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F.Ingel*1, V. Platonova,2 L. Katosova2
1 A.N. Sysin Institute of Human Ecology and Environmental
Hygiene, Russian Academy of Medical Sciences, Moscow,
Russia
2 Medico-Genetic Centre, Russian Academy of Medical
Sciences Moscow, Russia
* A.N. Sysin Institute of Human Ecology and Environmental
Hygiene, Russian Academy of Medical Sciences, Pogodinskaya
str. 10, Moscow, 119833, Russia,
tel. 7 095 246 48 13, fax.7 095 247 04 28, e-mail
f.ingel@chat.ru
Abstract
45 women from Chapaevsk town (three groups of 14-16
persons aged 20-40 years) with different exposure
to dioxins and different dioxins' level in blood were
tested by 4 standard psychological questionnaires
to detect emotional stress. Results of psychological
testing were compared with individual dioxin blood
contents and chromosome aberration level in blood
cells. Results of the investigation were the next:
1. three groups tested differed significantly (P ?
0,05) in emotional stress level thus that highest
level of stress was detected within group with highest
dioxin blood contents (group "Workers");
2. high level of correlation between emotional stress
and individual dioxins blood contents (up P ? 0,001)
as well as between emotional stress and individual
chromosome aberration level (up P ? 0,05) was revealed.
These results are discussed from the position of deadaption
induced by dioxins, what led to chromosome aberration
induction.
As H.Selye firstly demonstrated, any factors' action
can induce nonspecific adaptive answer in mammalian
organism (Selye, 1936). This phenomenon was determined
as stress. Later effects of emotional stress were
very extensive studied by physiologists, psychologists,
physicians, biochemists and immunologists (for generalization
of first steps of investigations see, for example,
Levi, 1965). Now is a period of more profound study
of effects induced by stress. So, in particular, it
was demonstrated that stress-induced neurotransmitters
can lead to proteinkinase C activation and tumorigenesis
(Belousova, 1993; Il'nitskij, 1991). C. Bartoloni
with co-authors detected important role of emotional
stress in aging (see review Guidi et al, 1998). Processes
of stress-induced immunodeficiency is to be demonstrated
by Wesker (1994), Pacak et al (1997) and many others
who proved that the link stress-immunedeficiency is
to be.
From the other hand, number of researchers (Belyaev,
1979, Borodin 1987, Ingel et.al, 1993,1995, 1997a;
Ingel, 1998; Diuzhikova et al, 1997; Fischman and
Kelly, 1999) shown that emotional stress induces mutations
in somatic and gender mammalian cells. Our studies
on mice and results of different human population
investigations demonstrated that emotional stress
not only induce, but modify sensitivity of an organism
to environmental mutagenic factors. (Ingel et al,
1993; Druzhinin et al 1995; Ingel et al, 1997b). So,
we revealed that total genetic effect of stress and
mutagens combined action depends of an organism adaptive
potential: in the period of deadaption number of genetic
damage, induced by mutagens, was higher than in period
of adaptive answer activation. That is to be ague
the link of stress and genetic damage.
Moreover, there was a proof that stress can modify
not only genotoxic effects of mutagens, but nonmutagenic
compounds' influence. So, Banerjee et al, 1997 demonstrated
that DDT-action in complex with immobilizing stress
at low temperature suppressed of humoral immune responses
more then individual action of the factors. From the
other hand, N. Khaytsev (1998) demonstrated that stress
(alterations of neurotransmitter level and activity
and hormonal misbalance) is the first reaction developing
in mammalian organism after nontoxic doses of toxicants.
These data, being in very good correlation with Selye'
doctrine and results of our previous human investigation
(Ingel et al, 1997b) allowed us to suppose that all
of adaptive alterations, induced by toxic and genotoxic
compounds, may be generally exhibited in different
forms of emotional stress. Vice versa, emotional stress
level may be in correlation with toxicants' contents.
