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M K Conner

Publications and source records attributed to M K Conner.

At least 19 recordsLinked to original sources
PubMed1992

Tumor formation and sister chromatid exchange induction by ethyl carbamate: relationships among non-pregnant murine females, gravid dams, and transplacentally exposed offspring.

Sister-chromatid exchange (SCE) induction and cell cycle kinetics alterations by ethyl carbamate in bone marrow of non-gravid murine Swiss Webster, ICR/Jcl, and C57Bl/6J dams were evaluated, and data from non-gravid females were compared with those previously reported for pregnant dams of the same strains. In addition, lung adenoma induction by ethyl carbamate in gravid Swiss Webster dams, their offspring, and in non-pregnant Swiss Webster females was also determined. Relative cytogenetic and tumor responses in non-gravid and gravid Swiss Webster females and their offspring were compared. In contrast to the increased sensitivity reported for gravid Swiss Webster dams versus ICR/Jcl and C57Bl/6J dams, SCE responses to 1.1, 2.2, or 3.3 mmol/kg of ethyl carbamate in non-gravid females were approximately equivalent among strains. In Swiss Webster and C57Bl/6J (but not ICR/Jcl) strains, SCE responses in non-gravid females at 2.2 and 3.3 were significantly lower than those of their pregnant counterparts. Tumor induction by 3.3 mmol/kg ethyl carbamate paralleled relative SCE induction with Swiss Webster dams, demonstrating a 5-fold increase in the number of tumors relative to their offspring and a 4-fold enhancement of tumor induction relative to their non-pregnant counterparts.

Adenoma↗
PubMed1990

Methods for the isolation and detection of etheno adducts in nucleotide pools in vivo following exposure to ethyl carbamate.

Cellular extraction and high-performance liquid chromatographic methods were developed for the isolation of etheno adducts from nucleotide pools formed in vivo following exposure to the chemical carcinogen ethyl carbamate. These techniques were employed to detect etheno adduct formation using BDF1 mice and rainbow trout (Salmo gairdneri) as test species following inter-peritoneal injection of the chemical. Ethenoadenine was detected in splenocyte nucleotide pools of mice after acute (24 h) exposure and chronic (two weeks) exposure. Several etheno adducts (i.e. ethenoadenine, etheno-AMP, etheno-ADP and etheno-ATP) were also detected in total spleen cell nucleotide pools of trout following acute ethyl carbamate exposure.

Adenine↗
PubMed1990

Comparative in vivo sister chromatid exchange induction by ethyl carbamate in maternal and fetal tissues of tumor-susceptible and -resistant murine strains.

Murine susceptibility to ethyl carbamate-induced carcinogenesis is strain dependent. In vivo sister chromatid exchange (SCE) responses to ethyl carbamate were evaluated in bone marrow cells of gravid adenoma-susceptible (ICR/Jcl), and resistant (C57Bl/6J) and (DBA/2J) murine dams, as well as in liver cells of their respective ICR/Jcl, C57Bl/6J X DBA/2J (BDF1), and DBA/2J X C57Bl/6J (BDF), fetuses following a single intravenous injection of 1.1, 2.2, or 3.3 mmol/kg of ethyl carbamate on gestation day 13/14. Bone marrow tissues of C57Bl/6J and DBA/2J, but not ICR/Jcl dams, demonstrated greater sensitivity to SCE induction than liver cells of their respective fetuses. Furthermore, relative SCE responses in bone marrow among dams indicated greater sensitivity of the more tumor-susceptible ICR/Jcl and C57Bl/6J strains to SCE induction by ethyl carbamate relative to the more tumor-resistant DBA/2J strain. In addition, concurrent alterations (stimulation or inhibition) of bone marrow cell cycle kinetics by ethyl carbamate were consistent with hormone-related, strain-dependent hematopoietic stress during pregnancy.

Animals↗
PubMed1990

Disparate cytogenetic responses of peripheral blood and spleen lymphocytes to ethenoadenine nucleotides in vitro; maximal expression in splenic lymphocytes under conditions of enhanced membrane permeabilization.

