bluuebunny/crossref_metadata_2025_split huggingface dataset:
The antioxidant butylated hydroxytoluene can retard cerebellar degeneration induced transplacentally by a single low dosage of N‐methyl‐n‐nitrosourea
Authors: Smith Sylvia B. , Cooke Carol Beck , Lemone Yielding K. 
Published: February 2006

AbstractLate‐onset cerebellar degeneration can be induced transplacentally in mice by a single low‐dose (1 mg/kg) injection of the direct‐acting DNA alkylating agent N‐methyl‐N‐nitrosourea (MNU) on day 16 of pregnancy. The offspring develop a mild ataxia that manifests by 12–16 weeks of age postnatally when the animals are challenged with a motor coordination task. Morphological evidence of degeneration includes pyknosis of Purkinje cells and abnormal foliation patterns. Additionally, these animals demonstrate a progressive retinopathy characterized by thinning of the nuclear and plexiform layers of the retina. Efforts to retard the cerebellar degeneration were undertaken in the present study. MNU‐exposed and control animals were fed a standard mouse chow diet supplemented with 0.75% butylated hydroxytoluene (BHT), an antioxidant. This supplementation commenced 24 h following exposure to the teratogen and continued throughout the life of the offspring. A second group of MNU‐exposed and control mice were fed a non‐BHT‐supplemented, standard Purina mouse chow diet. Quantitative histological evaluation of cerebellar coronal sections indicated that by 4 weeks of age BHT‐fed, MNU‐exposed mice had significantly fewer pyknotic Purkinje cells than non‐BHT‐fed, MNU‐exposed animals. This was true for the vermal, paravermal, and lateral areas of the cerebellum. The findings suggest the usefulness of teratogenic models of degenerative diseases for the testing of potential intervention strategies.
Genotoxic effects of estrogens in epithelial cells from the neonatal mouse uterine cervix: Modifications by metabolic modifiers
Authors: Hillbertz‐Nilsson Kerstin , Forsberg John‐Gunnar 
Published: February 2006

AbstractEpithelium from the neonatal mouse uterine cervix and uppermost part of vagina was cultured in vitro. The culture medium was supplemented with 17β‐estradiol (E2; 10–6–10–5 M) or diethylstilbestrol (DES; 10–8–10–5 M) alone or in combination with different metabolic modifiers (α‐naphthoflavone, β‐naphthoflavone, phenobarbital, metyrapone, indomethacin) with postulated activating or inhibitory effects on DES metabolizing enzymes (cytochrome P‐448‐ and P‐450‐dependent microsomal monooxidases, prostaglandin cyclooxygenase). E2 at 10–5 M and DES at 10–6 and 10–5 M concentrations increased the incidence of cells with a high number of sister chromatid exchanges (high‐frequency chromatid exchange cells, HFCEC). Indomethacin partially depressed DES‐induced HFCEC, whereas the incidence was increased by α‐naphthoflavone, which may be a result of stimulation of the fetal type of P‐448‐dependent enzyme activity or of DES increasing the metabolic activation of α‐naphthoflavone. Phenobarbital and β‐naphthoflavone did not affect the incidence of DES‐induced HFCEC. Metyrapone alone induced the highest incidence of HFCEC observed in this study, and this effect was inactivated by phenobarbital and/or DES. The mechanisms behind these results are discussed. This study shows that E2 and DES have a genotoxic effect (sister chromatid exchanges) in vitro in epithelial cells from the same target organ as in which epithelial aberrations occur after in vivo estrogen treatment in the neonatal period. The difference in incidence of tetraploid cells between stroma and epithelium is stressed (< 5% vs. 16–47% depending on experimental group).
Comparison of DNA alkylation, fragmentation, and repair in maternal and fetal tissues of pregnant rats treated with a single dose of ethyl methanesulfonate, ethyl‐N‐nitrosourea, N‐nitrosodiethylamine, and methyl‐N‐nitrosourea
Authors: Robbiano Luigi , Parodi Angela , Venturelli Simonetta , Brambilla Giovanni 
Published: February 2006

