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Antioxidant status and genetic damage: a review of some studies undertaken in Russia

Revazova J.A., Khripach L.V. and Ingel F.I.

Research Institute of Human Ecology and Environmental Hygiene,

Moscow, Russia

 

Abstract

This paper presents a review of some of our studies in mice and humans undertaken with the main goal of estimating possible relationships between the antioxidant state of an organism and its sensitivity to genotoxic damage. Different in vitro and in vivo rodent models were used to investigate this problem. The results obtained in acute and chronic mice studies were contradictory. Nevertheless, some findings obtained during the biomonitoring of occupationally exposed human cohorts have demonstrated the benefits of the measurement of antioxidant state when performed in parallel with conventional cytogenetic studies. Differences in the emotional state of human volunteers may have also contributed significantly in inter-individual variability of human responses to environmental genotoxic factors.

 

Introduction

Here we review some of the studies on antioxidant status and genetic damage undertaken in our laboratory over the last decade. The main goal of the investigations undertaken on mice and on human donors was to evaluate possible interrelations between the antioxidant state of an organism and its sensitivity to genotoxic damage.

It is well known that antioxidants are almost universal antimutagenic agents [Gonzalez de Mejia et al., 1997; Odin, 1997; Sarkar et al., 1997; Giri et al., 1998; McCall et al., 1999]. A reason for this effect is the genotoxicity of reactive oxygen species (ROS). ROS are by-products of normal cell metabolism during enzymatic electron-transporting processes, such as mitochondrial respiration and metabolism of xenobiotics by the microsomal system of monooxygenases. ROS can also be generated as the main products of membrane-bound NADPH oxidase in phagocytes. Under normal physiological conditions, when the functioning of antioxidant systems is adequate, ROS are probably of low hazard for an organism. However, there is an excessive increase in ROS generation under the influence of some exogenous or endogenous factors, and also when there is an insufficiency of antioxidant systems, which can result in development of oxidative stress. Oxidative stress is expressed as a disturbance of the stable equilibrium between pro- and antioxidant processes in a direction where prooxidant processes prevail. This disturbance leads to various types of damage at the molecular and cell level [Loft and Poulsen, 1996; Klaunig et al., 1998; Emerit, 1994; Farber, 1994]. Antioxidants in such cases can act as stabilizers of homeostasis. Davies (1988) distinguished primary and secondary systems of antioxidant protection. The first of these systems includes the antioxidant vitamins A, C and E, glutathione, uric acid and enzymes, such as superoxide dismutase, catalase and peroxidases. The second class of the systems includes lipolytic enzymes, proteases, DNA-repair enzymes, ligases and endo- and exonucleases. The differences in the levels of overall antioxidant systems is one of the reasons for the varying sensitivity of organisms to oxidative damage, including genotoxic damage.

Many methods can be applied for the direct estimation of oxidative DNA damage in animals and humans, such as the measurement of production of DNA breaks, 8-OH–guanine, thymine glycol, DNA – DNA/protein scissions [Laval 1996; Vijayalaxmi et al., 1998; Wang et al., 1998: Boiteux and Radicella, 1999]. Another approach includes the use of conventional cytogenetic analysis in parallel with various estimations of antioxidant state in human or animals as was used in our laboratory in the series of studies on mice and humans. Some of the results obtained have been published in Russian [Ingel at al., 1995; Khripach et al., 1995; Ingel et al., 1997] and to date some other work has only been published in abstract books of conferences and workshops [Ingel et al., 1994; 1996; Khripach et al., 1992; 1994; 1995 a,b; 1997; 1998; 1999 a,b,c; Khripach, 1998; Leitina et al., 1994; 1995; Revazova et al., 1999].

One of well known indices for the estimation of an organism's antioxidant state is the susceptibility of red blood cells to oxidative damage which can be measured using the method of peroxidative haemolysis [Kellogg and Fridovich, 1977]. The assay involves the incubation of fresh isolated erythrocytes in phosphate buffered saline, without (spontaneous haemolysis) or with (induced haemolysis) any model ROS source. The percentage of haemoglobin which leaked into the incubation medium for definite period of time is called the "peroxidative haemolysis value".

 

Results

As it can be seen in Fig.1, the mean levels of bone marrow chromosomal aberrations in response to acute cyclophosphamide (CP) injection were proportional to the corresponding peroxidative haemolysis values in mice of both sexes as well as in mice with or without transplantable tumours [Khripach et al., 1992; Khripach et al., 1995]. The prooxidant properties of CP are conditioned by one of its metabolites, i.e. acrolein, which is capable of binding to SH groups; transplantable tumours cause a sharp increase in free radical reactions in various tissue cells of tumour-bearing animals due to immune and phagocyte cell reactions.