Exogenously supplied 1,N6-ethenoadenosine triphosphate (epsilon-ATP) and 1,N6-ethenodeoxyadenosine triphosphate (epsilon-dATP) are potent inducers of sister chromatid exchanges (SCEs) in murine spleen lymphocytes but not in peripheral blood lymphocytes cultured in vitro. Data suggest that spleen lymphocyte membranes are inherently more permeable than blood lymphocytes to transient uptake of epsilon-ATP and epsilon-dATP. The effect of media pH and divalent cations on SCE frequency and chromosomal aberrations in spleen cells pulse-treated with epsilon-ATP were studied. The most dramatic responses were observed at pH 8.0 in Ca2+/Mg2(+)-free Hank's balanced salt solution (HBSS). Under the latter conditions, SCE and chromosomal aberration responses (mean +/- SD) of lymphocytes from replicate mice were 69.4 +/- 13.1 SCE/cell and 49 +/- 8.5% of cells with aberrations respectively. Chromosomal aberrations included multiple complex breakage and rearrangements. In HBSS containing Ca2+ (0.575 mM) and Mg2+ (0.4 mM) in concentrations equivalent to those in RPMI 1640, maximum SCE and aberration responses of 31.8 and 28% were observed in cells treated at pH 6.0. Similarly, maximum SCE frequencies (46 +/- 1.6 SCE/cell) and percentage of cells with aberrations (8 +/- 1.4%) were present in spleen cells treated at pH 6.0 in RPMI media. SCEs and aberrations decreased with increasing pH in either media containing divalent cations. In Ca2+/Mg2(+)-free HBSS, the highest mitotic index and fastest cell cycling were seen at pH 6.0. Mitotic indices dropped dramatically at pH 7.4 but recovered considerably at pH 8.0, in spite of a high frequency of cells containing aberrant chromosomes. The most dramatic cytotoxicity occurred at pH 6.0 in HBSS containing Ca2+ and Mg2+. Decreased cytotoxicity was apparent at higher pH and in RPMI medium. Conditions for optimal growth of control cells were obtained following pulse-treatment in Ca2+/Mg2(+)-free HBSS medium at high pH (8.0). Because of the dramatic cytogenetic toxicity of exogenously supplied epsilon-ATP, and the ubiquitous occurrence and biological importance of intracellular ATP, the latter should be considered a potential target for adduct formation by electrophilic metabolites of carcinogenic agents.

Adenosine Triphosphate↗
PubMed1989

Sister chromatid exchange induced by etheno-ATP derivatives in vitro.

Genotoxic activities of a series of commercially purchased 1,N6-ethenoadenosine (epsilon-Ado) and epsilon-deoxyadenosine (epsilon-dAdo) derivatives were assessed using the sister chromatid exchange (SCE) assay in murine spleen lymphocytes in vitro. Of the epsilon-Ado adducts evaluated for SCE induction epsilon-ATP and epsilon-dATP were highly active (5x baseline) SCE inducers over a concentration range of 50-150 microM. Moderate SCE-inducing activities were seen with epsilon-dAdo, epsilon-A, and epsilon-AMP. epsilon-A was of particular interest in that spleen lymphocytes from a single mouse were highly sensitive to SCE (greater than 50 SCE/cell at 75 microM). epsilon-Ado was weakly effective and epsilon-ADP and epsilon-dAMP did not produce significantly elevated SCEs. Cocanavalin A-stimulated T-lymphocytes and lipopolysaccharide-stimulated B-lymphocytes exhibited comparable SCE responses to epsilon-A, epsilon-AMP, and epsilon-dATP. However, B-lymphocytes were considerably less sensitive than T-lymphocytes to epsilon-dAdo and epsilon-ATP. Evaluation of the purities of specific epsilon-Ado derivatives, as performed by high-performance liquid chromatography and thin layer chromatography, failed to detect potential contaminants as cytogenetically active agents. However, a difference (about threefold) in cytogenetic activities of two lot numbers of epsilon-ATP paralleled the difference in UV absorbance of quivalent concentrations (mg/ml), prepared according to the manufacturers stated purity. Any impurities likely to be present were consistent with inactive nonchromophoric compounds such as buffer salts. Because of the direct genotoxic activity of epsilon-A in intact mammalian cells, we suggest that intracellular adenylate pools, including the prominent ubiquitous nucleotide ATP, are non-DNA targets for epsilon-modification by active metabolites and the resulting epsilon-adducts are likely to be active moieties in SCE induction and in neoplastic transformation produced by ethyl carbamate.

Adenine Nucleotides↗
PubMed1989

Intralitter variation in murine fetal sister chromatid exchange responses to the transplacental carcinogen ethyl carbamate.