Depending on genotype, life-style, temperament, personality
archetype etc. emotional stress may be manifest as
psychological depression, abnormal anxiety, overfatigue,
bad state of health, decreased background of mood
and others. If this liaison exists, several ultimately
uncorrelated parameters, such as genetic damage and
toxicants' contents in biosubstrates, may be connected
if to take into account alterations in level of adaptive
reactions (stress) developing in organism under toxic
exposure.
The investigation of Chapaevsk town human populations
carried out in our laboratory (Revazova et al) showed
high level of chromosome aberrations in blood lymphocytes,
but no correlation with blood dioxin contents was
detected. We supposed that these genetic damage were
resulted of stress induced by environmental dioxins.
For verification of the hypothesis, we use the data
of psychological testing obtained in the same investigation.
Subjects and Methods
The Study Groups.
Three groups of women - 45 persons at age of 20-40
(average 32,1) having a reasonable degree of the contact
with dioxins and with different level of dioxins in
blood were examined:
1. 15 women (average age of 32,9 ± 3,9) working at
the chemical fertiliser plant where occupational exposure
to dioxins is possible - group "Workers";
2. 16 women (average age of 30,8 ± 4,0) without professional
contact with dioxins, but living at a distance of
1-3 km from the plant (including 14 women from families
that had cows, whose milk represent a possible source
of supplying essential quantity of dioxins into organism)
- group "1-3 km";
3. 14 women (average age 32,7 ± 3,7) without dioxins
occupational exposure and living as far as 5-8 km
from the plant - group "5-8 km".
All the women were clinically healthy, and only 2
of them were smoking.
Tests
All persons were tested for detection chromosome aberration
level in blood and level of emotional stress. Special
questionnaire has been used for determination of kind
of life. This form (common questionnaire) included
questions about condition of life, number of children,
money per 1 member of family and others. Additionally,
in blood plasma of 4-6 persons from each group were
detected dioxin contents: 2,3,7,8- TCDD, 1,2,3,7,8-PeCDD,
1,2,3,4,7,8-HxCDD, 1,2,3,6,7,8-HxCDD, 1,2,3,7,8,9-HxCDD,
1,2,3,4,6,7,8-HpCDD, OCDD, 2,3,7,8-TCDF, 1,2,3,7,8-PeCDF,
2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, 1,2,3,6,7,8-HxCDF,
1,2,3,7,8,9-HxCDF, OCDF and total PCDD/PCDF (Revich
et al., 1999).
Psychological testing and analysis
The psychological state evaluation was carried out
by battery of standard psychological questionnaires
adapted for social conditions in Russia and giving
the estimation in points. As low as 4 psychological
questionnaires were used to determine the following
kinds of chronic (till 6 months) emotional stress:
1) psychological depression (Holms-Ray scale, the
range of norm average values is from 41 to 260 points,
maximum - 1476 points) - questionnaire 1 (Fontana,
1989);
2) personal and situate anxiety levels (two Spielberger's
scales, norm diapason values in interval of 15 - 30
points, maximum 70 points), - questionnaires 2 and
3, respectively (Spielberger, 1970);
3) degree of overfatigue (Ekklz's scale, norm diapason
values 3-7 points, maximum 14 points) - questionnaire
4 (Akhmedjanov, 1997);
In addition all of the persons examined were tested
for independent self-evaluation of health state, activity
and mood by means of the test map "HАM"
(Akhmedjanov, 1997), with norm average values as і
60 points (for each parameters). The HAM map can be
use for detection of short emotional status alteration.
All testing procedures were carried out just before
blood sampling. Every person tested used the individual
forms of each questionnaire. All of the data obtained
were accounted simultaneously after finishing of the
investigation and processed by standard Microsoft
Excel 7.0 programs.
Psychological scales had been used detected various
kinds of stress. For united estimation of individual
stress level (total estimation) the data in points
of each questionnaire (and of each person) were transformed
into ranks 1 - 5 in accordance with qualitative characteristic
of pointed estimation. So rank 1 was estimated as
"normal", and rank 5 - as "very bad".
This transformation of pointed estimation into ranks
was available for individual psychological state summarized
evaluation.
Statistical analysis was carried out using t-Student,
F-Fisher and U- Wilcoxon criteria. The significance
of the connections between tested parameters was detected
by correlative analysis .
Cytogenetic study
Analysis of chromosome aberrations in human blood
lymphocytes was carried out by routine procedure (
Hungerford, 1965).Venous blood samples were obtained
30-48 hours before the cultivation. Heparinized whole
blood (0.5 ml) was incubated in 6 ml Eagle's medium
supplemented with 1.5 ml fetal calf serum, 0.1 ml
phytohemagglutinin ("PANECO", Moscow) without
antibiotics. Cultures were incubated for 48 hours
with 0.5 mg/ml colhicine in the medium for the last
2 hours of incubation. Microscopic slides were prepared
according to standard procedure and stained with Giemsa.
300 metaphases per individual on coded slides were
analysed (excepted 1 individual of the "5-8 km"
group with 115 metaphases). Single and double fragments
and chromatid and chromosome exchanges were scored.
Gaps were not included.
Results
Firstly, all of the data psychological tests (in points)
were controlled for the connections with donors' age,
conditions of life and other parameters of common
questionnaire and no correlation were revealed. Then
the psychological data were controlled for the connection
with level of blood lymphocyte chromosome aberration
and no correlations were detected.
Inasmuch as the distinction between groups had been
demonstrated in average of dioxin plasma contents
("Workers" - 412,4 pg/TEQg/ lipid; "1-3
km" - 75,2 pg/TEQg/ lipid; "5-8 km"
- 41,0 pg/TEQg/ lipid), we examined whether there
were differences in emotional stress level too. In
table 1 are results of psychological testing. All
of the data are in points - standard apply in psychological
studies.
Application of Wilcoxon-Mann-Whitney criterion revealed
significant differences (Р Ј 0.05) in the degree of
overfatigue and self-estimation of state of health
between the groups "Workers" and "1-3
km" only. So, "Workers" demonstrated
higher degree of overfatigue and evaluated self estimation
of state of health than the inhabitants of "1-3
km". However, using of F-Fisher criterion allows
to discover more differences: woman from group "Workers"
had higher level of psychological depression, overfatigue
and self estimation of health, than donors from "1-3
km" and "5-8 km". Therefore using these
two criteria allow to conclude qualitatively that
woman from groups "1-3 km" and "5-8
km" were in more comfort psychological status
than ones from group "Workers".
These results are in good agreement with average level
of blood dioxin contents detected in each group (see
above). So it became possible to suppose that high
level of dioxin (group "Workers") may induce
higher emotional stress then 6 - 10 times lower dioxin
level (groups "1-3 km" and "5-8 km").
For control of this assumption we study correlation
between psychological tests' data and dioxin contents
in blood plasma. As it is shown on fig.1, levels of
depression and overfatigue were in good agreement
with biochemical data. This connection became more
evident if to take into account that both psychological
tests used indicate diapason of "norm" not
in the begin of scale (see " Subjects and Methods
"). Correlation analysis detected significant
level (P ? 0,05) of the connection between all of
the parameters presented on fig.1, what suppose that
our hypotheses might be correct. But the data on fig.1
concerns only definite kinds of emotional stress -
psychological depression and overfatigue. No correlation
was detected between level of anxiety and dioxin contents,
which reduces stability of our position. So we supposed
that united appraisal of individual stress level will
be more adequate for all data comparison. Therefore,
all of the psychological tests' data in points obtained
for each person were transformed into ranks 1 - 5
so that "norm" for each tests was estimated
as rank 1 and "very bad" - as rank 5. After
that procedure all ranks for each person were summarized.
This encompassing procedure became possible to evaluate
objectiveness of two assumptions: 1. whether there
are differences in emotional stress level between
groups and 2. whether there are correlation between
dioxin blood contents and individual emotional stress
level in total.
