摘要:

AbstractStrains ofSalmonella typhimuriumdeficient in topoisomerase I activity (topAmutants) are UV sensitive and non‐mutable (Overbye and Margolin:J Bacteriol146:170–178, 1981). Using lac‐operon fusions to DNA damage inducible (din) loci we investigated whether these observations could be explained by an inability oftopAstrains to efficiently induce DNA damage responses. Mitomycin C (MMC)‐induced expression of lac‐operon fusions touvrBand to a second SOS locus,din‐9, was largely eliminated intopAbacteria. The inducible expression of several otherdin‐fusions was also diminished. This inducibility defect was mimicked by growth ofdin‐9 topA+bacteria in media of high osmolarity, a condition that leads to increased DNA supercoiling. Inhibitors of DNA gyrase efficiently induceddin‐9 intopAbacteria. Together, these results suggest that thetopAeffect ondinexpression may be mediated at the level of DNA supercoiling. The sensitivities of a number ofdin‐fusions totopAparalleled the degree to which they were repressed by excess LexA, suggesting that mutations intopAmight influence LexA‐operator interactions and/or i

ISSN:0893-6692    

DOI:10.1002/em.2850190302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractIn the present study, the induction of sister chromatid exchanges (SCEs) and chromosomal aberrations were measured in normal human lymphocytes treated with low concentrations of arsenite alone (0.5–2.0 μM) and arsenite in combination with the potent DNA crosslinking agent diepoxybutane (DEB). Experiments were carried out with lymphocytes from blood donors with different sensitivities to SCE induction by DEB. Arsenite, beginning at concentrations as low as 1 μM, increased SCE frequencies; chromosomal aberration frequencies were increased at 2 μM of arsenite. DEB treatments alone increased SCE frequencies and chromosomal aberrations. The yields of chromatid deletions and exchanges in lymphocytes exposed to both arsenite and DEB were markedly increased above the levels expected if the effects of the two agents had been simply additive. The frequencies of chromatid deletions were 4‐ to 8‐fold greater than expected and chromatid exchanges were increased 7‐ to 40‐fold. Chromatid exchanges detected in cells treated with arsenite and DEB were predominately incomplete exchanges. The most dramatic increases in chromatid aberrations were observed in lymphocytes from an individual sensitive to SCE induction by DEB, indicating that individuals may vary in their sensitivity to the co‐clastogenic effects of arsenite. At concentrations that dramatically affect aberrations, arsenite had no effect on the induction of SCEs by DEB. These studies suggest a specific interaction of arsenite with the induction or repair of DNA damage produced by DEB that leads to chromosomal aberrations but not to SCEs. Based on the selective chemical reactivity of low concentrations of arsenite with proteins containing vicinal dithiols and the occurrence of these groups within DNA repair proteins, it is proposed that the specific co‐clastogenic effects of arsenite may be mediated by its interference with DNA r

ISSN:0893-6692    

DOI:10.1002/em.2850190303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

Abstract2,4‐Diaminotoluene (2,4‐DAT), a high volume synthetic compound, is moderately carcinogenic to rodents. We report here that 2,4‐DAT is a substrate for the peroxidase activity of prostaglandin H synthase (PHS). In contrast to many aromatic amines which are activated as mutagens by PHS, we find that 2,4‐DAT is not mutagenic to six S.typhimuriumstrains with this activation system. The strains tested include YG1006, YG1024, and YG1029, which are far more sensitive to the mutagenicity of aromatic amines and nitroarenes than are the standard tester strains. Although not mutagenic itself, 2,4‐DAT does enhance the mutagenicity of 2‐aminofluorene (2‐AF) in the PHS‐catalyzed system in strains TA98, YG1006, and YG1024, with maximal enhancement of 140%, 1831%, and 1216%, respectively. Half‐maximal enhancement of 2‐AF mutagenicity is observed at 15–20 μM 2,4‐DAT for strains YG1006 and YG1024, and about 80 μM for TA98. Studies with compounds structurally related to 2,4‐DAT revealed enhancement of 2‐AF mutagenicity with 2,5‐DAT and o‐phenylenediamine (o‐PD) but not for other DAT isomers, toluidines, and phenylenediamines. Maximal enhancement of 2‐AF mutagenicity observed in TA98 with PHS‐catalyzed activation was 110% for o‐PD and 60% for 2,5‐DAT. This comutagenic effect of 2,4‐DAT appears quite specific for 2‐AF, as it fails to enhance either the PHS‐dependent mutagenicity of the aromatic amines benzidine and 2‐naphthyl‐amine, or the direct mutagenicity of N‐acetoxyacetylaminofluorene,2‐nitrofluorene,4‐nitroquinoline‐N‐oxide and 1,1,1‐trichloropropene‐2,3‐oxide. Enhancement of 2‐AF mutagenicity by 2,4‐DAT is also observed with cytochrome P‐450‐dependent activation, however the half‐maximal 2,4‐DAT concentration was 400 μM, and the maximal enhancement was only 50%. The ability of 2,4‐DAT, under conditions where it is not itself mutagenic, to enhance the genotoxicity of the potent carcinogen 2‐AF comprises an intriguing toxicological interaction, and underscores the