Gravid Swiss Webster dams were injected via tail vein with a single (1.1, 2.2, or 3.3 mmol/kg) dose of ethyl carbamate (urethane) on days 13-17 of pregnancy. Relative sister chromatid exchange (SCE) responses in maternal bone marrow vs. individual fetal liver cells were assessed. In addition, in order to evaluate the significance of intralitter variability in fetal SCE responses, SCE in combined ("pooled") fetal liver tissue preparations were measured and compared with average individual responses. In contrast to maternal responses, average fetal SCE responses to ethyl carbamate varied with gestational age. In addition, significant variation was observed among individual littermate responses at all dose levels. Nonetheless, fetal SCE responses determined from "pooled" tissue preparations provided a valid estimate of average litter responses. Regardless of the method of SCE evaluation in fetal tissue or gestational age, maternal bone marrow exhibited greater sensitivity than fetal liver to SCE induction by ethyl carbamate.

Age Factors↗
PubMed1989

Induction of sister chromatid exchange in multiple murine tissues in vivo by various methylating agents.

In order to study the reliability of in vivo sister chromatid exchange (SCE) assays for predicting carcinogenicity, several known animal carcinogens were tested in a multicellular in vivo SCE assay and an in vivo/in vitro murine lymphocyte assay. The methylating agents 1,2-dimethylhydrazine.2 HCl (DMH), dimethylnitrosamine (DMN), methylnitrosourea (MNU), methyl methane-sulphonate (MMS), and methylazoxymethanol acetate (MAM) were tested for SCE induction in several murine tissues in vivo, including bone marrow, alveolar macrophages, regenerating and intact liver, and kidney from B6D2F1 mice. In all cell types, clear dose-responses were observed following exposure of mice to subcytotoxic fractions of the LD50 dose of DMH, MNU, or MMS. DMN (0.03-0.27 mmol/kg) produced small, although not dose-related, increases in SCE in all cell types. At the doses tested (0.06 and 0.08 mmol/kg), MAM did not induce elevated SCE in the various cell types. Following a series of multiple i.p. injections of low, non-toxic doses of DMH (0.15 mmol/kg, once a week, for 10 weeks), significant differences were observed in intact vs. regenerating liver and in single vs. multiple injections in regenerating liver. Following exposure of B6D2F1 mice to a single i.p. injection of 0.25 mmol/kg DMN, DMH, or MMS or 0.19 mmol/kg MNU, SCE responses were evaluated in Concanavalin A (Con A)- and LPS-stimulated blood and spleen lymphocytes. Considerable cytotoxicity was observed in blood lymphocytes. In Con A- and LPS-stimulated spleen lymphocytes, DMH-, and DMN- and MMS-induced SCE frequencies were approximately 1.5-2 x baseline levels and MNU-induced SCE were approximately three- to fourfold higher than baseline values in cultures initiated at 1 and 24 h postexposure. At 48 and 72 h after an i.p. injection of 0.131 mmol/kg MNU, SCE responses in lymphocytes were approximately 2 x baseline levels. At 24 h following one, two, or four injections (one/week) of 0.075 mmol/kg MNU dose-related increases in SCE were observed in spleen lymphocytes. These studies illustrate that carefully designed in vivo SCE assays may have the capacity to predict the tumorigenic potential of chemical agents.

Animals↗
PubMed1989

Temporal SCE and cytotoxicity responses of murine cells following in vivo treatment with MNU or L-PAM.

Time-dependent SCE responses of bone marrow and cultured spleen lymphocytes of BDF1 mice to in vivo treatment with MNU or L-PAM were studied. L-PAM was generally more active than MNU in producing elevated SCEs. Increases of 4-5 times control levels were produced in lymphocytes cultured at 1 or 24 h after i.p. injection of 4.95 mumoles/kg of L-PAM whereas an approximately 3-fold increase was produced by an acute injection of 190 mumoles/kg of MNU. Temporal SCE responses of bone marrow cells were carried out with doses of L-PAM (4.95 mumoles/kg) and MNU (131 mumoles/kg) found to be noncytotoxic by analysis of relative percentages of first, second, and third generation cells. The SCE response of second generation bone marrow cells (greater than 7 time baseline) to MNU was maximum when treatment was at the first cycle and decreased rapidly with increasing time prior to, or after the start of BrdUrd infusion. By contrast nonreciprocal (NR) SCE responses of third generation progeny never exceeded a 2-fold increase over baseline. Dramatic inhibition of cell cycling by MNU was evident as the reciprocal (R) SCEs in third generation cells increased, and exceeded NR SCEs, with increased treatment time intervals after the start of BrdUrd infusion. Similar dramatic cytotoxicity of L-PAM was apparent in time-dependent SCE response studies. An increased BrdUrd infusion time (28 h rather than the usual 26.5 h) was necessary to achieve adequate numbers of third division cells. Maximum SCE responses of the latter cells to L-PAM did not exceed 3 times baseline levels, whereas maximum responses of greater than 9 times control levels were produced in second generation cells. Comparison of SCE responses of second and third generation progeny of similarly treated cell populations, appears to provide a more sensitive assessment of cytotoxicity than does the conventional method of cell cycle analysis.

