Mutagenesis, Vol. 18, No. 1, 13-17,
January 2003
© 2003 UK Environmental Mutagen Society/Oxford University Press
Repairability during G1 of lesions eliciting sister chromatid exchanges induced by methylmethanesulfonate or ethylmethanesulfonate in bromodeoxyuridine-substituted and unsubstituted DNA strands
1 Departamento de Biología, Instituto Nacional de Investigaciones Nucleares, Apartado Postal 18-1027, D.F. Mexico, México
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Abstract |
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The repairability during G1 of DNA lesions eliciting sister chromatid exchanges (SCE) induced by methylmethanesulfonate (MMS) and ethylmethanesulfonate (EMS) in BrdU-substituted and unsubstituted DNA strands was determined in murine salivary gland cells in vivo. The SCE frequency was determined after exposure to MMS or EMS during early and late G1 in the first or second cell division. The inducibility and repairability of SCE-eliciting lesions during G1 in BrdU-substituted and unsubstituted strands were estimated considering that in the first division induction occurs on the unsubstituted strand and during the second division in one unsubstituted and one BrdU- substituted DNA strand. The results indicate that DNA lesions induced by MMS are 50% repaired in both the BrdU-substituted and unsubstituted strands and those induced by EMS are 60% repaired in the unsubstituted strand but only 20% in the BrdU-substituted strand. The increase in sensitivity of the BrdU-substituted strand to SCE induction with respect to the unsubstituted strand was 155 and 45% for MMS and EMS, respectively. These results imply that SCE-inducing lesions produced by MMS and EMS are only partially repaired and that BrdU incorporation could sensitize DNA not only to the induction of lesions eliciting SCE, but also to the induction of non-repairable lesions.
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Introduction |
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The sister chromatid exchange (SCE) assay is a sensitive method for detecting the genotoxic activity of agents and is used in many studies, although the genetic implications and the mechanism of SCE formation are not known. There is evidence indicating that this event is caused by inhibition of DNA synthesis or of the enzymes involved in this process (Rainaldi and Mariani, 1982
) and by persistent DNA lesions before the period of DNA synthesis (Wolff et al., 1974; Kato, 1980). This implies that DNA lesions that were not repaired during G1 could cause SCE in the succeeding division (Morimoto, 1983) and, if they persist beyond DNA synthesis, could cause SCE in successive divisions (Morales-Ramírez et al., 1984a, 1988, 1990, 1992, 1995a) unless they were repaired during the subsequent G1. There is some evidence in vitro for the repairability during G1 of lesions induced by different agents that cause SCE (Lambert et al., 1983, 1984; Hedner et al., 1984; He and Lambert, 1985). However, little emphasis has been placed on the repairability of lesions in BrdU-substituted DNA, even though BrdU seems to play an important role in sensitivity to SCE induction, either increasing or inhibiting the rate of SCE induction by different mutagens (Popescu et al., 1980; Ockey, 1981; Schvartzman and Tice, 1982; Zhao et al., 1992; Morgan and Wolff, 1984). Evidence with regard to these aspects is important, in order to establish the fate of lesions involved in SCE formation and the role that BrdU is playing not only on the sensitivity to induction of lesions eliciting SCE, but also on repairability of these lesions. This in turn permits an approach to the interpretation of SCE induction by genotoxicants.
We have developed an in vivo model in synchronized salivary gland cells that allows one to determine repair during G1 of lesions eliciting SCE (Morales-Ramírez et al., 1995b; González-Beltrán and Morales-Ramírez, 1999). The aim of the present study was to establish the repairabilty during G1 of DNA lesions eliciting SCE induced by methylmethanesulfonate (MMS) and ethylmethanesulfonate (EMS) in the unsusbtituted and the bromodeoxyuridine (BrdU)-substituted DNA strands in such a system.
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Materials and methods |
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Rationale
In order to determine the repairability during G1 of lesions eliciting SCE induced by MMS or EMS, salivary gland cells were induced to divide synchronously by administration of isoproterenol to mice while the mutagens were administered in either early or late G1. As SCE occurs during S phase, the frequency induced in late G1 represents the maximum possible induction of SCE-eliciting lesions and the frequency of SCE induced in early G1 represents the non-repaired lesions. Exposure during G1 of the first two cell divisions required for sister chromatid differentiation allows one to establish the inducibility and repairability of lesions produced in BrdU-unsubtituted strands. As during G1 of the second division the DNA has one BrdU-substituted and one unsubtituted strand, the inducibility and repairability of lesions in the BrdU-substituted strand were determined by the difference, assuming that half of the SCE induced during the first division would occur during the second division in the unsubstituted strand.