AbstractThe occurrence and persistence of DNA damage, as detected by the alkaline elution technique, have been studied in some tissues of both fetal and adult Sprague‐Dawley rats (18th day of gestation) after administration of a single equimolar dose (0.5 mmol/kg) of ethyl methanesulfonate (EMS), N‐ethyl‐N‐nitrosourea (ENU), N‐nitrosodiethylamine (NDEA), and N‐methyl‐N‐nitrosourea (MNU). EMS, ENU, and MNU, injected intravenously, produced a statistically significant increase of DNA elution rate, which is considered indicative of DNA fragmentation, in both maternal and fetal liver, kidney, and brain. NDEA, introduced by gastric gavage, induced DNA breaks in both liver and kidney of dams, but only in the liver of fetuses. The frequency of DNA lesions was found to vary with the four alkylating agents and in the three organs tested, to exhibit a different time course, and usually to be higher in maternal than in fetal tissues. Results provided by the concomitant determination of DNA binding levels demonstrated a satisfactory correlation with the amounts of DNA fragmentation. In contrast, the values of both these parameters did not show any positive correlation with the different susceptibility of the three organs to tumor induction. In conclusion, these findings suggest that when a compound is not available in radiolabeled form, measurement of DNA fragmentation may represent a useful alternative to the determination of DNA binding level in order to obtain information on the distribution of its reactive species in maternal and fetal tissues.
Teratogenicity and toxicity of ethylene glycol monomethyl ether (2‐methoxyethanol) in Drosophila melanogaster: Involvement of alcohol dehydrogenase activity
Authors: Eisses Karel T. H. 
Published: February 2006

AbstractEthylene glycol monomethyl ether (EGME) or 2‐methoxyethanol (2‐ME) is a toxic compound that has teratogenic effects in developing organisms similar to its oxidation product methoxyacetic acid (MAA). Alcohol dehydrogenase (ADH) is supposed to be involved with the oxidation of EGME into MAA. It has been shown here that Drosophila ADH dehydrogenates EGME in an in vitro test system. Three strains of Drosophila melanogaster, genetically different from each other with regard to ADH activities (qualitatively and quantitatively), were used to test the in vivo involvement of ADH with the oxidation of EGME into MAA. The toxicity of EGME in egg‐to‐adult and third instar larval‐to‐adult development is concentration and strain dependent. Higher detoxification occurs in the strain with increased ADH activity. EGME is much more toxic than its oxidation product MAA at the level of adult eclosion. Teratogenic effects were observed in the ADH‐negative strain in spite of lacking ADH activity. EGME is apparently a teratogenic compound by itself.
Chromosomal aberrations as a contributing factor for tumor promotion in the mouse skin
Authors: Kaina Bernd 
Published: February 2006

AbstractTumor promotion in mouse skin can be dissected in two stages: stage I (conversion) and stage II. Whereas for stage II clonal expansion of transformed cells is believed to play a major role, the mechanism(s) underlying conversion is still a matter of debate. Because conversion can be achieved upon treatment with phorbol ester tumor promoters prior to initiation, it is unlikely to represent simply proliferative stimulation of initiated cells (due to epigenetic changes induced). Since tumor promoters exert clastogenic activities and, on the other hand, the clastogen methyl methanesulfonate proved to be convertogenic, the possibility arises that chromosomal changes are involved in conversion. Based on this hypothesis, several findings concerning the action of tumor promoters and the process of tumor promotion in the mouse skin system are discussed and interpreted: the frequency, reversibility, and transient nature of conversion, dependence of tumor promotion on DNA synthesis, induction of DNA breaks by tumor promoters, and the protecting effect of scavengers of free radicals. A model is presented suggesting tumor formation in mouse skin (and other systems) to proceed in discrete, genetically determined steps. Initiation is considered to be due to the induction of point mutations in a dominant‐acting oncogene that becomes thereupon activated, whereas the decisive event in the conversion stage of tumor promotion is the induction of numerical and/or structural chromosomal changes with the consequence of loss or inactivation of gene(s) involved in suppression of the tumor phenotype.
Common Biochemical Pathway of Dysmorphogenesis in Murine Embryos: Use of the Glucocorticoid Pathway by Phenytoin
Authors: Kay Elizabeth D. , Goldman Allen S. , Daniel Jon C. 
Published: February 2006