Animals↗
PubMed1987

Evaluation of sister chromatid exchange and cytotoxicity in murine tissues in vivo and lymphocytes in vitro following methyl isocyanate exposure.

The purpose of this study was to assess sister chromatid exchange (SCE) levels and cell cycle kinetics in various murine tissues following MIC exposure. Following exposure of mice to MIC, these parameters were measured in bone marrow and alveolar macrophages labeled with BrdUrd in vivo and in peripheral blood and spleen lymphocytes cultured in the presence of BrdUrd in vitro. Target concentrations of MIC were 2, 15, and 30 ppm (3 hr). Neither elevated SCE frequencies nor inhibition of cell cycling were evident in lipopolysaccharide (LPS)- or concanavalin A (ConA)-stimulated spleen lymphocytes, or in LPS-stimulated peripheral blood lymphocyte (PBL) cultures from mice exposed for 3 hr to MIC concentrations as high as 30.5 ppm. Inhibition of cell cycling and poor culture success rates were apparent in ConA-stimulated PBLs following MIC exposures as low as 2.3 +/- 0.4 ppm for 3 hr. At the lowest MIC dose employed, the cycling characteristics of bone marrow and alveolar macrophages were not altered, and SCE frequencies were at control levels. However, severe cell cycle inhibition was observed in these tissues at MIC concentrations of 15 ppm or greater. A marker of cytotoxicity at this dose was a high frequency (approximately 33-90%) of occurrence of first division cells containing a late-replicating Y chromosome. Despite its apparent cellular toxicity, MIC is not genotoxic as measured by SCE analysis in the tissues examined in this study.

Animals↗
PubMed1986

Induction of sister chromatid exchange by ethyl carbamate and vinyl carbamate.

High levels of sister chromatid exchanges (SCEs) can be induced in murine bone marrow, alveolar macrophages and regenerating liver cells by carcinogenic carbamate esters; however, the frequencies observed in the latter two tissues, which are also common tissues for carbamate-induced tumours, are relatively enhanced compared to the frequency in bone marrow. Relative to these tissues, peripheral blood lymphocytes, which do not divide during in-vivo exposure but which can be cultured in vitro, exhibit considerably lower levels of ethyl-carbamate-induced SCEs. Lymphocytes, however, are uniquely able to accumulate SCE-inducing lesions produced by multiple treatments with ethyl carbamate. In the present study, significantly elevated levels of SCEs were still apparent in lymphocytes of BDF1 mice eight weeks after a series of 12 multiple injections (2.2 mmol/kg; 3 times weekly) of ethyl carbamate. Long-term persistence of genetic damage produced by ethyl carbamate in murine lymphocytes is in agreement with our previous findings of highly persistent SCE-inducing damage in murine bone marrow and alveolar macrophage cells. The highly persistent nature of ethyl-carbamate-induced DNA damage and/or its continued ability to induce SCEs is undoubtedly relevant to its tumourigenic activity.

Animals↗
PubMed1985

Persistence of cyclophosphamide-induced damage in bone marrow as indicated by sister chromatid exchange analysis.

Various treatment protocols were used to investigate the time-dependent decrease in sister chromatid exchanges (SCEs) in bone marrow cells following treatment of C57Bl/6J X DBA/2J F1 (DB2F1) mice by i.p. injection of cyclophosphamide (15 mg/kg). The major factor in the time-related decrease in SCE-inducing lesions is the considerable cytotoxicity or selection of less highly damaged cells over successive cyclophosphamide post-treatment cycles. A constant rate of selection of 0.61 and 0.65%, respectively, was apparent over post-treatment cycles 1-2 and 2-3. In addition, second- and third-division SCE data produced by various protocols indicate persistence of a fraction of cyclophosphamide's SCE-inducing lesions for at least three post-treatment cycles. Comparison of the persistence of cyclophosphamide's SCE-inducing lesions with our previously reported data for diepoxybutane and ethyl carbamate reveals that the rate of repair of SCE-inducing lesions is inversely related to tumorigenic activities.

