bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro genotoxicity studies using complex hydrophobic mixtures: Efficient delivery of a petroleum sample to cultured C3H/10T1/2 cells via lipid vesicle incorporation
Authors: Von Hofe Eric H. , Billings Paul C. , Heidelberger Charles , Landolph Joseph R. 
Published: February 2007

AbstractPetroleum fractions are a diverse group of extremely hydrophobic mixtures, some of which display strong carcinogenicity in animal skin painting experiments. Interpretation of in vitro genotoxicity experiments with these samples is complicated by inefficient delivery of these hydrophobic substances inside target cells. We therefore developed methods to assess and improve the efficiency of delivering a petroleum sample (Matrix, A.P.I. 81–17) to cultured C3H/10T1/2 cells for genotoxicity studies via lipid vesicle incorporation. Three radiolabeled compounds (14C‐benzo(a)pyrene, 14C‐decane, and 14C‐naphthalene) of widely differing volatilities, broadly representative of the spectrum of compounds in petroleum samples, were separately added to Matrix. Lipid vesicles containing Matrix and radiolabeled compounds were prepared by the classical methods for preparing neutral, positive, and negatively charged multilamellar and unilamellar liposomes. Of these, the classical methods for preparing neutral unilamellar liposomes were the most successful for delivering radiolabeled compounds in Matrix to cells. Vesicles optimal for the delivery of tracers in Matrix were prepared with DSPC:cholesterol:lyso‐PC (8.8:0.8:0.4, molar ratio) in a Matrix to lipid ratio of 31:69 (w/w). This new method of delivery resulted in proportional, dose‐depenendent dent, and reproducible uptake of all tracers. Further, cells treated with this preparation took up 2.5‐fold more 14C‐decane, 1.5‐fold more 14C‐BaP, and 18‐fold more 14C‐naphthalene added to Matrix than did cells treated with Matrix emulsified in tissue culture medium. In contrast, tracers were not taken up in aproportional or reproducible manner when emulsions were used, and in fact, uptake of 14C‐naphthalene was consistently very small. Two petroleum fractions, C2029188 and C3029194, were 4‐ and / more cytotoxic, respectively, when delivered to C3H/10T1/2 cells by lipid vesicles than emulsions. The carcinogenicpetroleum fraction C50292202 induces type II transformed foci in C3H/lOT1/2 cells when cells were treated with C50292202 incorporated into lipid vesicles. The methods for lipid vesicle incorporation described here are effective in deliveringhydrophobic petroleum fractions to cells and provide an alternative to the current inefficient and artifactual methods of emulsification currently used. With further validation and standardization, lipid vesicle incorporation of petroleum fractions and treatment of cells with these vesicles should be useful for studying the genotoxicity of complex hydrophobic mixtures in cell culture systems.
Target sequences for mutagenesis in Salmonella histidine‐requiring mutants
Authors: Hartman Philip E. , Ames Bruce N. , Roth John R. , Barnes Wayne M. , Levin David E. 
Published: February 2007

AbstractNucleotide target sequences involved in reversion to the wild type phenotype are diagrammed for Salmonella frameshift histidine‐requiring mutants hisD3052, hisD3018, hisD6610, and hisD6580 and for base‐substitution mutants hisG46 and hisG428. Frameshift strain hisC3076 probably reverts by nucleotide changes similar to those that occur during reversion of hisD3018 and hisD6610. Multiple modes of reversion characterize each strain. Each strain also has a particularly diagnostic mutagen‐susceptible sequence. These highly mutagen‐susceptible stretches are the hisD3052 GCGCGCGC sequence, the hisD6610 CCCCCC sequence, the hisD6580 AAAAA sequence, and the A/T containing codon of hisG428 and G/C containing codon of hisG46, respectively. Between them, hisG46 and hisG428 are reverted by all of the six possible base substitution transition and transversion mutations.
Effects of excision repair and plasmid PKM101 on mutagenic and cytotoxic potencies of anthracycline derivatives in test strains of Salmonella typhimurium
Authors: Thomas Harvey F. , Cole Janice A. 
Published: February 2007