Figure 1. Positive correlations between the in vitro sensitivity of erythrocytes to ROS injury and the in vivo sensitivity of bone marrow chromosomes to cyclophosphamide (CP) lastogenic action in F1 mice CBAxC57Bl [Khripach et al., 1997]).
A - female mice (light columns); male mice (dark columns);
B - female mice without tumours (light columns); female mice with inoculated Erlich ascite carcinoma (dark columns);
PH – peroxidative haemolysis value (% of haemoglobin released for 1 hour, 37oC incubation of isolated blood  erythrocytes with Fe+2/ascorbate);
CA-20 and CA-40 – total ChAb levels, % of aberrant metaphases in bone marrow in response to 20 and 40 mg/kg CP i.m. injection;
%mult-20 and %mult-40 - quota of cells with multiple ChAb in bone marrow in response to 20 and 40 mg/kg CP i.m. injection.

Figure 2. Antioxidant activities of natural orange concentrate and corresponding commercial vitaminized drink in vitro [Khripach et al.,1995].
X axis - concentration of additives, mkl / ml of incubation medium; Y axis - malondialdehyde (MDA) spontaneous generation in rat S9 preparation (90 min 37oC);
The drink composition: orange concentrate, citrate, starch, corn oil, flavors, vitamins A, B1, C (12.7; 1.81 and 86.9 mg / l correspondingly).hiThe concentrate was diluted by water (1 : 80 v/v) correspondingly to its content in the commercial drink. The drink supplemented by additional quantity of antioxidant vitamins A and C had, nevertheless, weaker in vitro antioxidant activity compared with the concentrate, due to the presence of corn oil.


Figure 3. Antioxidant activity of the vitaminized drink in F1 mice CBAxC57Bl) [Khripach et al.,1995].
PerHem, % – spontaneous peroxidative haemolysis value.
"control" - intact mice;
"drink" - 2 weeks pretreatment by vitaminized drink;
"acute stress" - immobilization of untreated mice 24 hours before the analysis;
"drink + stress" - immobilization of pretreated by drink mice 24 hours before the analysis.

We have undertaken some studies on mice to evaluate possible antioxidant and antimutagenic properties of a commercial fruit drink containing antioxidant vitamins A and C (see composition of the drink in Fig. 2 legend) [Leitina et al, 1994; Khripach et al., 1995]. The antioxidant activity (AOA) of the drink in vitro was directly determined by inhibition of malondialdehyde production in rat S9 preparations (Fig. 2). The AOA of the drink in vivo was shown by a reduction in the induced peroxidative haemolysis value for F1 mice CBAxC57Bl after their pretreatment with the drink over 2 weeks (Fig. 3). The same animals were analysed by the methods of bone marrow chromosomal aberrations (ChAb) and unsheduled DNA synthesis in blood lymphocytes. It was shown that the drink significantly decreased CP-induced bone marrow ChAb levels as well as UV-induction of UDS in lymphocytes of mice treated by the procedure of forced immobilization (Fig. 4). This drink was later used as a possible prophylactic agent in one of our biomonitoring investigations on occupationally exposed oil refinery workers (see below).

Figure 4. Antimutagenic activity of the vitaminized drink in F1 mice CBAxC57Bl [Khripach et al.,1995].
White columns – the percentage of aberrant metaphases in bone marrow cells;
Dark columns - coefficients of UDS UV-induction in blood lymphocytes.
"control" - intact mice;
"drink" - 2 weeks pretreatment with vitaminized drink;
"CP" – i.p. injection of 10 mg/kg cyclophosphamide;
"drink + CP" – i.p. injection of 10 mg/kg cyclophosphamide to the mice pretreated with vitaminized drink;
"stress" - immobilization (24 hours before the analysis);
"drink + stress" - immobilization (24 hours before the analysis) of the mice pretreated with vitaminized drink.

An analogous approach was used by another Russian group [Durnev et al., 1993] during their investigation of mutagenesis induced by mineral dusts and protection by natural and synthetic antioxidants. SOD, catalase and some concentrations of ascorbate and rutin significantly decreased the mutagenic effects of chrysotile-asbestos and zeolites dusts in human blood cultures. It was also shown in mice that ascorbic acid, rutin, chemically modified flavonoid and 2-mercaptobenzimidazole derivatives (bemitil and thomersol) decreased or completely reduced the clastogenic action of intraperitoneally introduced dusts. The most significant antimutagenic effect was shown with bemitil, which is now used, in clinical practice for diminishing the mutagenic effect of the antimicrobic drug dioxidin.

