Mutagenesis, Vol. 16, No. 3, 277-281,
May 2001
© 2001 UK Environmental Mutagen Society/Oxford University Press
Trans-stilbene oxide-induced sister chromatid exchange in cultured human lymphocytes: influence of GSTM1 and GSTT1 genotypes
Laboratory of Molecular and Cellular Toxicology, Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Topeliuksenkatu 41 b, FIN-00250 Helsinki, Finland
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Abstract |
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About 50% and 15% of Caucasians lack the glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genes and the corresponding enzyme activity, respectively. Both of these polymorphisms have been shown to affect the genotoxicity of some epoxides in cultured human lymphocytes. Especially GSTT1 appears to be important in whole-blood cultures, probably because GSTT1 activity is high in erythrocytes. The in vitro genotoxicity of trans-stilbene oxide (TSO), a model substrate for GSTM1, has been shown to depend on individual GSTM1 activity. The potential role of GSTM1 genotype, and the possible interference of GSTT1 genotype, has not previously been examined in this context. We have studied TSO-induced sister chromatid exchanges (SCEs) in 72 h whole-blood lymphocyte cultures from 24 healthy human donors, representing different combinations of GSTM1 and GSTT1 positive and null genotypes. TSO clearly increased SCEs in cultures of all donors. The mean number of SCEs per cell induced by 75 and 150 µM TSO was, respectively, 1.5- and 1.3-times higher in cultures of GSTM1 null than GSTM1 positive donors. In another experiment, GSTM1 null individuals showed, in comparison with GSTM1 positive subjects, a 1.8-fold SCE induction by 50 µM TSO. GSTT1 genotype did not have an unequivocal effect. Our findings suggest that the lack of the GSTM1 gene, resulting in reduced detoxification capacity, increases individual sensitivity to the genotoxic effects of TSO.
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Introduction |
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Glutathione S-transferases (GSTs) are a superfamily of enzymes primarily involved in the detoxification of various reactive molecules (Strange and Fryer, 1999
; Wormhoudt et al., 1999; Strange et al., 2000). Several GST isozymes (GSTM1, GSTM3, GSTP1 and GSTT1) have been found to be polymorphic. The GSTM1 polymorphism was detected by Seidegård et al. (1985a, b) who discovered that ~54% of Caucasians lack leukocyte cytosolic glutathione transferase activity towards trans-stilbene oxide (TSO). The ability to perform this reaction was observed as being inherited in an autosomal dominant way, and the activity was lower in heterozygotes than in homozygous wild-type individuals. The leukocyte GST was subsequently shown to be identical with hepatic GST mu (GSTM1), and the polymorphism turned out to be due to a deletion in the GSTM1 gene (null genotype; Seidegård et al., 1987–1989; Brockmöller et al., 1992).
GST deficiency is expected to increase individual sensitivity to chemicals that are detoxified by this route. Consequently, the genetic polymorphism of GSTM1 has become a subject of extensive research, in an attempt to associate GSTM1 genotype with risk of various diseases of environmental origin, especially cancer (Hirvonen, 1999; Strange and Fryer, 1999).
The analysis of sister chromatid exchanges (SCEs) offers an easily quantifiable and sensitive tool to measure genotoxicity of epoxides in vitro. Wiencke et al. (1990) previously observed that individual ability to perform TSO conjugation correlates with the induction of SCEs by TSO in cultured human lymphocytes, GSTM1-deficient subjects showing higher SCE induction than GSTM1-positive subjects. These findings suggested that GSTM1 deficiency, leading to impaired TSO detoxification, results in increased damage to DNA, reflected as an enhanced SCE response after in vitro TSO treatment. However, despite the phenotypic evidence, the association between increased sensitivity to TSO genotoxicity and GSTM1 gene deletion has not yet been proven.