AbstractThe effects of excision repair and presence of plasmid pKM101 on the mutagenicities and cytotoxicities of the anthracycline derivatives Adriamycin, daunomycin, carminomycin, and 4‐demethoxydoxorobicin were examined in strains of Salmonella typhimurium. Plasmid pKM101 has been shown to mediate inducible error‐prone repair in S. typhimurium. While the test compounds were shown to produce a range of mutational responses in excision repair defective (uvrB−), pKM101‐bearing strains of different his− backgrounds, proficiency in excision repair generally resulted in the elimination of mutagenic responses in all such strains except those that contain the hisG428 site. In the absence of pKM101, only hisD3052 uvrB− strain TA1538 was shown to be sensitive to anthracycline mutagenicity. A suspension (preincubation) test as well as a direct plating test showed that while proficiency in either excision repair (uvr+) or plasmid pKM101 errorprone repair afforded cellular protection against anthracycline cytotoxicity, plasmid‐free uvrB− strains were most sensitive to anthracycline cytotoxicity.
Targeting of chemical mutagens to differentiating B‐lymphocytes in vivo: Detection by direct DNA labeling and sister chromatid exchange induction
Authors: Bloom S. E. , Nanna U. C. , Dietert R. R. 
Published: February 2007

AbstractIn vivo systems for analyzing mutagen interactions with a specific differentiating cell population are rare. Taking advantage of the unique anatomical features of the bursa of Fabricius in the chicken, we explored the possibility of targeting chemical mutagens to a defined differentiating cell population in the animal, namely, the B‐lymphocytes series. Such cells are known to be the targets for the oncogene‐activating avian leukosis virus. Targeting of chemicals to cells of the bursa was demonstrated by application of the DNA‐specific fluorochrome 4′‐6‐diamidino‐2‐phenylindole (DAPI) to the anal lips of neonatal chicks. Bright nuclear fluorescence of cells in the bursa was demonstrated to occur within minutes after the application of 500 m̈l of DAPI. DAPI labeling of nuclei was detected up to several days after a single application. No nuclear labeling was exhibited in cells of neighboring tissues. Methyl methanesulfonate (MMS) (10 m̈l) was applied to the anal lips of day‐old chicks to study dose‐response kinetics for mutagen targeting to DNA of dividing B‐lymphocytes in the bursa. Since the mitotic index was found to be quite high (25‐30%) in the bursa, chromosome analysis was used to assay for genome damage. Sister chromatid exchange frequencies of 3.9, 7.3, and 9.0 (baseline 2.5) per cell were obtained at MMS dosages per animal of 50 m̈g, 100 m̈g, and 200 m̈g, respectively. These results indicate the rapid and quantitative localization of DNA‐binding chemicals to cells of the bursa, particularly the resident B‐lymphocytes. The bursa should be a useful system for studying mutagen‐DNA interactions in the differentiating B‐lymphocyte and subsequent influences on the development of immunity and lymphoproliferative disease.
Sister chromatid exchange analysis in lung and peripheral blood lymphocytes of mice exposed to methyl isocyanate by inhalation
Authors: Kligerman A. D. , Campbell J. A. , Erexson G. L. , Allen J. W. , Shelby M. D. 
Published: February 2007

