bluuebunny/crossref_metadata_2025_split huggingface dataset:
Standards in behavioral teratology testing: Test variability and sensitivity
Authors: Butcher Richard E. , Wootten Virginia , Vorhees Charles V. 
Published: February 2006

AbstractRegulatory guidelines have produced a need to develop behavioral screening techniques to accompany teratology and reproduction testing. In the repeated use of a provisional test battery, we have found that conclusions about the behavioral teratogenic potential of test compounds are most likely to be revealed using tests having intermediate levels of variability. The results obtained from examining animals exposed developmentally to brominated vegetable oil (BVO as 2.0, 1.0, 0.5, or 0.25 percent of the diet) and comparisons of the tests' co‐efficients of variation, offer an empirical example of this concept. Preweaning tests of locomotion and reflex development demonstrated numerous instances of developmental delay in the BVO‐treated subjects, but postweaning tests revealed few abnormalities. Behavioral testing revealed functional deficits from BVO administration at doses lower than those which have adverse effects on reproduction. Examination of the tests' variability by using coefficients of variation as a comparative index, disclosed that the postweaning test variability was almost twice that of the preweaning tests. Thus, the lack of effects of BVO on most of the postweaning tests should not be conclusively interpreted as indicative of recovery of function, because this pattern is equally likely to have resulted from the lower sensitivity of these tests. An acceptable standard for future behavioral teratology screening requires a close examination of test variability, as it appears to be an important element in the sensitivity and, hence, the interpretation of such procedures.
Alkylation of macromolecules for detecting mutagenic agents
Authors: Ehrenberg L. , Osterman‐Golkar Siv 
Published: February 2006

AbstractAt present, experiments with laboratory organisms and epidemiological studies are the major source of information about the genetic toxicology of environmental agents. Laboratory systems are limited in value by difficulties in the interpretation of negative results, in quantitation, and in extrapolation from experimental effects of chemicals to specific levels of activity in man. Epi‐demiologic methods measure effects in man but are weakened by long latency times, confounding environmental factors, imprecise endpoints, and high background levels, which reduce sensitivity. Several methodological improvements in genetic toxicity testing are needed, including increased resolving power, greater relevance of observations to effects in man, techniques for evaluating interactions of compounds in chemically complex systems, and improvements in quantitative risk assessment. Because most genetically toxic agents ultimately react as electrophilic agents with nucleophilic centers in cellular macro‐molecules, the quantitative analysis of the resulting products may be a useful approach to the evaluation of the risks posed by exposure to specific chemicals. The main nucleophilic centers in biological macromolecules are thiol and thioether sulfurs, nitrogens in amino groups and rings, and oxygen atoms. Using the laws of reaction kinetics of alkylation and the observed kinetics of induced mutagenic effects, it is possible to relate the formation of alkylated products in macromolecules to genetic toxicity. The alkylation of amino acids (eg, histidine and cysteine) in hemoglobin can be measured with sufficient sensitivity and accuracy to use it as a monitor of exposure to alkylating agents. By determining the degree of alkylation of a specific center, it is possible to calculate the internal dose of an agent and, because erythrocyte life‐spans are relatively uniform, the incremental daily exposure of an individual to an alkylating agent. Dosimetry can be equated with radiologic dose so that exposure can be expressed in rad‐equivalents and the effects of specific agents compared quantitatively to biologically well‐characterized doses of radiation.
Mutagenicity of dimethylsulfoxide (DMSO): In vivo cytogenetics study in the rat
Authors: Kapp R. W. , Eventoff B. E. 
Published: February 2006

AbstractVarious concentrations (1%, 10%, 50%, and 100%) of laboratory grade dimethylsulfoxide (DMSO) were administered by intraperitoneal injection to male Sprague‐Dawley rats for five consecutive days. Femoral bone marrow cells were harvested 24 hours after the last injection and were analyzed for cytogenetic aberration frequencies including chromosome breaks, chromatid breaks, markers, and severely damaged cells. Chromosome breaks revealed no differences between treated and control groups. Chromatid breaks were significantly elevated over the controls in all treated groups except at the 10% level. The incidence of markers was significantly elevated when compared to the controls in all treated groups. Only the high‐level (100%) group showed a significant increase in the incidence of severely damaged cells. When the above data were combined, the resultant percent of aberrant cells per animal was found to increase from 10% aberrant cells at the 1% DMSO level to 68.67% aberrant cells at the 100% DMSO level. The incidences of aberrant cells in all treated groups were significantly elevated when compared to the control (4% aberrant cells) group. These observations suggest that DMSO effectively disrupts the integrity of rat chromsome structure, and further investigation of the genetic activity of DMSO is warranted.
DNA repair and chromosome aberrations: The effect of cytosine arabinoside on the frequency of chromosome aberrations induced by radiation and chemicals
Authors: Preston R. J. 
Published: February 2006