In fact, Wiencke et al. (1990) found that the distribution of TSO sensitivity was trimodal, the GSTM1-deficient individuals being either moderately or highly sensitive. The highly sensitive individuals were considered possible carriers of a second genetic deficiency that further increases susceptibility to TSO. The lack of GSTT1 activity, due to a gene deletion affecting 10–20% of Caucasians, could possibly be such a deficiency, particularly as Wiencke et al. (1990) used cultures of whole blood containing erythrocytes, which (in GSTT1-positive individuals) are high in GSTT1 activity. Furthermore, the GSTT1 genotype has previously been shown to affect SCE induction by other epoxides such as 1,2:3,4-diepoxybutane, styrene-7,8-oxide and 3,4.epoxy-1-butene (Norppa et al., 1995; Wiencke et al. 1995; Landi et al., 1996, 1998; Pelin et al., 1996; Bernardini et al., 1998; Ollikainen et al., 1998; Schlade-Bartusiak et al., 2000) and could thus also influence TSO-induced SCEs. It is presently not known if TSO is a substrate for GSTT1.
It would be important to show if the previously observed correlation between TSO conjugation ability and genotoxicity is really associated with GSTM1 genotype. Likewise, the possible role of the GSTT1 genotype in this context should be clarified. In the present study, we used the lymphocyte SCE assay to examine these questions. Our results indicate that the homozygous deletion of the GSTM1 gene, but not of the GSTT1 gene, affects TSO genotoxicity.
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Materials and methods |
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Samples of heparinized peripheral blood were collected from 24 healthy volunteers representing the four combinations of GSTT1 and GSTM1 genotypes, as determined by a technique based on multiplex polymerase chain reaction (Hirvonen et al., 1993; Norppa et al., 1995
). Individuals classified as GSTM1 positive (GSTM1+) and GSTT1 positive (GSTT1+) had at least one allele of the respective gene, while GSTM1 null (GSTM1–) and GSTT1 null (GSTT1–) subjects had a homozygous deletion of the gene. The donors represented both sexes and different ages and were all current non-smokers (Tables I and II). The studies were performed in two independent experiments, using mostly the same donors.
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Whole-blood lymphocyte cultures, duplicated for each treatment and donor, were set up in air-tight glass injection bottles (20 ml) containing 0.3 ml of whole blood and 6.0 ml of culture medium with previously defined constitution (Norppa et al., 1995
). TSO (Aldrich, Germany; purity 98%; dissolved in acetone, Merck, Darmstadt, Germany) was added into the cultures 24 h after initiation by microsyringes at a volume of 10 µl. The first experiment included 50 and 150 µM concentrations and the second experiment 75 and 150 µM concentrations of TSO. Control cultures received 10 µl of acetone. The cultures were incubated at 37°C for a total culture time of 72 h, and 2 h before fixation 85 µl of Colcemid solution (10 µl/ml, final concentration 0.13 µg/ml) was added. After hypotonic treatment, fixation and coding for a blind analysis, the cell suspensions were dropped onto microscope slides and stained by a modification of the fluorescence-plus-Giemsa technique (Perry and Wolff, 1974; Husgafvel-Pursiainen et al., 1980). For each culture, one microscopist scored SCEs in 25 second-division cells, making a total of 50 cells per donor and treatment. In addition, the frequency of first (M1), second (M2) and third (M3) division metaphases was evaluated from 200 cells per culture for replication index (RI) (mean number of replications completed by the scored metaphases). The RI was calculated as: RI = (M1 + 2xM2 + 3xM3)/100. The SCEs (and RIs) were analyzed by a different scorer in experiment 1 than in experiment 2.
The data on SCEs and replication indices were analyzed statistically by using the t-test.