AbstractMice were exposed to 1, 3, or 6 ppm methyl isocyanate (MIC) for 6 hr/day for four consecutive days. Lung cells and peripheral blood lymphocytes (PBLs) were removed and cultured for analysis of sister chromatid exchange (SCE) and cell cycle kinetics. MIC caused a small but significant increase in SCE frequency of cultured lung cells from mice exposed to 1, 3, or 6 ppm MIC. MIC did not significantly increase SCE levels in PBLs of mice exposed to concentrations as high as 6 ppm. In cultured PBLs, MIC had a stimulatory effect on cell cycling rates as measured by the replicative index, and it caused a significant reduction in mononuclear leucocyte counts and the mitotic indices.
Disubstituted amino‐, nitroso‐, and nitrofluorenes: A physicochemical basis for structure‐activity relationships in salmonella typhimurium
Authors: Vance William A. , Wang Yi Y. , Okamoto Howard S. 
Published: February 2007

AbstractTwenty‐nine derivatives of fluorene were tested for mutagenic potency in four strains of Salmonella typhimurium with and/or without S9 microsomal activation. The effects of a second functional group on the mutagenic activity of an amino‐, nitroso‐, and nitrofluorene were correlated with its physical and chemical properties. When the functional group is conjugated by resonance, both inductive and resonance effects are determinants of mutagenic potency. Electron‐withdrawing groups such as the halogens (F, C1, Br, and I), nitro, nitroso, and cyano at C‐7 increased the mutagenic potency of 2‐nitrofluorene. Electron‐donating substituents such as hydroxy and amino groups at C‐7 decreased the mutagenic potency of 2‐amino‐, 2‐nitroso‐, and 2‐nitrofluorene. Acetylation of a hydroxy or an amino group at C‐7 increased the mutagenic potency of 2‐nitrofluorene, presumably by decreasing the electron‐donating properties of these groups. In contrast, acetylation of a nonresonance‐conjugated amino group decreased mutagenic activity. The physical properties of a second functional group are expected to exert their effect(s) at three points in the metabolic activation of 2,7‐disubstituted fluorene derivatives: 1) initial reduction of the nitro group (redox effect), 2) stabilization of the hydroxylamine (inductive effect), and 3) stabilization/destabilization of the nitrenium ion (resonance and inductive effects). The relationships between the physical properties of a second functional group and their effects on biological activities of nitro‐ and aminofluorenes in the Ames Salmonella assay may be of predictive value in a first approximation of both the mutagenic and carcinogenic potency of chemicals with comparable structures such as fluoranthene and biphenyl.
Responses of the L5178Y tk+/tk− mouse lymphoma cell forward mutation assay to coded chemicals. I: Results for nine compounds
Authors: McGregor Douglas B. , Martin Roger , Cattanach Pamela , Edwards Ian , McBride Douglas , Caspary William J. 
Published: February 2007

AbstractNine substances were tested for their mutagenic potential in the L5178Y tk+/tk− mouse lymphoma cell forward mutation assay, by means of procedures based upon those described by Clive and Spector (Mutat Res 44:269‐278, 1975) and Clive et al (Mutat Res 59:61‐108, 1979). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 μg/ml. The coded chemicals were tested at least twice. Significant responses were obtained with calcium chromate, 3‐(chloromethyl)pyridine, 1,2‐epoxybutane, monochloroacetic acid, dicyclohexylthiourea, 2,4‐diaminophenol hydrochloride, and pentachloroanisole. Apart from pentachloroanisole, rat liver S9 mix was not a requirement for the clearly mutagenic activity of any of these compounds. Compounds not identified as mutagens were 3‐amino‐1,2,4‐triazole and sucrose.
Effects of metals on chromosomes of higher organisms
Authors: Sharma Archana , Talukder Geeta 
Published: February 2007

