ASSOCIATION BETWEEN INHERITED THROMBOPHILIA
IN PREGNANCY AND MICRONUCLEUS FREQUENCY
IN PERIPHERAL BLOOD LYMPHOCYTES
Šošić GM1,*, Jović N2,5, Rakić B3, Dimitrijević A2,4, Varjačić M2,5
*Corresponding Author: Gordana M. Šošić, B.Sc., Department of Cytogenetic Diagnosis, Obstetrics and Gynecology
Clinic, Clinical Center “Kragujevac,” 30 Zmaj Jovina Street, 3400 Kragujevac, Serbia. Tel: +381-63-835-66-24.
Fax: +381-34-37-00-73. Email: gordana.sosic.2011.02@gmail.com
page: 11
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DISCUSSION
Micronucleus presence is an indicator of genomic
instability and accumulated damages that appeared during
the lymphocyte’s life cycle and can be detected in vitro
[3]. Every process that affects the DNA damage and/or
chromosomes and spindle apparatus directly or indirectly
increases the MN frequency. The most important processes
are oxidative processes in the cell [2], gene polymorphisms
and mutations that affect genomic instability [3].
Micronuclei are present in humans, as well as spontaneously
formed in the range of 0-12 MN/1000BN cells [7].
In our study, the individual variation of the MN frequencies
in the group of pregnant women was within a wide range of
MN frequency variations (1-25 MN/1000BN). Wide varia tions of the MN frequency in the same group may be the result
of different factors that influence chromosomal damage.
Kopjar et al. [3] reported mean frequency of 6.9 ±
3.32 MN/1000BN cells in their study performed on healthy
male and female subjects aged 20 to 61 in Croatia. The
authors concluded that due to the differences in the organization
of the research and the size of the population
examined, the mean MN frequency was often higher or
lower than the one determined in their research [3]. Our
research has shown that the mean MN frequency in the
studied population of pregnant women aged 20 to 33 is
6.09 ± 4.78 MN/1000BN cells.
The results of the previous studies have shown that
chromosomal aberrations could be found in the karyotype
of 3.0-6.0% of couples with recurrent miscarriages [24].
Fenech [20] wrote about MN frequency increase as one of
the factors that could be connected with recurrent miscarriages,
and Furness et al. [19] showed that in the high risk
group [patients who had recurrent pregnancy loss (RPL),
preeclamsia/eclampsia, intrauterine growth retardation
(IUGR), placental abruption or preterm delivery] there was
a statistically higher MN frequency comparing to low risk
group. Toljic et al. [25] showed that in gestational diabetes
(GDM) and pregnancy-induced hypertension (PIH), there
were elevated levels of oxidative stress, as well as damage
to DNA and chromosomal aberration, which could
be detected owing to elevated values of MNi in PBL of
pregnant women.
Upon the performed examination, we deduced that the
case group (>4MN/1000BN) contained more statistically
significant previous miscarriages and a higher number
of miscarriages. The results presented in this study show
that previous miscarriages and number of miscarriages are
separate independent variables and represent significant
predictors in the case group (>4MN/1000BN), while the
multivariate analysis allocated only thrombophilia as an
important predictor of an increased MN frequency in the
case group (>4MN/1000BN).
Studies analyzing the effects of smoking on MN frequency
have shown contradictory findings. Studies performed
by Kopjar et al. [3] as well as the one conducted
by Nefic et al. [26] showed that smokers have statistically
significant higher MN frequency than non smokers. In
most of the research studies, the link between smoking and
MN frequency was not found. Fenech et al. [27] concluded
that radical MN frequency increase can be found only in smokers who smoke more than 30 cigarettes a day and who
are not professionally exposed to genotoxic agents. In our
study, the maximal number of cigarettes was between 1
and 9 and this study was in accordance with some of the
previous findings that showed no link between smoking
status and an increased MN frequency.
Alcohol is a proven teratogenic agent that influences
normal embryo and fetal development and it is implicated
in the pathogenesis of the fetal alcohol syndrome. It is not
known if any amount of alcohol is safe in pregnancy, but
there are speculations that even a small amount of alcohol
may harm the fetus. It is well-known that ethanol can
easily cross the feto-placental barrier in both directions
and concentrations in fetal and maternal circulation thus
equalize [28]. Studies on animal models have shown that
ethanol may cause disorders on epigenetic level and that
it may also disturb the coordinated process of cellular
differentiation [29].
Alcohol toxicity can be seen not only as a direct effect
of the ethanol, but also as an indirect effect through
its metabolic products and reactive oxygen species (ROS)
that appear during alcohol biotransformation [30]. Studies
on animal models have shown that alcohol may induce
higher ROS production, cause oxidative stress and react
with proteins, lipid and DNA causing their damage or complete
degradation [31]. Different studies have confirmed
the genotoxic effect of ethanol by various cytogenetic
and molecular tests [32,33]. In the study by Santovito et
al. [34], significant differences in MN frequency between
alcoholics and controls were not found, but they did find
significant differences in frequency of sister chromatid exchanges
(SCEs) and chromosome aberrations (CAs). The
results of the studies by Benassi-Evans and Fenech [35]
support the hypothesis that chronic exposure to alcohol
induces formation of MN in two human B lymphoblastoid
cell lines: WIL2-NS and GM13705.
We have shown that in the group of pregnant women
with frequency of >4 MN/1000BN there were significantly
more women who consumed alcohol and the amount of
alcohol consumed by the pregnant women was higher, but
we did not find that these variables represented significant
predictors of an increased MN frequency in the group of
cases (>4MN/1000BN). A statistically significant difference
in the mean values of the MN frequency in women who
consumed and did not consume alcohol during pregnancy
was not found. This can be explained by the fact that the
minority of women in our study consumed alcohol (<10.0%)
and no pregnant women chronically consumed alcohol.
During pregnancy hypercoagulability and hypofibrinolysis
are present and together with inherited and
acquired thrombophilia disorders they can lead to early
complications of pregnancy (RPL) and late complications
of pregnancy [PE, IUGR, placental abruption, premature
birth and intrauterine fetal death (IUFD)] [24]. Prothrombophilic
genetic variants Factor V Leiden and Prothrombin
A20210G were significantly associated with a higher
prevalence of RPL [24,36]. Šošić et al. [37] found that in
the group of women with inherited thrombophilia from
Šumadija District, Serbia, previous miscarriages were
most commonly noticed in double owners of gene variants
plasminogen activator inhibitor-1 (PAI-1) 5G/4G and
MTHFR, C677T.
Karsli et al. [38] found that there was an impact of
inherited thrombophilia on the first trimester combined
aneuploidy screening test parameters. They determined
that PAPP-A levels were significantly higher, whereas
fbHCG levels and fetal NT measurements were lower in
women with inherited thrombophilia. In a similar study,
carried out by Cıkman et al. [39], the effect of inherited
thrombophilia on second trimester combined aneuploidy
screening test markers was investigated. They found that
unconjugated estriol multiple of median (MoM) levels
were significantly lower in women with inherited thrombophilia
[39]. In our study, the results of the first trimester
combined aneuploidy screening test were consistent with
previous research of the PAPP-A levels.
Micronucleus forming in human cells is connected
to many medical conditions. Pristov et al. [21] came up
with the result that in pregnant women with thrombophilia,
placental tissue is exposed to H2O2-mediated oxidative
stress, which can originate from the mother’s blood and
the endothelium. The occurrence of H2O2 can be initiated
by prothrombotic state present in mother, indicating a
potential relation between a pregnancy complicated with
thrombophilia and oxidative stress [21].
In our study, thrombophilia in pregnancy has a significant
partial contribution to the occurrence of frequencies
>4MN/1000BN. Pregnant women with thrombophilia are
26.69-times more likely to have a frequency of >4MN/
1000BN compared to pregnant women without thrombophilia.
In the population of pregnant women, thrombophilia
accounts for around one-third of variance in MN frequency.
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