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Results |
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The results of the SCE analysis of the TSO-treated lymphocyte cultures from the 24 donors are presented in Tables I and II
, separately for the two independent experiments. A highly significant increase (P < 0.001) in SCEs was obtained by all concentrations of TSO. The genotype effect was evaluated after subtracting, for each individual, the mean SCE frequency of the respective acetone control cultures from the SCE value obtained with each TSO treatment, to obtain the frequency of TSO-induced SCEs. In this way, individual baseline SCE frequency did not influence the data. Results from the first experiment (Figure 1a) showed that, at 50µM, the mean number of TSO-induced SCEs per cell was 1.7–1.8 times higher in GSTM1 null subjects, positive (4.4) or null (4.3) for GSTT1, than in GSTM1 positive donors (mean 2.5 for both GSTT1 null and positive). The differences between GSTM1 null and positive subjects were statistically significant among both GSTT1 positive (P = 0.047) and null (P = 0.049) donors. Our findings indicated that individual TSO sensitivity depends on GSTM1, but not on GSTT1 polymorphism. However, at 150 µM, quite similar mean induced SCE values (8.0–9.6 SCEs/cell) were obtained in all genotype groups, and no statistically significant differences were seen. Thus, no clear genotype effects could be demonstrated in this experiment at the higher concentration of TSO.
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In the second experiment (Figure 1b
), 75 µM TSO induced 1.5–1.6 times more SCEs in GSTM1 null donors than in GSTM1 positive donors among both GSTT1 positive (mean 10.0 versus 6.6; P = 0.026) and GSTT1 null (mean 9.9 versus 6.3; P = 0.006) donors. Thus, this series also suggested that GSTM1, but not GSTT1, influences TSO-induced SCEs. Results obtained with 150 µM TSO further supported this view, with 1.2–1.4-fold higher values obtained in GSTM1 null subjects. The difference between GSTM1 null and positive subjects was statistically significant for both GSTT1 positive (mean 15.5 versus 13.4; P = 0.027) and GSTT1 null (17.3 versus 11.9; P = 0.003) individuals. The excess number of induced SCEs per cell observed in the GSTM1 null subjects in comparison with GSTM1 positive donors was similar at 75 (3.4) and 150 µM (3.6), suggesting no additional protection by GSTM1 at the higher concentration. No significant differences in induced SCEs could be attributed to the GSTT1 genotype. The overall level of SCE induction was somewhat higher in the second experiment than in the first one, probably reflecting variation between experiments and the fact that two different technicians performed the two experiments. No effect of GSTM1 or GSTT1 genotypes on the baseline level of SCEs in control cultures was obvious, but it also has to be kept in mind that the study was not designed to reveal such effects which, if they exist, are expected to be small. RI, a measure of cell cycle delay, was not decreased significantly at 50 or 75 µM concentrations of TSO, but at 150 µM in the second experiment a drop in RI was seen. No effect of the GST genotypes on RI could be observed.
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Discussion |
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The present study demonstrated that GSTM1 null individuals are more sensitive than GSTM1 positive individuals to the genotoxic effects of TSO, as measured by SCE induction in cultured lymphocytes. This finding supports the earlier results of Wiencke et al. (1990) on the influence of GSTM1 activity on SCE induction by TSO, and agrees with the idea that GSTM1 is a major GST isozyme in the detoxification of TSO (Seidegård et al., 1987; Brockmöller et al., 1992
).
Our results did not show any important modulation of TSO genotoxicity by the GSTT1 polymorphisms. Thus, if there is a trimodal distribution of TSO sensitivity (Wiencke et al., 1990), it is probably explained by factors other than GSTT1 genotype, e.g., polymorphism of another GST isozyme or epoxide hydrolase. TSO is an effective inducer of a number of hepatic enzymes, including GSTs and epoxide hydrolase, and is a substrate for human leukocyte cytosolic epoxide hydrolase (Mukhtar et al., 1978; Bucker et al., 1979; Seidegård et al., 1979, 1984; Carlberg et al., 1981; Kuo et al., 1981, 1984). Sensitivity to TSO may also depend on polymorphisms of DNA repair enzymes or individual variation in protective factors present in blood. It may be useful to add that the trimodal SCE response to TSO does not appear to be due to GSTM1 heterozygotes, as the intermediate responders described by Wiencke et al. (1990) were GSTM1 deficient.