AbstractPhenytoin (5,5‐diphenylhydantoin), a common anticonvulsant drug, is known to produce anomalies in the craniofacial region of animals and humans. Furthermore, recent evidence suggests that phenytoin disrupts craniofacial and neural tube morphogenesis by inhibiting the arachidonic acid cascade, a pathogenesis already implicated for glucocorticoids and hyperglycemia in the palate. This study tested the hypothesis that phenytoin interferes with the arachidonic acid cascade via the same biochemical pathway demonstrated for glucocorticoids. The proposed pathway was tested at two levels. First, indomethacin, an inhibitor of the enzyme cyclooxygenase, was used in culture to block the correction of phenytoin‐induced defects by arachidonic acid. Second, cortexolone, an anti‐glucocorticoid that binds at the glucocorticoid receptor binding site, was tested for its ability to prevent phenytoin‐induced teratogenicity. Eighty‐four percent of the embryos cultured in phenytoin and 93% of those cultured in phenytoin plus arachidonic acid and indomethacin had neural tube and/or craniofacial deformities. In contrast, only 14% of the embryos cultured in phenytoin plus cortexolone were affected. Indomethacin itself produced anomalies in 83% of the exposed embryos. These data are consistent with the hypothesis that the teratogenic action of phenytoin in murine embryo cultures occurs via the glucocorticoid anti‐inflammatory pathway. Thus, the glucocorticoid receptor appears to be responsible for mediating phenytoin‐induced teratogenicity.
Species differences in carcinogenicity: The role of metabolism in human risk evaluation
Authors: Green Trevor 
Published: February 2006

AbstractThe assessment of human risk from exposure to chemicals is frequently confounded by differences in response to those chemicals in laboratory animals. In many cases, the basis of the species differences is differences in metabolism and pharmacokinetics. Since metabolic and pharmacokinetic data are readily accessible in both laboratory animals and humans, risk assessments can be significantly improved if these data are incorporated into the process. Several chlorinated solvents, perchloroethylene, trichloroethylene, and methylene chloride, have been investigated, and the species differences in carcinogenicity have been shown to be the result of pharmacokinetic differences between the species. The rates of metabolism of these chemicals have been measured in rats and mice in vivo, and the species differences observed have been reproduced in vitro using tissue fractions and hepatocytes. Identical experiments have been carried out using human tissues. The results of these studies together with species‐specific physiological parameters have been used in a mathematical model to predict human cancer risk over a wide range of exposures. This approach provides both an explanation for the species differences in response to these chemicals and also a more rational approach to human risk assessment.
Genetic activity profiles in the testing and evaluation of chemical mixtures
Authors: Waters Michael D. , Claxton Larry D. , Frank Stack H. , Brady Ann L. , Graedel Thomas E. 
Published: February 2006

AbstractSome knowledge of the potential genetic activity of a complex environmental mixture may be gained from an assessment of the genetic activity of its component chemicals. The expanded Genetic Activity Profile (GAP) data base provides a computer‐generated graphic representation of genetic bioassay data as a function of dose of the substance tested. In addition, the Atmospheric Chemical Compound (ACC) data base contains information on chemical structures, properties, detection methods, and sources of chemicals found in ambient air. Using the combined data bases, the quantity of an individual chemical present within a mixture or fraction of a mixture may be related to the quantity (lowest effective dose, LED) of the chemical, by itself, required to demonstrate a positive response in one or more genetic bioassays.
Potentiation of ethyl methanesulfonate‐induced germ cell mutagenesis and depression of glutathione in male reproductive tissues by 1,2‐dibromoethane
Authors: Teaf Christopher M. , Bishop Jack B. , Harbison Raymond D. 
Published: February 2006

AbstractEDB significantly depressed GSH in caput and cauda epididymis, but not in testis, 2 hours following injection. This depression was dose‐related. EDB enhanced EMS‐induced dominant lethal mutations at mating weeks 2 and 3 (of 6). At mating week 2 the fetal death rate was increased two‐fold, while at week 3, the fetal death rate had increased to nearly three‐fold greater than the EMS‐only controls. Enhancement of fetal death rate was confined to postimplantation loss. As with EMS alone, the EDB potentiation of EMS‐induced mutations was limited to postmeiotic stages of spermatogenesis. EDB also enhanced alkylation of rat spermatozoa by labeled EMS. Depression of GSH in reproductive tissues is correlated with a potentiation of dominant lethal mutations, as well as an increase in the binding of EMS to sperm heads.
Estrogen effects on chromosome number and sister chromatid exchanges in uterine epithelial cells and kidney cells from neonatal mice
Authors: Forsberg John‐Gunnar 
Published: February 2006

