the atomic-bomb survivors have been studied
for a number of indicators:
congenital defects
gender ratio
physical development
survival, cytogenetic abnormalities
malignant disease and
electrophoretic variants of blood proteins
A recent paper estimated the doubling dose to be about 2
Sv (200 rem), with a lower limit of 1 Sv (100 rem) and an
upper limit that is indeterminate because the increase in
mutations is not statistically significant.