AbstractThe frequency of x‐ray‐induced chromosome aberrations in G0 human lymphocytes was greatly increased when cells were incubated with cytosine arabinoside (ara‐C) after irradiation. The frequency of dicentrics increased with increasing ara‐C incubation times (one, two, and three hours). Lymphocytes from Down syndrome individuals were more sensitive to aberration induction by x‐rays in G0, and the increase in dicentric frequency with ara‐C incubation was much more rapid than with normal cells. When G2 normal lymphocytes were x‐irradiated and incubated for two or three hours with ara‐C until fixation, there was a large increase in deletion frequency compared to cells x‐irradiated and incubated in the absence of ara‐C. However, no exchanges were observed in the presence of ara‐C, compared to 0.29 per cell as when x‐rays alone were given. These results form the basis for a discussion of the mechanism of aberration induction by x‐rays.Experiments with two chemicals, 4‐nitroquinoline‐N‐oxide and methyl methanesulfonate, show that chromosome‐type aberrations can be induced in G1 treated lymphocytes incubated with ara‐C. However, these chemicals, in the absence of ara‐C incubation, induced no aberrations in G1 at the concentrations used. The mechanism of aberration induction is discussed, particularly in terms of whether or not chemicals can be defined as S‐phase dependent.
Correlation of the chemical structure of 4‐nitroquinolines inactivating human cytomegalovirus and established in vivo carcinogenicity tests
Authors: Albrecht Thomas , Speelman Dan J. , Ramanujam V. M. Sadagopa , Lund Howard W. , Legator Marvin S. , Trieff Norman M. 
Published: February 2006

AbstractInactivation of the infectivity of human cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV‐1) and type 2 (HSV‐2) has been observed following exposure to 4‐nitroquinoline 1‐oxide (NQO) or its metabolite, 4‐hydroxyaminoquinoline 1‐oxide (HAQO). The present study of the specificity of the chemical structure of 4‐nitroquinolines demonstrated that both the 4‐nitro and 1‐oxide groups were required for inactivation of virus infectivity. Reduction of the 4‐nitro group to a 4‐hydroxyamino group enhanced activity, while further reduction to an amino group resulted in loss of activity against virus infectivity. The capacity to inactivate virus was also lost by substitution of the pyridine ring for the quinoline nucleus of NQO. The relationship between the chemical structure and the ability to inactivate viruses studied here correlates well with earlier in vivo carcinogenicity studies of the same group of chemicals.
An in vitro investigation of genetic susceptibility to cancer in diploid fibroblasts from retinoblastoma patients
Authors: Weichselbaum Ralph R. , Nove John , Albert Daniel , Little John B. 
Published: February 2006

AbstractThirty‐two diploid fibroblast strains from individuals with the three forms of retinoblastoma were examined with an in vitro clonogenic survival assay to determine their sensitivity to killing by X rays. Strains from sporadic unilateral retinoblastoma patients and normal controls were indistinguishable from one another (group D0's = 147 ± 15 rads and 146 ± 5 rads, respectively) while the strains from patients with the hereditary form of the disease were significantly more X‐ray sensitive (D0 = 111 ± 12). Strains derived from individuals with the D‐deletion form of the disease resembled the hereditary strains with respect to sensitivity and heterogeneity, suggesting a possible, common etiology for these two forms of the disease.A DNA‐repair defect is hypothesized as reflected by the observed hypersensitivity to X‐irradiation in these cells. We suggest that this defect may be associated with the enhanced frequency of spontaneous and radiationinduced second tumors seen in some retinoblastoma patients.
Interactions between initiating chemical carcinogens, tumor promoters, and adenovirus in cell transformation
Authors: Fisher Paul B. , Dorsch‐Häsler Karoline , Weinstein I. Bernard , Ginsberg Harold S. 
Published: February 2006