The above is true assuming that the probability of one lesion expressed as an SCE is 1.0 and that the lesions are not involved in SCE at the same site in subsequent divisions; the latter means that there is no cancellation. Other possibilities theoretically explored, such as a 0.5 probability of expression of the lesions as SCE in the presence or absence of cancellation, also produced a nearly 1:1 proportion of SCE by exposure in the first and second divisions. The exception is when cancellation exists and the probability of lesions expressed as SCE is 1.0; in such a case the proportion of SCE induced in the first division with respect to those induced in the second division should be 1:2. All this is shown in Figure 1.
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Protocol
The experimental protocol is based on stimulation of synchronous division of salivary gland cells in vivo by isoproterenol (Barka, 1965
; Baserga, 1970). Each treatment induces a single cell division that takes ~40 h. S phase begins at ~14 h and mitosis at 28 h after isoproterenol administration; the first was demonstrated by incorporating tritiated thymidine and the second by scoring the number of mitoses (Morales-Ramírez et al., 1995b). In practice, synchronous division was induced by s.c. injecting groups of between five and seven mice (see Table I) with 0.3 mg/kg body wt isoproterenol in aqueous solution. Fourteen hours later, at the time when the cells were undergoing DNA synthesis, the animals were i.p. injected with a BrdU–charcoal aqueous suspension (0.6 mg BrdU/g body wt) (Morales-Ramírez, 1980; Morales-Ramírez et al., 1984b). BrdU was only administered in the first division. Forty-eight hours after the first isoproterenol injection a second was administered. The fact that the cell divisions are separated by 48 h and the BrdU dose is very low implies that the chromosomes could only incorporate BrdU during the first cell division. The treated groups of mice were injected with MMS (0.27 µM/g body wt) or EMS (1.2 µM/g body wt) at either 6 (early G1) or 13.5 h (late G1) after the first or the second isoproterenol injection. Finally, the animals were i.p. injected with colchicine (3.75 mg/kg body wt) 28 h after the second stimulation with isoproterenol and killed 3 h later by cervical dislocation. A mutagen-untreated control group was included.
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Animals
Two- to three-month-old BALB/c male mice weighing 30 g were used in these experiments. The animals were housed in plastic cages under controlled conditions of temperature and dark–light periods and were fed with Purina chow for small rodents and water ad libitum.
Chemicals
Isoproterenol hemisulfate, BrdU and colchicine were obtained from Sigma Chemical Co. MMS and EMS were obtained from Aldrich Chemical Co.
Slide preparation
The salivary glands were dissected, cleaned of ganglia and adipose tissue and minced with scissors in phosphate-buffered saline. The fragments were subjected to hypotonic treatment with 0.75 M KCl for 15 min each in a 3:1 methanol/acetic acid solution and afterwards stored at 4°C for at least 18 h. The tissue fragments were dissociated in a drop of 60% acetic acid on a slide and briefly heated on a hotplate. The cell suspension was dispersed on the slide by heating and moving the drop along the slide until it was completely dry (Morales-Ramírez et al., 1995b).
Differential staining
Differential staining of the sister chromatid was done using the fluorescence plus Giemsa method (Perry and Wolff, 1974), with slight modifications (Goto et al., 1975).
Analysis and statistical methods
Considering that the method used to obtain the metaphase figures does not always allow conservation of the full chromosome complement and since ~10% of the cells are tetraploid (Morales-Ramírez et al., 1984b), SCE were scored for at least 1200 chromosomes per mouse, equivalent to ~30 cells (see Table I
). The minimal number of chromosomes scored per cell was 15, because it was observed that this number allows one to calculate the SCE frequency per cell (Morales-Ramírez et al., 1995b). The statistical significance between groups was determined with Student's t-test, using Microsoft Excel.
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Results |
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Table I
shows the results of SCE induction by exposure to MMS or EMS in early and late G1 of the first and second divisions, i.e. before or after BrdU incorporation. Induction of SCE in all the treated groups was statistically significant with respect to their current control groups. MMS induces nearly twice as many SCE in late G1 as in early G1 in cells exposed before BrdU incorporation. This difference was statistically significant. A similar difference in SCE frequency was obtained in the second cell division, i.e. in the cell cycle after BrdU incorporation. This implies that in both cell divisions there is a reduction of nearly 50% in SCE-inducing lesions during G1.
During the first cell division the increase in SCE induction by EMS in early G1 is nearly one-third of that induced at late G1. In the second division induction of SCE during early G1 is two-thirds of that induced in late G1. This can be interpreted to mean that SCE-inducing lesions are reduced during G1, although those induced after BrdU incorporation are reduced less.