AbstractAn analysis of the available data on the clastogenic effects of metals and their compounds on higher organisms indicates some general trends.Following chronic exposure to subtoxic doses, a decrease in mitotic frequency and an increase in the number of chromosomal abnormalities are observed. These effects are usually directly proportional to the dose applied and the duration of treatment within the threshold limits. Recovery after acute treatment is inversely related to the dosage.The ultimate expression of the effects depends on certain factors, including the mode and vehicle of administration; the form administered; the test system used; the rate of detoxification, distribution, and retention in the different tissues; and interaction with foreign and endogenous substances as well as the mode of action with the biological macromolecules.In mammals, the clastogenic activity of the metals within each vertical group of the periodic table is directly proportional to the increase in atomic weight, electropositivity, and solubility of the metallic cations in water and lipids, except for Li and Ba. This pattern of inherent cytotoxicity increases with successive periods in the horizontal level. It is enhanced by the formation of covalent and coordinate covalent complexes by heavy metals with the biological macromolecules.In plants, the solubility of the metals in water is of much greater importance. The degree of dissociation of metallic salts and the rate of absorption affect significantly the frequency of chromosomal aberrations.In assessing the effects of environmental metal pollution, the presence of other metals and toxic chemicals and the level of nutrition should be taken into account, since in nature, metals occur in combination and these factors modify the cytotoxic effects to a significant extent.
Comparative cytogenetic analysis of bone marrow damage induced in male B6C3F1 mice by multiple exposures to gaseous 1,3‐butadiene
Authors: Tice Raymond R. , Boucher Raymond , Luke Carol A. , Shelby Michael D. 
Published: February 2007

AbstractGroups of male B6C3F1 mice (N = 12) were exposed to ambient air or to gaseous 1,3‐butadiene (BD) at 6.25, 62.5, and 625 ppm for 10 exposure days (6 hr + T90/day). Exposure to BD induced in bone marrow: 1) a significant increase in the frequency of chromosomal aberrations (CA); 2) a significant elevation in the frequency of sister chromatid exchanges (SCE); 3) a significant lengthening of the average generation time (AGT); 4) a significant depression in the mitotic index (MI); and, as measured in the peripheral blood, 5) a significant increase in the proportion of circulating polychromatic erythrocytes (%PCE), and 6) a significant increase in the level of micronucleated PCE (MN‐PCE) and micronucleated normochromatic erythrocytes (MN‐NCE). The most sensitive indicator of genotoxic damage was the frequency of SCE (significant at 6.25 ppm), followed by MN‐PCE levels (significant at 62.5 ppm), and then by CA and MN‐NCE frequencies (significant at 625 ppm). The most sensitive measure of cytotoxic damage was AGT (significant at 62.5 ppm), followed by %PCE (significant at 625 ppm), and then by MI (significant by trend test only). Because each cytogenetic endpoint was evaluated in every animal, a correlation analysis was conducted to evaluate the degree of concordance among the various indicators of genotoxic and cytotoxic damage. The extent of concordance ranged from a very good correlation between the induction of MN‐PCE and the induction of SCE (correlation coefficient r = 0.9562) to the lack of a significant correlation between the depression in the MI and any other endpoint (r < 0.37).
Mutagenicity and toxicity studies of several α,β‐unsaturated aldehydes in the Salmonella typhimurium mutagenicity assay
Authors: Cooper Kathryn O. , Witz Gisela , Witmer Charlotte M. 
Published: February 2007

Abstractα,β‐Unsaturated aldehydes are reactive compounds which are ubiquitous in the environment. This class of compounds has been tested for mutagenicity in Salmonella typhimurium by a number of groups who have obtained differing results. The present studies were undertaken to test the mutagenicity and toxicity of two novel α,β‐unsaturated aldehydes, specifically trans,trans‐muconaldehyde and trans‐4‐hydroxynonenal, and to re‐examine the mutagenicity of crotonaldehyde. Trans,trans‐muconaldehyde is a newly found microsomal metabolite of benzene, and trans‐4‐hydroxynonenal is a toxic aldehyde formed endogenously during lipid peroxidation. Compounds were tested in S. typhimurium strain TA 100 using a 30‐min liquid preincubation procedure. The present mutagenicity studies indicate that these α,β‐unsaturated aldehydes at first appear to be mutagenic, although only at concentrations which decrease survival counts, and result in a disappearance of the bacterial lawn. The colonies observed on mutagenicity test plates are not mutants but rather pin point survivors.
Factors that affect the frequency of thioguanine‐resistant lymphocytes in mice following exposure to ethylnitrosourea
Authors: Jones Irene M. , Burkhart‐Schultz Karolyn , Strout Cheryl L. , Crippen Tawni L. 
Published: February 2007