AbstractCell culture systems that respond to the combined action of initiating chemical carcinogens, tumor promoters, and transforming viruses represent useful model systems for studying the complex multifactor nature of the carcinogenic process. We have utilized both secondary rat embryo (2° RE) and a clonal population of established Fischer rat embryo (CREF) cells to study the effect of multiple agents on the process of adenovirus transformation. In the present review we summarize our investigations on the effects of polycyclic aromatic hydrocarbons, tumor promoters, a bee venom polypeptide‐melittin (MEL), and the polypeptide hormone epidermal growth factor (EGF) on transformation of rat embryo cells by a temperature‐sensitive mutant of human adenovirus type 5 (H5ts125). We also describe the effect of tumor promoters on the progression of the transformed phenotype, ie the temporal acquisition of anchorage‐independent growth in adenovirus‐transformed clones and the ability of MEL and EGF to elicit effects similar to those of tumor promoters in adenovirus‐transformed cells.
Association between the presence of the Ah receptor in embryonic murine tissues and sensitivity to TCDD‐induced cleft palate
Authors: Dencker Lennart , Pratt Robert M. 
Published: February 2006

AbstractTCDD (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin) causes a high percentage of isolated cleft palate in the fetus when administered to the pregnant dam at day 10 of gestation but only in certain strains of mice (ie, C56BL/6J (C57BL)). These strains are also known to have a specific cytosolic receptor protein (Ah‐receptor) in the liver for polycyclic hydrocarbons and TCDD, and respond to these compounds by increased levels of cytochrome P‐450 mediated monooxygenase activities and probably several other enzyme systems. We have shown that midgestational embryos of sensitive strains exhibit high levels of the TCDD cytosolic receptor in the maxillary processes and secondary palatal shelves prior to palate closure. Binding studies and Scatchard plot analysis revealed an apparent Kd of 1.1 nM and a Bmax of 32 fmole bound TCDD/mg cytosolic protein from C57BL maxillary processes on day 13 of gestation. The TCDD resistant strain, AKR/J, did not show any specific binding of TCDD. Mesenchymal cells from C57BL secondary palatal shelves retained the cytosolic receptor for TCDD when grown in culture. These results suggest that the teratogenic effects of TCDD in sensitive murine strains are dependent upon the binding of TCDD to the cytoplasmic receptor in the fetus.
Teratology study with the synthetic prostaglandin ONO‐802 given intravaginally to rabbits
Authors: Petrere Judith A. , Humphrey Ronald R. , Sakowski Raymond , Fitzgerald James E. , de la Iglesia Felix A. 
Published: February 2006

AbstractONO‐802, a synthetic E1 prostaglandin, was administered intravaginally via pessaries to Dutch belted rabbits at doses of 250, 62.5, and 12.5 μg/kg on days 6 through 18 of gestation. Rabbits in a vehicle control group were treated with pessaries that did not contain ONO‐802 during the same period. Another group of animals remained untreated throughout gestation. Necropsies were performed on rabbits found dead and on those killed on gestation day 30. Body weight, food and water consumption, and clinical signs were monitored during the experiment. Major organs were weighed when the dams were necropsied on gestation day 30, and litter and fetal data were collected.Abortion and maternal deaths occurred in drug‐treated groups. Body weight gains and food and water consumption were adversely affected by treatment particularly at the 250 and 12.5 μg/kg dose levels. Wastage (postimplantation loss) was significantly increased among treated groups (all dose levels), while other litter and fetal parameters were unaffected. ONO‐802 was not teratogenic at maternal and embryotoxic dose levels.
Metabolic activation of cyclophosphamide by yolk sac endodermal cells of the early chick embryo
Authors: Gamett Daniel C. , Klein Norman W. 
Published: February 2006

AbstractEndodermal cells isolated from the yolk sacs of day 3 chick embryos were able to activate metabolically cyclophosphamide. This was demonstrated by the cytotoxicity of cyclophosphamide to the endodermal cells themselves as well as by the ability of endodermal tissue to mediate a cytotoxic response in coculture with KB cells, a human tumor cell line unable to activate cyclophosphamide. Yolk sac endodermal cells from day 3 embryos were sensitive to cyclophosphamide when the drug was added immediately after the start of culture, but not when the drug was added after 24 hr of culture. The ability to metabolize cyclophosphamide by the day 3 embryo appeared limited to the endodermal cells of the yolk sac as cells derived from neither the embryo proper nor yolk sac mesoderm‐ectoderm tissue were positive in these tests. Using whole blastoderms, cyclophosphamide activation was detected as early as 12 hr of egg incubation.
Inhibition of metabolic cooperation between Chinese hamster V79 cells by structurally diverse teratogens
Authors: Welsch Frank , Stedman Donald B. 
Published: February 2006