The susceptibility of SCE induction in unsubstituted and BrdU-substituted strands was established by comparing SCE induction in late G1 in both cell cycles, which means in conditions that permit less repair. MMS induces three SCE more (77.5%) during the second division, i.e. after BrdU, than during the first division. Under the same conditions EMS only increased the frequency by 0.7 SCE (22.6%). In order to determine the effect of BrdU incorporation more accurately, it was necessary to consider that in the second division only one strand is BrdU-substituted. The frequency of SCE-inducing lesions per cell caused in the BrdU-substituted strand was calculated by difference, as in the second division there is one substituted and one unsubtituted strand and the induction of SCE in the unsusbtituted strand during the second division would be half of that induced during the first division.
As shown in Table II, the results indicate that BrdU increases the susceptibility of DNA to SCE induction by MMS by 2.5 times and that repair of the lesions in the BrdU-substituted and unsubstituted strands is ~45 and 55%, respectively. BrdU slightly increased the susceptibility to SCE induction by EMS; the repair of SCE-inducing lesions in the unsubstituted strand was 61%, while in the BrdU-substituted strand it was only 20%. The conclusions obtained from the analysis are as follows: (i) BrdU induces a much higher sensitivity to SCE induction by MMS than by EMS; (ii) the lesions caused by MMS and EMS in unsubstituted DNA that elicit SCE are repaired with similar efficiency during G1; (iii) the lesions induced by EMS in the BrdU-substituted strand are poorly repaired.
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Both the susceptibility of SCE induction and repairability can also be analyzed in the cell populations by comparing the curves of cumulative frequency of cells with respect to SCE number (Figures 2 and 3
). Comparison of the curves obtained by exposure to MMS clearly indicates that in the second division there is greater SCE induction than in the first and that SCE-inducing lesions are partially repaired in both divisions. The curves obtained by exposure to EMS indicate that induction before and after BrdU incorporation were almost identical, but there are differences in the repairability of lesions induced before and after BrdU. In fact, the curve obtained in early G1 after BrdU incorporation is very similar to that obtained during late G1, i.e. the difference in frequencies of cells with six or more SCE between the curves was only 10%. This implies that there are no differences in susceptibility to SCE induction by EMS in the two cell divisions and that lesions induced in BrdU-substituted DNA are less efficiently repaired during G1.
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Discussion |
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The interpretation of SCE induction by exposure to mutagens in the first and second divisions has created some controversy, because a higher induction of SCE in the second division with respect to the first could be due to the cancellation (Stetka, 1979
) phenomenon or to DNA sensitization by BrdU incorporation (Morales-Ramírez et al., 1984a, 1994). The cancellation phenomenon is due to the occurrence of SCE at the same site in subsequent divisions, which makes it impossible to score them, as shown in Figure 1. In fact, there are several factors that could determine the differences between the SCE frequencies obtained in the first and second divisions. The fate of DNA lesions surely plays an important role in producing such differences: (i) their repairability (Morales-Ramírez et al., 1995b; González-Beltrán and Morales-Ramírez, 1999); (ii) the probability of their expression as SCE (Morales-Ramírez et al., 1990); (iii) the formation of secondary lesions, i.e. the generation of SCE-inducing lesions from others incapable of producing SCE (Kaina and Aurich, 1985); (iv) as mentioned earlier, the possibility of lesions causing SCE in subsequent divisions (Morales-Ramírez et al., 1988, 1990, 1992, 1995a). Also, the heterogeneity of lesions induced by alkylating agents (Beranek, 1990) and their respective fates increase the difficulty of analysis.
In order to determine the effect of the above mentioned factors, the theoretical proportions of SCE induced by exposure during the first and second divisions were estimated for lesions with a 0.5 or 1.0 probability of expression (Morales-Ramírez et al., 1990), as were the persistence and occurrence of SCE at the same locus in successive divisions (Morales-Ramírez et al., 1988, 1990, 1992, 1995a) or for the opposite circumstances (Schvartzman and Goyanes, 1980) (Figure 1). The latter is relevant because it opens up the possibility that cancellation occurs. In this figure the probability of producing the different kinds of chromosomes is displayed, considering only those chromosomes that could be induced under the different circumstances. For exposure only in the second division the descendents of the damaged unifilarly BrdU-substituted strand are considered, which would cause 0.5 or 0.1 SCE per lesion according to their probability of expression.