AbstractThe frequency of thioguanine(TG)‐resistant lymphocytes in mice treated with ethylnitrosourea (ENU) was followed for a period of 51 wk using our clonogenic assay [Jones et al, 1985a,b]. The effects of dose (0‐58 mg/kg), time since treatment (2‐51 wk), dose rate (5 weekly × 11.7 mg/kg versus 1 × 58 mg/kg), and age at time of treatment (3 vs 15 mo) on the frequency of TG‐resistant, concanavalin A‐responsive spleen cells were evaluated. The frequencies of TG‐resistant spleen cells were generally dose responsive for 51 wk after exposure to ENU. They also were dependent upon the time that had elapsed since treatment with ENU, increasing to maximal values at 10 wk as previously reported [Jones et al, 1985a], and holding essentially stable at values of ∼20% of the maximum frequency from week 15 until at least week 40 for the 3‐month‐old mice. Fractionation of 58 mg ENU/kg into 5 weekly doses did not affect the frequency of ENU‐induced TG‐resistant cells detected in the spleen but did increase the rate of appearance in the spleen, and the efficiency of induction by the unit dose, of TG‐resistant cells. The mice exposed to ENU at 15 mo of age appeared to have a 4‐fold reduction in the rate of increase in frequency of ENU‐induced TG‐resistant spleen cells. One set of control mice was found to have a 10‐fold elevated frequency of TG‐resistant cells in both the spleen and thymus, indicating that mutations can occur in stem cells of untreated animals.
Development of an intact hepatocyte activation system for routine use with the mouse lymphoma assay
Authors: Brock Karen H. , Moore Martha M. , Oglesby Linda A. 
Published: February 2007

AbstractWe have developed a method for cocultivating primary rat hepatocytes with L5178Y/TK+/− −3.7.2C mouse lymphoma cells. This method should provide a means of simulating more closely in‐vivo metabolism compared to metabolism by liver homogenates, while still being useful for routine screening. Hepatocytes were isolated from 200–250 gm adult male Sprague‐Dawley rats; 1 × 106 viable hepatocytes were seeded per flask. Rapid attachment of the hepatocytes (2 hr) was obtained by using fibronectin‐coated 25−cm2 tissue culture flasks. Cocultivated cultures were incubated at 37°C on a platform rocker at 32 oscillations per minute. A 16‐hr cocultivated period was selected. With this hepatocyte activation methodology, CP, DMN, DMBA, and B(a)P, genotoxins that require metabolic activation, could be detected as mutagens in L5178Y/TK+/− cells.
Interlaboratory evaluation of the c3h/10t1/2 cell transformation assay
Authors: Dunkel Virginia C. , Schechtman Leonard M. , Tu Alice S. , Sivak Andrew , Lubet Ronald A. , Cameron Thomas P. 
Published: February 2007

AbstractThe C3H/10T1/2 transformation assay was evaluated for its responsiveness and interlaboratory reproducibility. Two laboratories participated in this study and tested a series of 46 chemicals. The majority of these chemicals were tested under code. Of the 46 chemicals tested, seven were determined to be active in both laboratories, and 14 were determined to be inactive. When the total number of chemicals is adjusted for assays considered “no test” in either one or both laboratories as well as for tests of chemicals yielding positive results in only one laboratory, reproducible responses were obtained for 21/35, or 60%, of the chemicals tested.
Species and sex differences in genotoxicity of heterocyclic amine pyrolysis and cooking products in the hepatocyte primary culture/dna repair test using rat, mouse, and hamster hepatocytes
Authors: Yoshimi Naoki , Sugie Shigeyuki , Iwata Hitoshi , Mori Hideki , Williams Gary M. 
Published: February 2007