AbstractCell‐cell communication through chemical messengers is a fundamental event required for the differentiation of embryonal cells. Interference with this process by xenobiotics may disrupt embryogenesis. Chinese hamster cells (V79) which display a specific form of cell‐cell communication called metabolic cooperation were cultured in the presence of structurally diverse chemical teratogens. Among them were 12‐0‐tetradecanoyl‐phorbol‐13‐acetate (TPA), diphenylhydantoin (DPH), warfarin, and a series of monoalkyl ethers of ethylene glycol with alcohol chain lengths from methyl to butyl. Sodium saccharin and ascorbic acid were examined to represent two chemicals which have been thoroughly tested for teratogenic effects in laboratory animals and cause no birth defects. Recovery of 100 6‐thioguanine‐resistant V79 (6‐TGr) cells in coculture with 400,000 6‐thioguanine‐sensitive V79 (6‐TGs) cells in the presence of 6‐thioguanine (6‐TG) and the chemical agent was measured. In amounts that neither interfered with colony forming ability nor caused cytostasis when 100 6‐TGr cells were plated alone, all of the substances except for saccharin and vitamin C increased the number of surviving 6‐TGr cells in a concentration‐related manner. The recovery was increased by the presence of TPA (to 100% by 4 ng/ml), DPH (from 26% at 91 μM to 43% at 274 μM), warfarin (from 15.5% at 162 μM to 44.5% at 487 μM) and to variable extents by all five glycol ethers. The most efficacious in the latter group of compounds was the isopropyl ether which raised 6‐TGr recovery from 8% at 0.017 M to 66% at 0.087 M. Based on the evidence accumulated by previous studies involving TPA, we postulate that the teratogens employed inhibited metabolic cooperation. These observations suggest that V79 cells may be suitable to study inhibition of cell‐cell communication as a mechanism of teratogenesis.
Effects of endotoxin on placental labyrinth formation in the golden hamster: A light and electron microscopic study
Authors: Lanning John C. , Hilbelink Don R. 
Published: February 2006

AbstractAnimal studies of endotoxemia during pregnancy have suggested that the placenta is the primary site of action. This study was designed to evaluate the effects of endotoxin at previously established resorptive and teratogenic dose levels during the development of the placenta in the hamster. At the higher dose levels, total necrosis of the placenta was observed within 24 hr after treatment. Formation of fibrin thrombi was only apparent well after the initiation of necrotic events. At the teratogenic dose, a marked decrease in the formation of the placental labyrinth was evident, but invading fetal capillaries and fetal blood cells appeared normal. However, scattered necrotic foci of trophoblastic cells were observed.
Comparative teratogenic activities of two retinoids: Effects on palate and limb development
Authors: Kochhar D. M. , Penner John D. , Tellone Carmella I. 
Published: February 2006

AbstractTwo closely related retinoids, all‐trans and 13‐cis retinoic acids, were assessed for their relative activities as teratogens in ICR mice by monitoring the frequency with which either isomer produced discrete dysmorphogenesis of the embryonic limb and the secondary palate. A single oral dose of all‐trans retinoic acid at 100 mg/kg on either day 11.5 or 12.0 of gestation (plug day = day one) was maximally effective; more than 90% of the treated embryos developed reduction defects of the limb bones and an equally high percentage also had cleft palate. The limb development was most sensitive on day 11.5 of gestation while the peak susceptibility for palatal clefts began on day 12.0. Under identical experimental conditions, treatment with 100 mg/kg 13‐cis retinoic acid produced no apparent teratogenic effects. By assessing the relative incidence of readily identifiable malformations of the limb and palate associated with various doses of the two isomers, we found that 13‐cis retinoic acid was four to eight times less embry‐opathic than all‐trans retinoic acid. Since the mechanism of teratogenic action of retinoids is still far from clear, it is suggested that further studies on causative factors will be greatly assisted by the use of these two closely related retinoids, which substantially differ from each other in their teratogenic potency.
Genetic activity of the carcinogen N‐ nitrosodiethanolamine (NDELA) on unstable mutant alleles of the white locus in Drosophila melanogaster
Authors: Fahmy Myrtle J. , Fahmy O. G. 
Published: February 2006