ISSN:0893-6692    

DOI:10.1002/em.2850190304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractPreliminary results from the National Toxicology Program (NTP) bioassays of furan given by gavage indicate the induction of hepatocellular carcinomas in male F‐344 rats and in both sexes of B6C3F1 mice, and cholangiocarcinomas in both sexes of rats. To assess the genotoxicity of furan, chemically induced unscheduled DNA synthesis was evaluated in the in vivo hepatocyte DNA repair assay. Furan did not induce unscheduled DNA synthesis in hepatocytes isolated after single gavage treatment of male F‐344 rats (5, 30, and 100 mg/kg) or male B6C3F1 mice (10, 50, 100, and 200 mg/kg). Furan induced cytotoxicity and enhanced cell proliferation were evaluated in livers of rats and mice as events that also might give rise to mutations and/or drive tumor formation. The labeling index (Ll, percentage of hepatocyte nuclei in S‐phase) was measured histoautoradiographically following a single gavage administration of furan (30 mg/kg, male rats; 50 mg/kg, male mice) followed by an injection of3H‐thymidine 2 hr prior to sacrifice. Hepatocellular necrosis and a sharp increase in Ll (23.9 for mice and 17.8 for rats vs. less than 0.5 for controls) was observed 48 hr after treatment with furan, indicative of restorative cell proliferation secondary to cytotoxicity. Hepatocyte proliferation was evaluated also at the highest NTP bioassay dose (15 mg/kg/day for mice and 8 mg/kg/day for rats, 5 days/week) by labeling with3H‐thymidine administered via a 6 day osmotic pump implanted subcutaneously. Necrosis and inflammation were observed along the subcapsular visceral surface of the left or caudate liver lobes, likely due to diffusion of furan directly through the stomach to the liver. After 6 weeks of furan administration, male and female rats, but not mice, exhibited bile duct hyperplasia as well as metaplasia in the areas of fibrosis along the subcapsular visceral surface of the left or caudate liver lobes. The fold increase in hepatocyte Ll in treated animals relative to the combined controls measured at weeks 1, 3, and 6 ranged from 39 to 5 for male mice, 18 to 51 for male rats, and 12 to 19 for female rats. Taken together, these data suggest that mechanisms other than direct DNA‐reactivity might explain the profile of oncogene mutations observed in the mouse liver tumors, including selective promotion of different subpopulations of preneoplastic cells and/or mutational events secondary to sustained cell proliferation or inflammation. The extensive amount of furan‐induced cell proliferation subsequent to cytotoxicity likely had a significant impact on tumor development, and such data should be considered in risk evaluations for

ISSN:0893-6692    

DOI:10.1002/em.2850190305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractSister chromatic exchanges (SCE) and chromosome aberrations (CA) in mice after in vivo exposure of Green S were carried out following single acute treatment. Except for the lowest dose (25 mg/kg body weight) a significant increase in the SCEs were observed in all the other doses (50, 100, and 200 mg/kg) tested. In CA study two higher doses (200 and 400 mg/kg) showed a significant increase in CA when compared with control. The minimum effective dose which induced SCE and CA was 50 and 200 mg/kg of body weight, respectively. The trend tests for the evidence of dose response effects were also significant for both SCE and CA. No significant differences were observed in cell replication kinetic (Rl) analysis. A significant increase in the mitotic index (Ml) was also observed in the highest dose (400 mg/kg) tested when compared with control. Thus the present study indicates that Green S can induce both SCE and CA in vivo in bone marrow cells of mice.

