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Polymorphisms in DNA Repair Genes, DNA Repair Phenotype and Genotoxic Effects in Radiation Exposed Workers

donderdag, 22 december, 2005 - 15:00
Campus: Brussels Humanities, Sciences & Engineering campus
Faculteit: Science and Bio-engineering Sciences
G
1.021
Peter Aka
doctoraatsverdediging

The primary public health concern for the study of the effects of low dose ionising radiation
is the protection of people from relatively low dose, protracted or fractionated exposures
such as those received by the public in the general environment, by patients through
repeated diagnostic procedures and by radiation workers. The risk associated with
exposure to low dose ionising radiations are not only neoplastic diseases but also somatic
mutations that may contribute to other illnesses (including birth defects and diseases) and
heritable mutations that may increase the risk of diseases in future generations. Physical
dosimetry cannot always be relied upon, so dose estimates and determination of past
radiation exposure must often be based upon biological indicators.

The results presented in this thesis are based on studies, using biological indicators,
performed on 2 groups of workers acutely or chronically exposed to low level ionising
radiations in a nuclear power plant. The third study was performed on young, healthy
university students recruited as volunteers. In the first approach we compared the DNA
strand break repair phenotype and genotoxic effects in these two groups of workers using
the Comet assay and the micronucleus test. There was a slight and statistically non
significant increase in tail DNA in the exposed population of the acute exposure study and
a slight decrease in tail DNA in workers chronically exposed compared to their controls.
The acutely exposed smokers had higher tail DNA compared to the acutely exposed non
smokers. The ex-vivo micronucleus assay showed that there was no influence of exposure
on micronuclei frequency. In the acute exposure study, the control smokers had higher
micronuclei frequency compared to the control non smokers. The same was true only for
the control population of the chronic exposure study. These results are an indication that
smokers may be at an increased risk of genetoxic effects.

In the second approach, we genotyped all workers, exposed and controls alike in order to
identify their genotype with respect to the following DNA repair genes polymorphisms:
hOGG1, XRCC1 and XRCC3. We then compared the DNA strand breaks repair capacity and
genotoxic effects to observe any differences that could be attributed to genotype alone.
Results showed that at the population level, a significant contribution of the hOGG1
genotypes to the in vitro DNA strand break repair capacity was found. Genetic
polymorphisms in XRCC1 and XRCC3 did not significantly influence repair capacity. At an
individual level, the hOGG1 variants Ser/Cys and Cys/Cys genotypes showed a slower in
vitro DNA repair than the Ser/Ser hOGG1genotype. Genetic polymorphisms in XRCC1
resulted in higher residual DNA values and the Met/Met variant of XRCC3 resulted in an
increased frequency of micronuclei. These results demonstrate the important role genetic
polymorphisms can play in individual susceptibility to repair of induced DNA damage.
Furthermore, this analysis confirmed that MN frequencies are reliable biomarkers for the
assessment of genetic effects in workers exposed to ionising radiation.

Third, we were interested to know if what we observed in this relatively old population
would be the same for a healthy, young population of no known history of exposure. We
therefore performed a DNA strand breaks phenotype assay, micronucleus test and
genotyping on 20 young university students. We compared the influence of 3 DNA repair
(hOGG1, XRCC1 and XRCC3) and 2 folate metabolic (MTHFR and MS) genes on the DNA
repair capacity and the induction of micronuclei. Results obtained confirmed that genetic
polymorphisms in hOGG1 gene were an important determinant of repair of induced DNA
damage. We also observed the influence of genetic polymorphisms in XRCC3 on the late
phase (120 minutes) of repair during which repair involves mostly the rejoining of double
strand breaks. We did not observe a significant influence of polymorphisms in the folate
metabolic genes on the DNA strand breaks repair. The induction of micronuclei was not
dependent on genetic polymorphisms for any of the genes in this study.
Finally we attempted to optimise a protocol for the measurement of hOGG1 activity in
human blood. This protocol will be used in subsequent studies.

MN are reliable biomarkers for medical surveillance at the population of workers exposed
to IR. In case of an unexpected increase in MN frequencies when population biomonitoring
is performed, genotyping for XRCC3 could provide some valuable information to decide
about the adequate measure to recommend for individual follow-up (exposure control
or/and individual measures). Moreover, genotyping for hOGG1 and XRCC1 could provide
additional information for these workers in danger of oxidative damage. Therefore we
advise a combined analysis of the three genotypes, OGG1, XRCC1 and XRCC3
polymorphisms in order to assess individual susceptibility to ionising radiation. As an
alternative or complement, the in vitro DNA strand break repair phenotype which
integrates several repair pathways is recommended. In any case, the workers with OGG1
polymorphisms who smoke and who are exposed to ionising radiation represent a specific
population requiring a closer medical surveillance because of their increased
mutagenic/carcinogenic risk. Knowledge folate status may be important in assessing the
global risk.