bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of sister chromatid exchange as an indicator of sensitivity to N‐ethyl‐N‐nitrosourea‐induced carcinogenesis in rats
Authors: Aitio A. , Cabral J. R. P. , Camus A.‐M. , Galendo D. , Bartsch H. , Aitio M.‐L. , Norppa H. , Salomaa S. , Sorsa M. , Husgafvel‐Pursiainen K. , Nurminen M. 
Published: February 2006

AbstractSister chromatid exchange (SCE) frequencies in peripheral lymphocytes are a frequently used endpoint to indicate exposures to genotoxins in groups of humans. The aim of this study was to ascertain, in an experimental design, whether or not SCE rates have any association with the risk of cancer at the individual level in rats exposed to a known carcinogen. Individual SCE rates were determined in three consecutive analyses in cultured blood lymphocytes of 50 adult male Wistar rats. Analyses were done before as well as 24 hr and 7 days after a single intraperitoneal administration of 0, 25, 50, or 75 mg/kg of N‐ethyl‐N‐nitrosourea (ENU). The animals were followed until death; also, the relationship between SCEs and carcinogenic outcome, i.e., the presence or absence of tumors, and their latency period were examined. ENU significantly decreased the life expectancy of the rats. The tumor types most clearly associated with ENU treatment were various gliomas and thyroid‐gland and testicular tumors. ENU induced a moderate (maximally 1.6‐fold) increase in the mean frequency of SCEs/cell at both sampling times after treatment. The effect was somewhat more pronounced 1 day rather than 1 week after treatment. The mean SCE rates in rats with ENU‐specific cancers or in animals with early or multiple tumors did not differ from those in animals that survived no less than 65 weeks or longer without developing tumors. In ENU‐treated animals with tumors, no relationship was found between the mean SCE rate and survival time. It is concluded that in outbred Wistar rats the SCE response in cultured lymphocytes does not indicate individual susceptibility to the carcinogenic action of ENU. On a group basis, however, animals with high SCE rates were shown to have increased risk of cancer.
Studies of mutagenesis and neoplastic transformation by bivalent metal ions and ionizing radiation
Authors: Little John B. , Frenial Jean‐Michel , Coppey Jacques 
Published: February 2006

AbstractWe examined the influence of nontoxic concentrations of each of two essential (Zn++ and Mn++) and one nonessential (Ni++) bivalent metal ions on spontaneous and radiation‐induced neoplastic transformation and specific gene mutations in mammalian cells. All three metals induced low levels of transformation in mouse BALB/3T3 cells but exerted no mutagenic effect in CHO cells (hprt locus) over a broad range of concentrations. Continuous incubation for 8 or 15 days with each of the metal ions did not enhance the frequency of cell killing, transformation, or mutations induced by acute exposure to x‐rays. Zn++, however, had a small but consistent protective effect on the induction of all three endpoints by xirradiation.
Mutagenicity of topoisomerase‐active agents in bacteriophage T4
Authors: Demarini David M. , Kay Lawrence B. 
Published: February 2006

AbstractRecently, the antitumor agent 4′‐(9‐acridinylamino)‐methanesulfon‐m‐anisidide (m‐AMSA) was shown to revert a frameshift mutant of T4 (rFCll), and its mutagenicity was shown to be mediated by T4 DNA topoisomerase II [Ripley et al.: J Mol Biol 200: 665–680, 1988]. Here we report dose‐response data on the mutagenicity and toxicity of m‐AMSA in T4 rFCll. We find that m‐AMSA is among the most potent frameshift mutagens observed in T4, inducing a 10‐fold increase in mutant frequency in the absence of toxicity and a 500‐fold increase in mutant frequency at 31% survival. In addition to m‐AMSA, the topoisomeraseactive agents ellipticine, oxolinic acid, and nalidixic acid also reverted rFCll; however, they required concentrations 10–100 times greater than those required by m‐AMSA in order to be mutagenic, and they did not produce mutant frequencies as high as those produced by m‐AMSA. Unlike m‐AMSA, all three agents were mutagenic only at toxic doses. The other agents evaluated—actinomycin D, adriamycin, 9‐aminoellipticine, 9‐methoxyellipticine, teniposide (VM‐26), and novobiocin—were toxic but not mutagenic to T4 rFCll. Thus, m‐AMSA appears to be distinctly different from the other topoisomerase‐active agents in exhibiting such potent mutagenic activity in T4 rFCll. Because E. coli DNA gyrase may substitute for T4 topoisomerase II, we examined the ability of two inhibitors of E. coli DNA gyrase, novobiocin and nalidixic acid, to inhihit m‐AMSA's mutagenicity. Both agents substantially reduced the mutagenicity of m‐AMSA in T4 rFCll, further suggesting that topoisomerase mediates the mutagenicity of m‐AMSA.
Micronucleus induction in mouse and rat fetuses treated transplacentally during histogenesis with mitomycin c and 7,12‐dimethylbenz(a)anthracene
Authors: Müller Lutz 
Published: February 2006