AbstractFemale mice of the NMRI strain were treated with a high dose (5 μg) or a low dose (10−2 μg) of the synthetic estrogen diethylstilbestrol (DES) or estradiol‐17β (E2) 48 and 24 hr, 24 hr, or 12 hr before death on day 3 after birth. Cultures of epithelium from the uterine cervix and uterine horns as well as of kidney cells were set up, and, after a culture period of 3 days, cells were studied for chromosome number and sister chromatid exchanges. Cervical cells from control females had a distinct peak of tetraploid cells, which was depressed after DES treatment but less so after E2 treatment. The tetraploid peak was lower in uterine horn epithelium and was less influenced by DES. No indications were obtained for an estrogen‐induced aneuploid cell population in the uterine horn epithelium or cervical epithelium. The incidence of cells with a high number of sister chromatid exchanges (HFCECs) was only about one‐fifth in uterine horn epithelium from control females compared with cervical epithelium from the same females. In the cervical epithelium, DES at both dose levels and E2 at the high dose induced an increased and similar incidence of HFCECs (from about 12.5% in controls to about 35%), which was not related to estrogen exposure time. In uterine horn epithelium, the incidence of HFCECs increased from 2.5% in controls to 8.5% after DES treatment. It is postulated that there is a more pronounced genomic plasticity in the cervical epithelium compared with the uterine horn epithelium. The estrogens had no effect on chromosome number or HFCECs in kidney cells.
Effects of QA 208‐199 and its metabolite 209‐668 on embryonic development in vitro after microinjection into the exocoelomic space or into the amniotic cavity of cultured rat conceptuses
Authors: Bechter R. , Terlouw G. D. C. , Lee Q. P. , Juchau M. R. 
Published: February 2006

AbstractThe objective of this study was to determine the direct embryotoxic effects in vitro of N‐hydroxy‐N‐methyl‐7‐propoxy‐2‐naphthalene‐ethanamine (QA 208‐199, QAB) and of one of its metabolites, 7‐propoxy‐naphthalene‐2‐ylacetic acid (209–668, QAA), after circumventing the bioconverting conceptal membranes. The compounds were, therefore, microinjected either into the exocoelomic space or into the amniotic cavity of rat conceptuses of 10 d at prenatal age at doses of up to 84.9 ng (QAA) and 180 ng (QAB) per conceptus respectively. The conceptuses were subsequently cultured for 28 h after which their development was assessed. QAB produced marginal effects on embryonic differentiation only after microinjection of the compound into the amniotic cavity. Dysmorphogenic effects, however, occurred in a dose‐dependent fashion after either exocoelomic or intraamniotic microinjections of the compound. The frequencies and types of anomalies were similar after either exposure route and consisted predominantly of anomalies associated with axial rotation. QAA also impaired embryonic differentiation at only the high dose level of 84.9 ng per embryo and after intraamniotic injections only. Dysmorphogenic effects were observed in all experimental groups, although the differences were not statistically significant when compared with the concomitant controls. An increased proportion of anomalies observed were in the cephalic region as compared to the defects produced by QAB. These data suggest that QAA most probably is not the QAB metabolite responsible for the embryotoxic action of QAB in vitro. Furthermore, the results tend to confirm the suggested involvement of the visceral yolk sac membrane in mediating QAB embryotoxicity.
Induction of micronuclei in rat bone marrow by four model compounds
Authors: Shi Xiao‐Chun , Krishna Gopala , Ong Tong‐Man 
Published: February 2006

AbstractStudies have been performed to determine the dose and sampling time responses of micronuclei after Sprague‐Dawley rats were treated wth triethylenemelamine, mitomycin C. dimethylbenzanthracene, and vincristine by a single intraperitoneal injection. Three doses were tested for each compound. Animals were sacrificed 24, 48, and 72 h after chemical treatment. Slides prepared from the bone marrow were stained with May‐Gruenwald and Giemsa stains. The number of micronucleated polychromatic erythrocytes among 2,000 polychromatic erythrocytes (PCEs) and the ratio of PCEs to normochromatic erythrocytes were determined for each animal. The results show that all four compounds cause micronucleus formation in rat bone marrow. The peak response sampling time, either 24 or 48 h posttreatment, is dependent on the chemical as well as the dose. In all cases, however, an increase in the micronucleated PCEs was detected 24 h after chemical treatment. These results seem to indicate that two sampling times, 24 and 48 h, may be adequate for the micronucleus assay using rat bone marrow cells. © 1992 Wiley‐Liss, Inc.
Evaluation in a battery of in vivo assays of four in vitro genotoxins proved to be noncarcinogens in rodents
Authors: Allavena Alessandra , Martelli Antonietta , Robbiano Luigi , Brambilla Giovanni 
Published: February 2006