The expected proportions of SCE 1 and SCE 2 would be almost the same for all conditions, with the exception of those obtained for lesions with a 1.0 probability of expression and with the possibility of occurrence of SCE in the same locus. Under such circumstances SCE 2 would be double SCE 1. The results presented here indicate that the frequency of SCE 2 is more than twice that of SCE 1 on exposure to MMS, but only slightly higher after exposure to EMS. This could imply that MMS induces a higher proportion of SCE-inducing lesions with a high expressivity as SCE and with the possibility of causing SCE in the same locus. This disagrees with the 50% probability of being repaired during the subsequent division. In the same context, EMS mainly induced SCE-eliciting lesions that were persistent but with either low probability of expression or inability to induce SCE in subsequent divisions at the same locus.
In our previous studies using the three-way differential staining protocol, which permits the analysis of SCE per cell cycle, we observed that only a fraction of SCE-inducing lesions are capable of inducing SCE in subsequent divisions. One-third of the SCE-eliciting lesions caused by MMS were capable of inducing SCE at the same locus (Morales-Ramírez et al., 1992), while only one-sixth of those induced by EMS were (Morales-Ramírez et al., 1995a). However, the conditions of the protocol used did not eliminate other possibilities.
Under these circumstances the higher frequency of SCE 2 with respect to SCE 1 could not be explained by cancellation, or at least not totally, although it could be explained by exposure to mutagens of the BrdU-substituted strand during the second division. However, evidence has been reported that BrdU incorporation inhibits SCE induction by MNNG (Popescu et al., 1980) and also by MMS (Okey, 1981). This latter result is clearly at variance with the results obtained in the present study; the contradiction could be explained in terms of the difference in the method used to calculate SCE induction in the BrdU-substituted and unsubstituted strands, but more probably by the fact that in the present study BrdU was only incorporated in the first division.
Our results indicate that BrdU increases the susceptibility of DNA to SCE induction by MMS by 155% and repairability of the lesions in both the BrdU-substituted and unsubstituted strands is ~50%. BrdU increases the susceptibility to SCE induction by EMS by only 45% and the repairability of SCE-inducing lesions in the unsubstituted strand is 60%, while in the BrdU-substituted strand it is only 20%.
The increase in sensitivity to SCE-eliciting lesions due to BrdU could be attributable to the new electrophilic site represented by the bromine atom and the affinity of the mutagens for this site. Application of the previously mentioned analysis of BrdU susceptibility to data published earlier, obtained in the same salivary gland system using methylnitrosourea (MNU) and ethylnitrosourea (ENU) (González-Beltrán and Morales-Ramírez, 1999), indicates that both agents increased SCE induction in the BrdU-substituted strand with respect to the unsubstituted one by nearly 144%. The increase in sensitivity was very similar to that obtained with MMS. The implication is that BrdU incorporation increases the probability of SCE induction by these three agents at the same rate, and with a much lower probability for EMS. This could not be explained by the reactivity of these mutagens with the new and highly nucleophilic site represented by the bromine atom, because MMS, MNU and ENU have very different s (Swain-Scott constant) values (Beranek, 1990).
With regard to the repairability of SCE-eliciting lesions during G1 induced in the BrdU-substituted strand, the results obtained in the same experimental model with MNU and ENU (Gonzalez-Beltrán and Morales-Ramírez, 1999) indicate that lesions induced by MNU are not repaired and that ENU-induced lesions are 50% repaired, as are those induced by MMS. This implies that, if the bromine atom is the target, the consequences of the reaction with the mutagens produce different damage, as is inferred by the differences in repairability. This damage does not seem to be dependent on whether the adduct produced is a methyl or an ethyl.
The conclusions of the present study are as follows: (i) MMS-induced lesions eliciting SCE in unsubstituted DNA are partially repaired during G1; (ii) BrdU incorporation doubles the sensitivity to SCE induction by MMS; (iii) these additional lesions were also partially repaired; (iv) EMS-induced lesions involved in SCE induction are partially repaired during G1; (v) BrdU substitution slightly sensitizes DNA to SCE induction; (vi) lesions induced in BrdU-susbtituted DNA are poorly repaired.
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Acknowledgments |
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We wish to thank Angel Reyes Pozos, Perfecto Aguilar, Felipe Beltrán and Miguel Angel García for excellent technical assistance and Rosa María Noriega for English editing. This study was supported by the `Consejo Nacional de Ciencia y Tecnología' (National Council of Science and Tecnology), project PN-33167-N.
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Notes |
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1 To whom correspondence should be addressed. Tel: +52 5 3297200; Fax: +52 5 3297332; Email: pmr{at}nuclear.inin.mx
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References |
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Received on May 4, 2001; revised on January 30, 2002; accepted on February 7, 2002.
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