AbstractEleven mutagenic heterocyclic amines, 3‐amino‐1,4‐dimethyl‐5H‐pyrido[4,3‐b]‐indole (Trp‐P‐1), 3‐amino‐1‐methyl‐5H‐pyrido[4,3]indole (Trp‐P‐2), 2‐amino‐6‐methyl‐dipyrido[1,2‐a:3′,2′‐d]imidazole (Glu‐P‐1), 2‐aminodipyrido[1,2‐a:3′,2′‐d]imidazole (Glu‐P‐2), 2‐amino‐9H‐pyrido[2,3‐b]indole (AαC), 2‐amino‐3‐methyl‐9H‐pyrido[2,3‐b]indole (MeAαC), 2‐amino‐3‐methylimidazo[4,5‐f]quinoline (IQ), 2‐amino‐3,4‐dimethylimidazo[4,5‐f]quinoline (MeIQ), 2‐amino‐3,8‐dimethylimidazo [4,5‐f]quinoline (MeIQX), 2‐amino‐3,4,8‐trimethylimidazo[4,5‐f]quinoxaline (4,8‐diMeIQX), and 2‐amino‐3,7,8‐trimethylimidazo[4,5‐f]quinoxaline (7,8‐diMeIQX), were studied for genotoxicity in the hepatocyte/DNA repair test employing hepatocytes of male rats, male and female mice, and male hamsters. In these four assay systems, all compounds elicited DNA repair in at least three systems, except Trp‐P‐2, which was uniformly inactive. However, there were several significant differences in the responses of different systems. Rat and hamster hepatocytes responded to nine of the ten genotoxic compounds with the exception of Glu‐P‐2. Male and female mouse hepatocytes responded to Glu‐P‐2, whereas female, but not male, mouse hepatocytes responded to MeIQX and 4,8‐diMeIQX. These results illustrate species and sex differences in response to these heterocyclic amines and suggest that a number of these compounds are carcinogenic in hamsters, as they have been in rats and mice.
Statistical exploration of four major genotoxicity data bases: An overview
Authors: Benigni R. , Giuliani A. 
Published: February 2007

AbstractThis report puts into perspective a series of exploratory statistical analyses carried out on the major genotoxicity data bases. While large compilations of data, even though computerized, suffer from their own size and are quite intractable to scientific reflection and judgement, the multivariate data analysis methods used by us are specifically designed for reorganising the information in a rational way and highlighting the underlying regularities of the data.The analyses reported here refer to the following data bases: the International Program for the Evaluation of Short‐Term Tests for Carcinogens, the International Program on Chemical Safety Collaborative Study on In Vitro Assays, the Gene‐Tox data base, and a subset of the U.S. National Toxicology Program data.Although the various data bases consisted of different sets of chemicals and had different underlying rationales, a number of invariant associations among short‐term test performances were highlighted. The overall evidence indicated that the traditional classification of assays (according to the criteria of genetic end‐point and phylogenetic position of the assays) was in contrast with the actual, operational similarities among assay performances, in that the experimental responses of the tests to the large variety of chemicals under consideration pointed to an alternative classification scheme. This consisted of three major classes: 1) a class comprising the in vivo assays; 2) a class grouping together many of the most widely used in vitro assays (Salmonella, chromosomal aberrations, and sister chromatid exchanges in Chinese hamster ovary cells, the various mutation tests in mammalian cell systems, etc.); 3) a second in vitro assay class (with Syrian hamster embryo cell transformation, Saccharomyces cerevisiae XV185‐14C, B. subtilis rec‐, Escherichia coli pol A). Such classes had clearly differentiated features with respect to carcinogenicity prediction. The implications of these findings for the current debate on mutagenicity testing are discussed.