On fig.2 (A) are presented data of individual stress
level united appraisal. Statistic analyses (T-test)
strongly reveals that woman from group "1-3 km"
had significantly lower total level of emotional stress
than the ones of group "Workers" (P Ј 0,05).
From the position of these data our hypotheses become
more adequate.
On table 2 are results of calculations of the connection
between individual blood plasma dioxin contents and
emotional stress summarized estimation. These data
demonstrate existence of direct connection on very
high level of significance (P ? 0,001). From the light
of the data demonstrated on fig. 2 (A) and table 2,
the hypotheses of dioxin-induced human emotional stress
is appeared to be correct.
Next important problem of this investigation connects
with the question what is the reason of high level
of chromosome aberrations detected in blood of woman
examined. For its resolution we used two approaches.
Firstly we tried to detect the ultimate correlation
between individual chromosome aberration level and
stress estimation in ranks. No connection was detected
when we used arrays of data where persons tested were
divided in groups in accordance with level of its
contact with dioxins (see "Subjects and Methods").
But if to compare distribution of psychological and
cytogenetic data (fig 2 A,B), it should to take in
consideration the identity of correspondent curves.
Then, because significant differences in total chromosome
aberration level between groups were not detected
(see article above), we used all of the data in common
(without subdividing in groups). A statistical analysis
discovered that coefficient of correlation was 0,209
(P ? 0,1). This is good result, which shows that the
connection exists in principal. However, this level
of correlation is insufficient for correct conclusions.
Therefore, array of individual cytogenetic data (without
taking into account groups) was reorganized in accordance
with estimation of stress in points and divided into
two parts "Norm" and "Discomfort"
and ranged with increasing. This procedure was made
for each psychological test. Then rows of ranged data
(individual % chromosome aberrations) from arrays
"Norm" and "Discomfort" was compared
(fig.3). Significant differences (Wilcoxon criterion,
P ? 0,05) were detected only for psychological depression
and overfatigue and stable tendency (P ? 0,1) - for
other parameters.
Secondary, we compared individual levels of chromosome
aberrations (in %) for each person of 3 groups with
correspondent individual stress estimation in ranks.
Than 3 arrays of data were ranged in accordance with
stress level increasing. Results of this approach
are presented on fig.4. It was found that all of 3
curves were practically (excluding 2 bending points)
in parallel and it possible to see that % of chromosome
aberrations for each person from group "5-8 km"
are lower than for other groups.
It is well known that results of all human cytogenetic
studies are accompanied by high level of chromosome
aberration level dispersion and this problem is one
of stumbling-block in environmental investigations
at all. The reason of high dispersion of the parameter
is one of the important problem. Psychological data
allow to compare dispersions of chromosome aberration
levels between groups with different level of contacts
with dioxins, but between donors in stress and in
state of comfort (fig. 5). As it is seen, lowest dispersion
- 43% - among groups, composed in accordance with
epidemiologic rules - was detected in "5-8 km"
one. But if we used subdividing all donors to groups
"Stress" and "Comfort", level
of depression was significantly altered: in group
"Stress" it was 29 % ( compare with 70 %
in group "Comfort").
Thus, in spite of absence of ultimate correlation
all of these results once more prove the connection
between emotional stress and genetic damage.
Discussion
In accordance with Selye' doctrine, nonspecific alteration
in resistance of an organism - stress reaction - develops
without depending on kind of factors acted and usually
has common dynamics. Selye demonstrated that after
long influence - in state of stress - adaptative potential
of an organism exhausts and its resistance decreases,
so state of stress is characterized as higher sensitivity
of all systems to any influences. Principle important
that stress is the first reaction arising in organism
under exposure with doses lower then threshold of
any effects. Therefore, high level of correlation
detected in this study between stress reaction and
blood plasma dioxin contents (table 2) and absence
of any ones with age of people tested, conditions
of their life or income supports the hypotheses that
one of possible reasons of emotional stress in Chapaevsk-town
population is toxic action of the compounds.