Analysis of Variance↗
PubMed1985

Long-term persistence of ethyl carbamate-induced sister chromatid exchanges in murine lymphocytes.

Ethyl carbamate-induced sister chromatid exchange (SCE) was evaluated at 20 min and 1, 3, 4.5, 5.5, 7, and 9 h postexposure (acute dose, ethyl carbamate, 3.3 mmol/kg) in concanavalin A (Con A)- and lipopolysaccharide (LPS)-stimulated murine peripheral blood lymphocytes (PBL). In both Con A- and LPS-stimulated PBL, SCE responses peaked between 4.5 and 5.5 h postinjection, a time which corresponds to complete biotransformation of ethyl carbamate. Peak induced SCEs for Con A- and LPS-stimulated PBL were 6.43 and 7.44, respectively. SCE responses were also evaluated in Con A- and LPS-stimulated PBL at 3 and 24 h following the last of a series of two, four, or six i.p. injections of ethyl carbamate (3.3 mmol/kg) given every other day. Dose-related increases (presumably reflecting the accumulation of unrepaired SCE-inducing damage) in SCEs were observed at both times following two and four injections of ethyl carbamate. However, following six injections a decrease in SCE response and increased cytotoxicity were observed. Persistence of SCE-inducing DNA lesions was observed in blood, spleen, and parathymic node lymphocytes following the last of a series of 12 i.p. injections (three times weekly) of ethyl carbamate (2.2 mmol/kg). With the exception of LPS-stimulated blood lymphocytes, exposed blood and spleen Con A- and LPS-stimulated lymphocyte populations contained a significantly higher number of high-frequency cells than did their respective controls at 16 weeks postexposure. The gradual return of SCE levels to base-line values appears to be primarily a consequence of slow population turnover. Parathymic node lymphocytes exhibited elevated SCE responses (2 times base-line levels) for up to 4 weeks postexposure.

Animals↗
PubMed1984

A path probability model for sister-chromatid exchanges induced by alkylating agents.

A path probability model is described for evaluation of sister-chromatid exchanges (SCEs) induced by alkylating agents following treatment of G1 cells at the beginning of the first or second cycles of BrdUrd incorporation, or during G1 corresponding to an exact cell-cycle interval preceding BrdUrd incorporation. Algebraic expressions are derived for calculations of expected induced SCE frequencies (over baseline levels) in second and third (reciprocal and nonreciprocal SCEs) division cells for the described treatment protocols. The derivations take into consideration: p, the probability of a specific lesion inducing an SCE; rn, the extent of repair within the nth post-treatment cycle; and X, the number of lesions induced. Expressions are also derived for expected ratios of single: twin exchanges in endoreduplicated or tetraploid cells.

Alkylating Agents↗
PubMed1984

Simultaneous assessment of ethyl carbamate-induced SCEs in murine lymphocytes, bone marrow and alveolar macrophage cells.

At 3, 6, and 24 h after acute treatment of BD2F1 mice with 3.3 mmol/kg of ethyl carbamate, blood was drawn and cultured for SCE analysis. After blood sampling, the same mice were infused with BrdUrd for simultaneous assessment of SCEs in bone marrow and alveolar macrophage cells. In bone marrow and alveolar macrophage cells, maximum SCE responses (24.1 +/- 4.3; 24.2 +/- 3.8, respectively) were observed at 3 h post-exposure. Decreased SCE frequencies were observed at each later time. Relative to a single (3.3 mmol/kg) acute treatment, multiple treatment (10 X 3.3 mmol/kg; every other day) did not produce significantly elevated SCE levels in bone marrow (18.3 +/- 1.5) and alveolar macrophage cells (22.2 +/- 5.8). By contrast, the maximum lymphocyte response (18.8 +/- 2.2), following a single acute injection, was observed at 6 h post-exposure. In addition, a considerable accumulation of SCE frequencies occurred in lymphocytes (27.3 +/- 3.4) following multiple injections of ethyl carbamate.

Animals↗
PubMed1984

Accumulation and persistence of cyclophosphamide-induced sister chromatid exchange in murine peripheral blood lymphocytes.