ISSN:0893-6692    

DOI:10.1002/em.2850190306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractTwelve percent of the chemicals tested for mutagenicity by the National Toxicology Program (NTP) using theDrosophilasex‐linked recessive lethal assay have been classified as producing equivocal results. We have reexamined the published data and the criteria used to determine mutagenicity in light of the historical distribution of the concurrent negative controls for this project. Many of the chemicals that originally produced equivocal results have been retested under code. As a result of changes to incorporate a comparison with the historical control in the algorithm used to determine mutagenicity and as a result of new data accumulated, 4 of the 25 chemicals that gave equivocal results are judged to be mutagenic, and 11 others are judged to be nonmutagenic under our test condition

ISSN:0893-6692    

DOI:10.1002/em.2850190307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractA series of in vitro experiments were conducted to determine if there are innate differences in the sensitivity of peripheral blood lymphocytes (PBLs) from different mammalian species to clastogens. Mouse, rat, and human whole blood samples were exposed to either 0, 0.38, 0.75, 1.5, or 3.0 Gy x‐radiation or 0, 5, 10, 20, 40, or 80 (μg/ml bleomycin for 4 hr. Bromodeoxyuridine‐containing cultures were initiated and the PBLs stimulated to divide with phytohemagglutinin. All cultures were harvested following a 3‐hr colcemid treatment. Slides were made and differentially stained, and first‐division metaphases were scored for chromosome aberrations. In the x‐radiation studies human PBLs were significantly more sensitive than mouse PBLs which were in turn more sensitive than rat PBLs as measured by either the total percent aberrant cells or the number of dicentrics. Data from all three species could be fitted to a linear‐quadratic model. Results with bleomycin suggest that the mouse and human PBLs are equally sensitive to the clastogenic effects of bleomycin. Both appeared to be more sensitive than the rat PBLs, but the variation between experiments was such that the results among species were not significantly different. These results indicate that there may be inherent differences in sensitivity among PBLs of mammalian species; however, more studies are needed to determine if the differences presented here hold for

ISSN:0893-6692    

DOI:10.1002/em.2850190308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractGlucose autoclaved in an alkaline phosphate solution (heated glucose + salts,HGS) results in the production of a moiety that is nonmutagenic but can interact with a series of 4‐[2‐(aryl)ethenyl]‐2,6‐dimethylphenols to result in an increase in bacterial revertants that is dependent on the amount ofHGSin the minimal agar plates. The reaction between theHGSand the chemical to form a mutagen is independent of the presence of bacteria, does not result in a nutritive analog to enhance growth of the auxotrophic bacteria, and is effective only inSalmonella typhimuriumandEscherichia collstrains that contain the plasmid pKM101. A sufficient amount of this glucose product may be formed in normal plate preparation to produce apparent mutagenic activity of these ch

ISSN:0893-6692    

DOI:10.1002/em.2850190309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractComparison of the mutagenicity of nine isomeric benzo(a)pyrenyl [B(a)P] phenols conjugated with either sulfate or glucuronide was carried out using strainSalmonella typhimuriumTA98. Of the nine conjugates tested, only B(a)P‐1‐sulfate was mutagenic. Accordingly, the mutagenicity of B(a)P‐1‐sulfate was compared with that of B(a)P and 1‐hydroxybenzo(a)pyrene [B(a)P‐1‐OH] in the presence and absence of rat lung S9 and Aroclor‐induced liver S9 with and with out an NADPH‐generating system. B(a)P‐1‐sulfate was slightly mutagenic, whereas B(a)P and the 1‐hydroxy derivative were nonmutagenic when S9 fractions and NADPH were omitted. Addition of induced liver S9 with NADPH caused mutagenicity with B(a) ‐1‐OH>B(a)P>B(a)P‐1‐sulfate. B(a)P‐1‐sulfate was the only mutagenic species when lung S9 was added. This mutagenicity did not require NADPH. Sodium sulfite, an inhibitor of arylsulfatase, decreased the mutagenicity of B(a)P‐1‐sulfate. These data suggest that a unique mutagenic species is generated from B(a)P

ISSN:0893-6692    

DOI:10.1002/em.2850190310

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractOur recent syntheses of chryseno[4,5‐bcd]thiophene together with its potential sulfone metabolite, chryseno[4,5‐bcd]thiophene‐4,4‐dioxide, have made these compounds available for genotoxicity testing. Such toxicity testing is of interest as this thiophene is an isoster of the established carcinogen benzo[a]pyrene and is one of the thiaarenes which are potential environmental contaminants found in fossil fuels. Although the thiophene was less mutagenic than benzo[a]pyrene inSalmonellastrains TA98 and TA100 after S9 activation, it exhibited in vivo chromosomal aberration activity equal to that of benzo[a]pyrene in the bone‐marrow cells of mice. A reduced activity withSalmonellaas well as in the bone‐marrow cell assay for the sulfone does not support its role as the key active metabolic intermediate for the genotoxicity of the thiophene. Our molecular orbital calculations would be consistent with the concept of activation through a diol‐epoxide mechanism and of fers an explanation for the reduced genotoxicity of the sulfone via this mechanism. These genotoxicity studies support the concern that sulfur isosters of established carcinogenic polycyclic aromatic hydrocarbons could themse

ISSN:0893-6692    

DOI:10.1002/em.2850190311

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY