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Why
This Project?
There is
concern about the possible genetic effects of low-dose radiation
exposure. As a result, much effort has gone towards understanding
mutation of cells due to radiation exposure. While recognition
of the potential for mutation from exposure to ionizing radiation
has led to extensive research, less effort has been given to
the possible delayed risk of radiation exposure transmitted
to the offspring of the exposed parent. Data from animal models
show that parental exposures to DNA-damaging agents such as
ionizing radiation predispose the offspring to serious health
effects, including cancer offspring. Additionally, data from
both humans and animal models indicate that there may be individuals
carrying particular genetic factors that cause increased radiation
sensitivity. We believe that, following low dose irradiation,
the father may transmit factors that influence the susceptibility
of his offspring to further radiation exposure.
Project
Goals:
- Understand
the mechanisms by which the inherited effects of irradiated
reproductive cells are transmitted across generations.
- Test
the hypothesis that a radiation-sensitive genetic factor can
be transmitted to the offspring by the father, caused by the
irradiation of developing sperm.
Research
Approach:
Male mice
carrying a factor predisposing them to radiation sensitivity
will be irradiated. Subsequently, three generations of offspring
from these males and from non-exposed males will be evaluated
for changes in the activities of enzymes and the levels of proteins
essential to cell growth and DNA repair processes. Ongoing DNA
damage in the offspring of the irradiated male mouse will be
evaluated in nucleated cells in peripheral blood using two methods
of detecting DNA breaks-the comet and micronuclei assays. Repeated
DNA sequences will also be evaluated differences as another
indicator of genomic instability . The ration of the liver weight
to the body weight will be evaluated as a general indicator
of increased liver size, liver enzymes and protein levels. Adult
whole-body weights will be evaluated as an indicator of overall
health and vigor.
Expected
Outcomes:
- The
results of these analyses will test our hypothesis that a
genetic factor can increase individual susceptibility to the
transmission of heritable effects following paternal germ-cell
irradiation.
- This
study will further characterize the heritable biological phenotype
resulting from radiation of a father, and extend our understanding
of the mechanism that underlies this phenomenon.
- The
biochemical endpoints used in this study could be adapted
for screening human populations for high-risk individuals.
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