Abstract2‐Chlorethanol, 8‐hydroxyquinoline, 2,6‐toluenediamine, and eugenol, previously found to behave as genotoxins in in vitro systems and as noncarcinogens in rodents, were evaluated for their ability to induce genotoxic effects in vivo. Rats were given by gavage a single or two successive doses equal to one‐half the corresponding LD50, killed at different times after treatment, and examined for the following end points: the frequency of both micronucleated polychromatic erythrocytes in the bone marrow and micronucleated hepatocytes (after partial hepatectomy); the in vivo—in vitro induction of DNA fragmentation, as measured by the alkaline elution technique, and of unscheduled DNA synthesis, as measured by autoradiography, in hepatocyte primary cultures. The two latter end points were also evaluated after in vitro exposure of hepatocytes to log‐spaced subtoxic concentrations. 2‐Chloroethanol, 8‐hydroxyquinoline, and eugenol never produced effects indicative of genotoxic activity. The same happened with 2,6‐toluenediamine, with the exception of a significant increase over controls in the amounts of DNA damage and repair displayed by hepatocyte cultures obtained from rats given two 1/2 LD50 separated by a 24 h interval. Our results, which, apart the above mentioned exception, are in concordance with the rodent carcinogenicity results, contribute to underline the role of in vivo short‐term tests for the detection of potential genotoxic carcinogens. © 1992 Wiley‐Liss, Inc.
Further in vitro and in vivo mutagenicity assays with thiram and ziram fungicides: Bacterial reversion assays and mouse micronucleus test
Authors: Crebelli R. , Zijno A. , Conti L. , Crochi B. , Leopardi P. , Marcon F. , Renzi L. , Carere A. 
Published: February 2006

AbstractThe fungicides thiram and ziram have been assayed in a battery of nine bacterial strains of different genetic specificity. The results obtained suggest the induction of excisable DNA lesion(s), and indicate similar mutability of strains with AT or GC base pairs at target sites. This mutagenic profile is clearly distinct from that of oxidative mutagens, and it does not support the proposed role of oxidative stress in the mechanism of dithiocarbamates mutagenicity in bacteria.Furthermore, the bone marrow micronucleus test has been carried out in B6C3F1 mice with intraperitoneal administration of high grade thiram (12.5–50 mg/kg) and ziram samples (2.5–10 mg/kg in males, and 5–20 mg/kg in females). Thiram produced a significant increase of micronucleated PCEs in male mice sampled 48 h after treatment with 25, 37.5, and 50 mg/kg. No significant increase was detected in treated females. Ziram, tested in a lower range of doses because of its higher toxicity, resulted negative in both sexes. Both the acute toxicity and the ratio polychromatic/normochromatic erythrocytes indicated some sex specificity in the toxic effects induced by these dithiocarbamates in the B6C3F1 mouse. © 1992 Wiley‐Liss, Inc.
A novel model to assess developmental toxicity of dihaloalkanes in humans: Bioactivation of 1,2‐dibromoethane by the isozymes of human fetal liver glutathione S‐transferase
Authors: Mitra Ashoke , Hilbelink Don R. , Dwornik Julian J. , Kulkarni Arun 
Published: February 2006

AbstractGlutathione S‐transferase (GST) isozymes from human fetal liver (16–18 weeks gestation) were purified by affinity chromatography followed by ion‐exchange high performance liquid chromatography (HPLC). The purified isozymes were used to investigate toxicity of 1,2‐dibromoethane(EDB) in an in vitro model of rat embryos in culture as passive targets. At least five isozymes of GST were found in the human fetal liver. Two anionic forms [pI values 5.5 (P‐2) and 4.5 (P‐3)] and one basic form [pI value 8.7 (P‐6)] were clearly separated. The presence of two near‐neutral forms was also identified. All the isozymes of the human fetal liver GSTs tested metabolized EDB (specific activities were 2.1, 7.0, and 2.0 μmol of GSH consumed/min/mg protein for P‐2, P‐3, and P‐6 isozymes, respectively). Covalent binding of EDB to DNA and protein was 144% and 212% higher, respectively, with the P‐3 anionic isozyme when compared to the P‐6 basic isozyme of GST. No covalent binding to either protein or DNA was observed with the P‐2 isozyme.EDB bioactivation by the GST isozyme P‐3 (15 units; 1 unit = 1 nmol of GSH consumed/min) resulted in toxicity to cultured rat embryos. Significant reductions of crown rump length, yolk sac diameter, and the composite score of morphological parameters (Brown and Fabro method) were observed. The central nervous system, optic and olfactory systems, and the hind limb were most significantly affected. The results of this investigation suggest that EDB may be classified as a suspected developmental toxicant in humans. © 1992 Wiley‐Liss, Inc.