AbstractDuring histogenesis, mouse and rat fetuses were treated transplacentally with mitomycin C (MMC) and 7,12‐dimethylbenz(a)anthracene (DMBA). The micronucleus (MN)‐inducing effects of MMC were analysed in mouse fetal blood and liver; the effects of DMBA were analysed in mouse fetal and rat fetal blood and in maternal bone marrow of both species. Both test substances were clearly clastogenic during the period of development in which the embryos were analysed—i.e., MMC from gestational day 14 until day 18 in mice and DMBA on days 14 and 17 in mice and days 16 and 19 in rats. In mouse fetal liver and blood the MMC‐induced MN frequencies did not vary significantly during the whole period. MMC was more effective in fetal blood than in fetal liver. DMBA‐induced MN frequencies in maternal bone marrow were slightly higher in rats than in mice. Compared to maternal bone marrow, fetal MN frequencies were about four to five time higher in rats but less than two times higher in mice. Thus, rat fetuses were far more susceptible to the clastogenic action of DMBA than mouse fetuses. These results are discussed with respect to fetal development and maternal/fetal metabolism.
Evaluation of the developmental toxicity of nicotine and cotinine with frog embryo teratogenesis assay: Xenopus
Authors: Dawson Douglas A. , Fort Douglas J. , Smith Gregory J. , Newell Deborah L. , Bantle John A. 
Published: February 2006

AbstractThe teratogenic potential of nicotine and a primary metabolite, cotinine, was examined with FETAX (Frog Embryo Teratogenesis Assay: Xenopus). Early embryos of Xenopus laevis were exposed for 96 hr to nicotine or cotinine in two separate static renewal tests of each compound without addition of the metabolic activation system (MAS). Two static renewal tests of nicotine with the MAS were also conducted. Addition of the MAS to nicotine reduced the LC50 from an average of 136 to 20 mg/L. However, the EC50 (malformation) was increased from 0.4 to 5.8 mg/L upon activation. The LC50 and EC50 values for cotinine averaged 4,340 and 720 mg/L, respectively. Based on mortality/malformation index values, growth end points, and the types and severity of the induced malformations, nicotine and cotinine scored as potential teratogens. Metabolism of nicotine to more polar metabolites increased the nicotine concentration required to induce terata. The results are indicative of the versatility of FETAX in developmental toxicity testing.
Sister chromatid exchange in human lymphocytes exposed to ascorbic acid and the cancer chemotherapeutic agent 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea
Authors: Best Robert G. , McKenzie Wendell H. 
Published: February 2006

AbstractThis study examines sister chromatid exchange (SCE) induction by ascorbate, a weak in vitro SCE inducer which acts through free radical intermediates, and low doses of 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU), a potent SCE inducer which acts primarily through DNA interstrand cross‐links. A small dose‐dependent increase in SCE was observed in human peripheral lymphocytes exposed to ascorbate in the 0.5–10 mM dose range for 59 hours, with significant slowing of cell cycle kinetics at concentrations at and above 5 mM. CCNU concentration was selected to approximate the maximal increase in SCE induced by ascorbate. SCE frequencies in cells exposed sequentially to both agents were not significantly different from expectations under an additivity‐of‐effect model based on SCE response to each agent individually. Despite clear differences in the types of lesions induced, ascorbate and CCNU appear to act independently to induce SCE in a manner consistent with, though not exclusive to, Painter's replicon cluster model.
Induction of estrogen receptor, peroxidase activity, and epithelial abnormalities in the mouse uterovaginal epithelium after neonatal treatment with diethylstilbestrol
Authors: Andersson Christer , Forsberg John‐Gunnar 
Published: February 2006