Although GSTM1 activity of mononuclear leukocytes has been demonstrated in a number of studies, experiments associating GSTM1 genotype with toxicological endpoints in lymphocytes have been scanty. Earlier studies with other epoxides showed that GSTM1 polymorphism affects the genotoxicity of 1,2-epoxy-3-butene, a metabolite of 1,3-butadiene (Uusküla et al., 1995; Sasiadek et al., 1999). On the other hand, GSTM1 genotype did not influence SCE induction by another 1,3-butadiene metabolite, 1,2:3,4-diepoxybutane, or by styrene-7,8-oxide, a reactive metabolite of styrene (Norppa et al., 1995; Landi et al., 1996, 1998). However, SCE induction by all of these three epoxides was higher in GSTT1 null than GSTT1 positive individuals (Norppa et al., 1995; Wiencke et al., 1995; Landi et al., 1996, 1998; Bernardini et al., 1998; Ollikainen et al., 1998; Schlade-Bartusiak et al., 2000). Ethylene oxide induced SCEs only in blood cultures of subjects deficient in erythrocytic GST (GSTT1) (Hallier et al., 1993). GSTT1 activity is particularly high in erythrocytes, and removal of erythrocytes strongly reduced individual variation in SCE induction by 1,2:3,4-diepoxybutane (Landi et al., 1995; Pelin et al., 1996; Kligerman et al., 1999). SCE induction by a third epoxide metabolite of 1,3-butadiene, 3,4-epoxybutane-1,2-diol, was not affected by GSTM1 or GSTT1 genotype (Bernardini et al., 1996).
The existing information indicates that the lymphocyte SCE assay can distinguish rather small differences among various genotypes in genotoxic response, when variations among experiments and among investigators are taken into account in the experimental design. Such in vitro data may be used to predict in vivo sensitivity of a genotype. As the spectrum and level of various metabolic enzymes varies among tissues, lymphocyte assays may be predictive of risk in blood and blood-forming tissues but not necessarily, e.g., in the liver. It should, however, be kept in mind that the importance of various metabolic routes could depend on exposure levels. In the present study, the GSTM1 genotype effect was relatively stronger at the low rather than the high TSO concentration, suggesting saturation in the protective effect of GSTM1. Since the genotoxic effects of TSO (and experimental variation) increase with TSO concentration, it becomes more difficult to show a difference between the genotypes at higher doses. This might explain why we could not see the GSTM1 genotype effect at 150 µM concentration in the first experiment. It is unclear how such findings should be extrapolated to long-term low-level exposure in vivo.
As genetic polymorphisms of xenobiotic-metabolizing enzymes (XMEs) can affect the result of genotoxicity assays with human cells, the choice of the donor may greatly influence the outcome of the test, creating a great variability in results among different studies and complicating the use of assay data in risk assessment. Although the genotype effect in the present experiments was relatively small (1.2–1.8-fold differences in SCE induction between the genotypes), polymorphisms of XMEs could in other circumstances yield a positive effect in one group but a complete lack of response in another (Hallier et al., 1993). Therefore, understanding the spectrum of XMEs and control of their polymorphisms appear to be important issues when human cells are used for toxicity testing.
In conclusion, individuals with a homozygous deletion of the GSTM1 gene were found to be more sensitive than GSTM1 positive donors to the genotoxicity of an in vitro treatment with TSO, as measured by SCE induction in cultured lymphocytes. This finding indicates that GSTM1 activity protects against the DNA-damaging effect of TSO, supporting previous findings associating TSO sensitivity with GSTM1-deficient phenotype. The genotype of GSTT1, another polymorphic GST earlier found to modulate epoxide genotoxicity in whole-blood cultures, could not be shown to influence TSO genotoxicity.
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Acknowledgments |
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We wish to thank the blood donors for participating in the study. The visit of S.B. to Finland was supported by the Centre for International Mobility (CIMO) under the European Scholarship Programme of the Ministry of Foreign Affairs.
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Notes |
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1 To whom correspondence should be addressed. Tel: +358 9 47472336; Fax: +358 9 47472110; Email: hannu.norppa{at}occuphealth.fi
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Received on September 27, 2000; accepted on January 8, 2001.
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