AbstractThe genetic activities of the carcinogen N‐nitrosodiethanolamine (NDELA) were assayed somatically and germinally on two stocks carrying unstable alleles of the white (w+) eye colour gene: one incorporating a TE (z TE w+; coded UZ), the other with a tandem duplication of part of the encoding w+ sequence (wi16). Treatment was applied topically on late embryonic and early larval stages over a wide dose range (0.01–2.0 M) and the general mutagenic levels actually achieved were measured in terms of the X‐recessive mutations (lethals and visibles) recovered in Muller‐5 tests on samples of the males scored for somatic sectoring. The carcinogen was germinally ineffective on the z TE w+ and wi16 loci even at the maximal tested dose (2.0 M), and was only weakly mutagenic with respect tothe X‐recessives (lethals + visibles) at massive doses (1.0–2.0 M). In contrast, it proved to be genetically effective somatically, inducing red eye sectors through regulatory effects involving the TE in the UZ stock and complete reversion to w+ in the case of wi16 at comparatively moderate doses (≤0.26 M). The possible implications of the demonstration of the genetic activity of NDELA in the soma to the carcinogenic process, and to the wider problem of screening for environmental genotoxic compounds, are discussed.
Transplacental genetic and cytogenetic effects of alkylating agents in the mouse. I: Induction of somatic coat color mutations
Authors: Braun Rolf , Hüttner Edith , Schöneich Jörg 
Published: February 2006

AbstractInduction of somatic coat color mutations by the alkylating agents ENU, MNU, EMS, MMS, DES, DMS, and trenimon and by the tuberculostatic drug INH was investigated in the mammalian spot test. Positive results were obtained with EMS (100 mg/kg), ENU (20–60 mg/kg), and INH (100 mg/kg), while trenimon (100 μg/kg), DES (225 mg/kg), and MNU (2 mg/kg) yielded inconclusive data. No mutagenic activity was found for MMS (125 mg/kg) and DMS (50 mg/kg). The mutagenic potency of monofunctional alkylating agents at subtoxic doses decreases as follows ENU > EMS > DES > MMS = DMS. The hypothesis that somatic coat color mutations in the mouse are predominantly due to intragenic changes is discussed. Differences in the RS frequency between offspring of the crosses NMRI × DBA and C57 × T are due to differences in loci available for mutation induction. Mutations that uncover the recessive allele p contribute to a significant extent to the total RS frequency observed in the mammalian spot test.
Effect of repeated ether anesthesias on the mono‐oxygenase system of rat liver S‐9 fraction
Authors: Paolini M. , Bauer C. , Corsi C. , Tonelli F. , Hrelia P. , Bronzetti G. , Forti G. Cantelli 
Published: February 2006

AbstractThis study was designed to investigate the effect of ether anesthesia in rats, before i.p. injections to induce the mono‐oxygenase enzyme system, on biochemical properties of liver S9 fractions. Aminopyrine N‐demethylase and ρ‐nitroanisole O‐demethylase activity levels, their stability, and lipid peroxidation were determined in S9 fractions after etherization (about 1 min in ether vapor chamber daily for 3 consecutive days, before i.p. injections of Na‐phenobarbital and β‐naphthoflavone) and compared with controls receiving the same injections without etherization. The activities were slightly (but not significatively) enhanced after this treatment, but stability was markedly and significatively greater after 1 h of incubation in the conditions of the liver microsomal assay (+ 14.8% and +74.7%, respectively); lipid peroxidation was strongly and significatively depressed (−76.0%). Etherization sufficient to kill the animals on the 4th day resulted in equally active but less stable S9 fraction enzymes. Dimethylnitrosamine (as a standard premutagen) was assayed with the D7 strain of Saccharomyces cerevisiae using S9 fractions obtained from both anesthetized and nonanesthetized rats. According to biochemical data, results obtained with S9 from partially anesthetized rats were comparable with the conventional ones (S9 from nonanesthetized rats). On the contrary, the use of more prolonged ether anesthesia, including one on the day the animals are killed, gives S9 fraction significantly less effective.We conclude that if brief etherizations are used, for i.p. injections only, the S9 fractions obtained are entirely satisfactory and the procedures involved in production are simplified; the additional animal treatment (etherization) must be specified.