AbstractNeonatal female NMRI mice were treated with daily doses of 10−2 or 5 μg diethylstilbestrol (DES) on one or more of days 1–5 after birth. Using immunohistochemical techniques and a monoclonal antibody to the estrogen receptor, we demonstrated an estrogen‐induced precocious appearance of receptor protein in the nuclei of the uterovaginal epithelium. High levels of peroxidase activity and a pronounced stromal infiltration with peroxidase positive cells occurred in the uterine cervix and upper vagina after estrogen treatment. This regional restriction in peroxidase activity was similar to the regional restriction for estrogen‐induced epithelial abnormalities (heterotopic columnar epithelium, adenosis). A combined treatment with DES and corticosterone depressed peroxidase activity but not to the control level. The distribution of abnormal epithelium was similar in DES‐and DES‐corticosterone‐treated females. The conclusion is that neonatal estrogen treatment induces an epithelial receptor for estrogen and a high level of cervical peroxidase activity, but the relationship between these parameters and the appearance of abnormal cervicovaginal epithelial changes could not be settled in the present study.
Relationship of periventricular overgrowth to hydrocephalus in brains of fetal rats exposed to benomyl
Authors: Ellis William G. , De Roos Francis , Kavlock Robert J. , Zeman Frances J. 
Published: February 2006

AbstractBenomyl, a benzimidazole fungicide, was administered by gavage to pregnant Sprague‐Dawley rats in a daily dose of 62.5 mg/kg of maternal body weight beginning at gestational day (GD) 7. Fetuses examined histologically at GD16 or GD20 revealed a high incidence of craniocerebral anomalies—82.6% of those examined at GD16 and 100% of those examined at GD20. Hydrocephalus occurred in 65.2% of fetuses examined at GD16 and in 58.8% at GD20 but was more severe in the GD20 fetuses. A second common anomaly, termed periventricular “overgrowth” (PVO), consisted of subependymal cell masses that in some fetuses obliterated normal subcortical structures. PVO occurred in 34.8% of fetuses examined at GD16 and 76.5% at GD20. The size of the subependymal masses and the regions involved were considerably greater in the GD20 than the GD16 fetuses. Less common anomalies in the GD20 fetuses were periventricular necrosis (41.2%), a single fetus with exencephaly and another with porencephaly.In the majority of malformed fetuses, the severity of hydrocephalus did not parallel the severity of PVO around the lateral and third ventricles. PVO involved tissues surrounding the cerebral aqueduct in 17.4% of GD16 fetuses and 38.2% of GD20 fetuses. This “overgrowth” distorted the cerebral aqueduct in a large number of fetuses with ventriculomegaly, and at GD20 moderate and severe ventriculomegaly was in every instance associated with a narrow or completely occluded cerebral aqueduct. These relationships suggest that PVO in the midbrain may play a role in the production of aqueductal stenosis and hydrocephalus in this experimental model.
Limb defects in gray short‐tailed opossums (Monodelphis domestica) following postnatal injection with ethanol or saline
Authors: Fadem Barbara H. , Tassava Roy A. , Miller Sheldon I. , Congleton Lori A. 
Published: February 2006

AbstractBecause the hindlimbs of marsupials at birth are in an embryonic stage of development, this group can prove useful for studies of limb teratology. In this study, injection of neonatal gray opossums with 2 mg ethanol (ETOH) or saline (SAL) in the right or left hindquarter resulted in defects of the associated limb in 44% of ETOH animals and 16% of SAL animals. Affected SAL animals showed gait abnormalities, foot clubbing, and moderately reduced limb size. Affected ETOH animals showed these abnormalities as well as fused digits, missing digits, and, in one case, a partially missing limb. Thus, while injection itself may have resulted in altered limb development, local infusion of alcohol had a further teratogenic effect on such development.
Sister chromatid exchange in human chromosomes from normal individuals and epileptic patients on combinations of anticonvulsants
Authors: Goyle Shobha , Maurya A. K. , Rout U. K. , Kailash S. , Maheshwari M. C. 
Published: February 2006