Sister chromatid exchange (SCE) responses were evaluated in lipopolysaccharide-stimulated murine peripheral blood lymphocytes assayed at various times following single or multiple injections of cyclophosphamide (3 mg/kg). Following a single injection, SCE levels in cultured lymphocytes from blood sampled at 5 min, 20 min, 35 min, 1 hr, and 3 hr postexposure were 17.1 +/- 2.0 (S.D.), 19.9 +/- 3.0, 19.3 +/- 1.8, 21.6 +/- 2.4, and 20.6 +/- 2.3, respectively. The control base-line SCE frequency was 11.2 +/- 1.2. The rapid initial increase in SCEs is consistent with the rapid increase reported previously in circulating active metabolites in rats following cyclophosphamide treatment. In peripheral blood lymphocytes cultured at 1 and 24 hr after serial injections of cyclophosphamide (3.0 mg/kg) two, four, and six times (every other day), a dose-related accumulation of SCEs occurred. Accumulation of SCEs was also observed in lymphocytes cultured at 24 and 72 hr following 12 multiple injections (three times weekly) of cyclophosphamide (3 mg/kg) (24.8 +/- 1.5 and 17.6 +/- 1.4, respectively) as compared to the single-injection group assayed at 24 and 72 hr postexposure (16.0 +/- 2.4 and 12.9 +/- 1.4, respectively). In the 12-multiple-injection study, an initial rapid decline at 72 hr was followed by a gradual decrease in SCE levels (1 week, 16.9 +/- 1.3; 2 weeks, 15.2 +/- 0.7; and 4 weeks, 13.4 +/- 1.1) which returned to near base-line (11.2 +/- 0.9) levels at 8 weeks. In the 12-multiple-injection study, successful growth of parallel concanavalin A-stimulated cultures was achieved only at 1, 2, and 4 weeks postexposure. Elevated SCE frequencies were observed at these intervals (16.2 +/- 2.1; 16.7 +/- 0.9; 14.2 +/- 0.3, respectively) relative to base-line SCE levels in concanavalin A-stimulated cells (12.1 +/- 1.8). The observed accumulation of SCEs with repeated exposure and persistence of SCE-inducing lesions parallel human data reported previously. The maximum induced (total minus baseline) SCE levels (10.2) observed in cultured lipopolysaccharide-stimulated lymphocytes from blood sampled at 1 hr after a single 3.0-mg/kg injection of cyclophosphamide were comparable or slightly higher than those (7.1) produced by the same dose of cyclophosphamide in murine bone marrow cells labeled with BrdUrd in vivo. However, in contrast to lymphocytes, bone marrow and alveolar macrophage cells did not accumulate SCEs upon repeated cyclophosphamide treatments.

Animals↗
PubMed1983

Induction and rapid repair of sister-chromatid exchanges in multiple murine tissues in vivo by diepoxybutane.

Sister-chromatid exchange (SCE) induction by the direct-acting bifunctional carcinogen, diepoxybutane (DEB), was investigated in multiple tissues in vivo. The log-log dose SCE response relationship was found to be parallel to that previously reported for DEB induction of lung adenomas. However, the SCE assay is approximately 20 times as sensitive in detecting genotoxic effects of DEB than indicated by the lung adenoma assay. Examination of second and third division cells following various treatment protocols revealed that regardless of the nature of initially induced lesions, they are rapidly repaired with no evidence of persistence beyond 1 cell cycle.

Animals↗
PubMed1983

Persistence of ethyl carbamate-induced DNA damage in vivo as indicated by sister chromatid exchange analysis.

Various treatment protocols were designed to investigate sister chromatid exchanges (SCEs) induced over successive posttreatment cell cycles in bone marrow and alveolar macrophage cells following treatment of C57BL/6J X DBA/2J F1 mice by i.p. injection of ethyl carbamate (3.3 mmol/kg). The same initial extent of alkylation in bone marrow and alveolar macrophages was suggested by identical SCE frequencies produced in both cell types by a one-cycle exposure protocol. The relatively lower responses in bone marrow cells by all other protocols may be a result of its faster mean population-cycling time. Second- and third-division cell SCE data produced by the various protocols indicate persistence of SCE-inducing lesions with no evidence of repair. In spite of the demonstrated lack of repair, first-cycle ethyl carbamate treatment was less effective than was second-cycle treatment in inducing SCEs. These results could not be attributed to selection of less-damaged cells over 2 cycles or to enhanced bromodeoxyuridine sensitivity in the second-cycle treatment protocol. It is speculated that the apparent cancellation of SCEs occurring over two successive cycles in the two-cycle exposure protocol may indicate the transient presence of ethyl carbamate-induced DNA interstrand cross-links. A possible mechanism of action of ethyl carbamate involving the formation of a transient cross-link and a persistent DNA monoadduct is postulated.

Animals↗