Figure 5. Different dynamics of peroxidative haemolysis value and level of chromosomal aberrations in bone marrow during chronic exposure to mutagens in mice (Ingel et al., 1995).
Triangles (solid line) - 10 mg / kg of cyclophosphamide i.m. once per five days (24 hours before sacrifice);
Circles (dotted line) - stress (immobilization during 4 hours daily).
A – relative changes in peroxidative haemolysis value (experimental mean to control mean ratio, %);
B – relative changes in mean levels of bone marrow chromosomal aberrations (experimental mean to control mean ratio).
Each group have included 5 F1 CBAxC57Bl males.

It was of interest to us to investigate chronic mutagenic impacts in mice using the examples of chronic CP exposure and chronic immobilisation stress. In contrast to our acute mutagenesis models (Fig. 1) where a positive correlation was obtained between the peroxidative haemolysis value and cytogenetic damage of bone marrow cells, these parameters had quite different dynamics during chronic exposure to damaging agents (Fig.5) [Ingel et al., 1994; Khrypach et al., 1994; Ingel et al., 1995; Khrypach et al., 1995; Leitina et al., 1995]. Hence, tissue specific differences between erythrocytes and lymphocytes were especially apparent during repeated damage of the organism.

Nevertheless, it is still possible to expect that oxidative stability and cytogenetic damage could be correlated in the human population, because chronic environmental factors may act over long periods. During our three recent studies of human volunteers occupationally exposed to oil refinery products or polychlorinated dioxins (more than 120 persons including corresponding control cohorts) it was revealed that the relation between individual peroxidative haemolysis values and ChA levels in blood lymphocytes was complex.

A

B

C

Figure 6. Probable localization of mutagenic risk zones in human cohorts of Jaroslavl town residents, if to consider differences in oxidative stability of their cell membranes (from poster presentation [Khripach et al., 1997]).
A - engineering workers ; B - oil refinery workers; C – workers of the same oil refinery who have received the vitaminized drink (see text) for 1 month prior to the investigation. Dark columns - peroxidative haemolysis value (released Hb, %); white columns – blood lymphocyte ChAb level (% of aberrant metaphases). The data for each human subcohort are ranged in the order of peroxidative haemolysis value increasing from the left to the right, using the same vertical axis calibrated in %.

The data shown in Fig. 6 were obtained during the investigation at Jaroslavl town oil refinery. Jaroslavl inhabitants were divided into three sub cohorts: (A) control group of engineering workers; (B) an occupationally exposed group of oil refinery workers; (C) workers at the same oil refinery who received the vitaminized drink for one month prior to the study. Bar graphs for these three human subcohorts (Fig. 6) were plotted using individual values of ChA frequencies in cultured lymphocytes ranked in the order of increasing of peroxidative haemolysis values. As it is seen in the graphs, at least two areas of elevated mutagenic risk can be identified by the graphic presentation [Khripach et al., 1997]. Surprisingly, the left zone of mutagenic risk corresponds to the persons with the most stable erythrocyte membranes, while the second one is situated approximately in the centre of the distribution. Furthermore, there was no significant difference between (B) and (C) mean ChAb levels. Nevertheless, as it is seen in Fig.6, the drink pretreatment lowered the ChAb level for all persons in addition to those who belong to the left risk zone of the figure, where ChAb increases were revealed [Khripach et al., 1997; Khripach, 1998].

In principle, our next two observations in Moscow (1996) and Chapaevsk (1998) gave analogous results confirming the above described supposition about the existence of several (probably two or three) genotoxic risk zones in the human population associated with different oxidative stability of cell membranes (unpublished data).

Certain benefits can be obtained by estimating emotional stress level during cytogenetic biomonitoring (Fig. 7). The data were obtained in the course of two successive observations (February and March 1995) among the same human cohort of Jaroslavl town inhabitants. The second observation in March was carried out during a registered influenza epidemic. For humans in a state of psychological discomfort (determined by the sum of three scales) a higher genome sensitivity to environmental genotoxicants was revealed, with a greater increase in mean ChAb levels and a decrease in mean UV-induced UDS in response to additional genotoxic factors [Ingel et al., 1996; 1997].

Figure 7. The percentage of cells with chromosomal aberrations (white columns) and the coefficients of UDS UV-induction (dark columns) in blood lymphocytes of Jaroslavl town residents [[Ingel et al., 1997]. Two consequent observations among the same cohort of donors are presented: F – February; M – March.