Affirmation of higher sensitivity of living systems
in stress is correct for genetic structures too. So,
it is possible to discuss the question of stress-induced
or stress-modified ( to increase) reasons of genetic
damage in Chapaevsk-town. Specifically, the causal
connection between dioxins and genetic damage may
be the next: dioxins (nonmutagenic compounds, IARC,
1997) modify activity of cytochrom systems, what reduces
possibility to prevent other environmental mutagens
(ATSDR, 1998). From the other hand, dioxin may induce
stress, which weakens immune-endocrine system of an
organism (Stress. Basic mechanisms and clinical implications,
1996). In complex these effects may led to situation
when cells with damaged genome doesn't identify and
eliminate by immune system, what realize as increasing
of aberrant cells quantity. Taking into account that
emotional stress as injuring factor may induce genetic
damage, question concerning the reason of high level
cells with aberrations in Chapaevsk-town population
may resolve in favor of their
From the other hand, dioxins act as hormone-like compounds,
which activates both estrogen, endorphine and dophamine
receptors (Millan et al, 1998,. Balaguer et al 1999)
what led to hormonal misbalance increasing and, as
a result, to stress, because of preventing endogenous
extinguishing of stress reaction, what normally observing,
for example, under endorphins action. As a result,
under long TEQ action organism in stress, devoid of
normal detoxicative activity and normal potency to
prevent stress, became in state of deadaption (or
distress). By mechanism of positive feedback, which
led to strengthening of this misbalance, antimutagenic
defense of an organism decreases and genetic damage
level may increases.
Because of stress is in anamneses of many diseases,
including cancer and immunodeficiencies, just the
same mechanism of nonspecific deadaption may apply
for explanation that in Chapaevsk town was revealed
higher level of cancer mortality, frequency of spontaneous
abortions and several congenital malformations, etc.
than in other towns of Samara province (Revich et
al., 1999; Revazova et al., 1999).
It should note that from the mechanism presented above
does not conclude that the only reason of emotional
stress in Chapaevsk' people tested are dioxins and/or
other environmental pollution. Chapaevsk town is situated
at the main railroad from Middle Asia to Central Russia
- the one of way of narcotics' transport. Moreover,
near the town locates one of largest in Russia gypsy's
camp, which is constant source of criminal danger.
In discussion about situation in Capaevsk town also
have to take into account low level of life quality,
which is characteristic of small Russian towns now.
But for correct evaluation of social factors influence
on human emotional stress need additional sociologic
investigation.
In addition should mark that during many decades Chapaevsk
town was one of a center of military industry connected
with production of different chemicals, what ceased
to function not more then 10 years ago and was additional
source of environmental pollution. Presence in environment
unidentified compounds, which could possess, in particular,
mutagenic activity may be one of the reason of high
level genetic damage detected in this town. But lowering
of dispersion of chromosome aberration level discovered
in subgroup with stress (fig.5) supports our main
hypotheses of stress induced origin of genetic damage
in Chapaevsk town.
For conclusion need to say that estimation of psychological
investigations' data accompanied with some difficulties
with which other researchers, as a rule, did not encounter.
In particular, should note that the quota sample generally
used for groups comparing should be more than 15 persons.
Such size of the representative sample usually use
because as a rule psychological data characterized
by a considerable scatter and it is often difficult
to identify significant differences in the smaller
groups. In this work, the quota sample was less than
the above-mentioned one, and for this reason, the
data should be interpret with care. From this position
high level of ultimate correlation detected between
human stress level and blood dioxin content scares
of its definiteness. In this investigation such correlation
were shown for the first time, therefore it have to
be reexamined in future.
Acknowledgements
We wish to thank Prof. B.Revich for organization complex
investigation in Chapaevsk town and for providing
authors with opportunity to use data of TEQ contents
in blood plasma and PhD V.Yurchenko for collection
of psychological questionnaries.
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