During a recent study in Chapaevsk, a town polluted by polychlorinated dioxins and furans (PCDD/Fs), the evaluation of human antioxidant state was carried out using two methods, i.e. the method of peroxidative haemolysis and the method of blood plasma luminol-dependent chemiluminescence (CL). Blood plasma luminol-dependent CL is known as a useful measure of pro- and antioxidant balance in an organism [Halliwell and Cutteridge, 1985; Sahnoun et al., 1997; Zwart et al., 1999]. Cytogenetic examinations included the measurement of ChAb in cultured blood lymphocytes and the scoring of buccal micronuclei and several other nuclear abnormalities in inner cheek scrappings. Direct estimation of different PCDD/Fs congeners in blood plasma lipids was carried out for 14 persons from total number of 45 with the use of HRGC/MS by E. Brodsky and N. Klyuev (Severtsev’s Research Institute of Ecology and Evolution, Moscow). The results of the correlative statistical analysis for these 14 women with known PCDD/Fs blood burdens are presented in Table 1.

As is shown in Table 1, blood plasma luminol-dependent CL show significant correlations with PCDD/Fs blood burdens [Khripach et al., 1998; Khripach et al., 1999 a,b,c]. In contrast, peroxidative haemolysis value was not a good marker of the exposure. Linear correlations were also revealed for several psychological tests, especially for overfatigue (P<0,01) [Ingel and Tsutsman, unpublished data]. No correlations were found between PCDD/Fs body burdens and the cytogenetic data (ChAb in blood lymphocytes and micronuclei in buccal epithelium).

Table 1. Coefficients of Pearson linear correlations between PCDD/F's blood plasma content and various biological parameters (Chapaevsk town, N= 14, see text for explanations).

 

Blood plasma contentof PCDD/Fs congeners

 

ChAb 1

 

Buccal
MN 2

 

PerHem 3

 

Blood
Plasma CL4

total PCDD + PCDF,
pg/g lipids
-0.0034
p=.991
-0.072
p=.807
0.035
p=.905
0.5371
p=.048*
total PCDD,
pg/g lipids
-0.0874
p=.766
0.0114
p=.969
0.0728
p=.805
0.585
p=.028*
2,3,7,8-TCDD,
pg/g lipids
-0.3715
p=.191
-0.0293
p=.921
0.1559
p=.595
0.7503
p=.002*
total PCDD + PCDF,
TEQs
0.0504
p=.864
-0.1769
p=.545
0.0667
p=.821
0.4456
p=.110
total PCDD,
TEQs
-0.0493
p=.867
-0.1474
p=.615
0.1306
p=.656
0.5185
p=.057

Notes:

PCDD/F – polychlorinated dibenzo-p-dioxins and furans;
2,3,7,8-TCDD - 2,3,7,8- tetrachlorodibenzo-p-dioxin;
TEQs – toxic equivalents of the mixtures relatively to 2,3,7,8-TCDD toxicity;
1 ChAb – the level of chromosomal aberrations in blood mononuclears;
2 Buccal MN – frequency of micronuclei in buccal epithelium;
3 PerHem – peroxidative haemolysis value;
4 Blood plasma CL – luminol-dependent chemiluminescence of blood plasma.


Using standard statistical criteria, there was a decreasing tendency in the numbers of chromosomal aberrations per 100 cells among the human study groups 1 (plant), 2 (site near plant) and 3 (central area of town). No significant differences between these groups were found for the number of single fragments and the number of chromatid exchanges. Nevertheless, differences in the number of chromosomal exchanges between groups 1 and 3 were statistically significant (P<0.05). The predominance of chromosomal exchanges (dicentrics with paired fragments, acentric rings) was observed in all the groups compared with other types of exchanges. This indicated the possibility of "fresh" new exchanges formation being produced within the investigation period [Zhurkov et al., 1999; Revazova et al., 1999].

The character of the relationships between blood plasma CL and blood ChAb levels provided evidence to suggest that chromosomal breakage had probably increased and then fallen during the period of chemical exposure [Khripach et al., 1999a,b,c]. This finding can explain contradictory cytogenetic effects of PCDD/Fs human exposure published up to now in the scientific literature.

We are now participating in a large complex programme investigating the health of Moscow children. This includes physiological, psychological, immunological, biochemical and cytogenetic examinations. We are using two non-invasive methods for risk group identification, i.e. buccal micronuclei scoring and saliva luminol-dependent CL. Saliva CL was evaluated as a possible non-invasive analogue of blood plasma CL. Preliminary analyses have shown that saliva CL and some cytological indices in buccal epithelium can be useful markers of the children’s health when injured by polluted urban atmosphes.

 

Discussion

In conclusion, it is necessary to note that the approach described raises many methodological and analytical difficulties, and suggests more questions than answers. Nevertheless, some advances in this area have been produced. Preliminary estimation of pro and antioxidant properties for substances can be used for the prediction of their potential mutagenic or antimutagenic activities. Estimation of human antioxidant status as well as of their psychological status is valuable as one of the possible ways to evaluate human individual sensitivity to environmental genotoxicants. This additional information can be especially useful for the analysis of relatively small human cohorts.

 

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