AbstractSister chromatid exchange (SCE) frequency, a sensitive indicator in mutagenicity testing, and mitotic index (MI) have been studied to observe genotoxic effects in epileptic patients on routine combinations of anticonvulsant therapy. All patients, both male and female and from various age groups, revealed an increased frequency of SCE per metaphase and a low MI (P < 0.001) with respect to controls. A nonsignificant decrease in SCE frequency has been observed with an increase in the age of onset of epilepsy. Although the SCE frequency increased and the MI decreased in some groups with respect to the duration of epilepsy, there was no difference observed in SCE frequency with the duration of therapy.
Interference of prenatal and postnatal exposure to Ca2+‐antagonist agents on rat functional development of vascular system
Authors: Angrisani M. , Loffreda A. , De Santis D. , Filippelli A. , De Paola C. , Maione S. , Berrino L. , Matera C. , De Pasquale M. , Mauro C. , Guarino V. , Vitagliano S. , Molinario L. , Camarri F. , Marmo E. 
Published: February 2006

AbstractExposure to drugs during pregnancy can alter functional development of the vascular system. The present investigation was carried out in order to evaluate the effects of prenatal and postnatal exposure to Ca2+‐antagonist (diltiazem, verapamil, and nimodipine) drugs on the development of rat vasomotor reactivity. Studies were carried out on pregnant female albino rats exposed from the first day of pregnancy until weaning to diltiazem and verapamil (6 and 24 mg/kg in their drinking water ad libitum) and nimodipine (3 and 12 mg/kg in their food ad libitum). After weaning, pups were exposed until the 60th day of age to the same treatment as their mothers were. Afterwards, pups from the 60th to 90th day of age were fed with a normal diet.In 30‐, 60‐, and 90‐day‐old conscious and anaesthetized pups, we evaluated the following: 1) systolic arterial blood pressure; 2) vasomotor responses elicited by various agents: L‐noradrenaline (0.1, 1, and 5 μ/kg IV), L‐isoprenaline (0.01, 0.1, and 1 μ/kg IV), and acetylcholine (0.01, 0.1, and 1 μ/kg IV) and by sinus‐carotid baroreceptor stimulation; and 3) catecholamine, acetycholinesterase, and adenosinase plasma levels.Prenatal and postnatal exposure to Ca2+‐antagonist drugs significantly (P < .05) decreased the pressor response to sinus‐carotid baroreceptor stimulation and to L‐noradrenaline and increased the hypotensive responses to L‐isoprenaline and acetylcholine.Moreover, this type of treatment, although it induced a significant (P < .05) decrease of catecholamine plasma levels, did not modify the acetylcholinesterase and adenosinase plasma levels in 30‐ and 60‐day‐old rats. On the 90th day of age, the evaluated parameters were not different from those of control rats.Our results showed that exposure to Ca2+ antagonists during pregnancy and the postnatal period may alter the functional development of rat vasomotor reactivity.
Biochemical effects of three carcinogenic chlorinated methanes in rat liver
Authors: Kitchin Kirk T. , Brown Janice L. 
Published: February 2006

AbstractThree chlorinated methanes, carbon tetrachloride, chloroform, and methylene chloride, known to cause liver tumors in rodents, were given by oral gavage to adult female rats both 21 h and 4 h before sacrifice. Then hepatic DNA damage, ornithine decarboxylase (ODC), cytochrome P‐450, glutathione content, and serum alanine aminotransferase (SGPT) activity assays were performed. Carbon tetrachloride increased rat hepatic ODC activity and decreased cytochrome P‐450 content at doses both below and above cytotoxicity (as measured by increased SGPT activity). At 54 and 160 mg/kg, chloroform increased hepatic ODC activity with minimal or no elevation in SGPT activity. At 480 mg/kg chloroform increased hepatic ODC and SGPT activity. A dose of 1,275 mg/kg methylene chloride caused a small, but significant amount of hepatic DNA damage. When these three compounds are compared on either an equimolar or equitoxic (1/5 LD50) basis, their ability to induce hepatic ODC or increase SGPT activity was carbon tetrachloride > chloroform > methylene chloride. The results of this biochemical study are interpreted with respect to the ability of chemicals to cause hepatic cancer by either genetic or epigenetic mechanisms.
Ozone and ultraviolet light act as additive cocarcinogens to induce in vitro neoplastic transformation
Authors: Borek Carmia , Ong Augustinus , Mason Herbert 
Published: February 2006

AbstractOzone, a major chemical oxidant in our environment, is an environmental air pollutant with putative carcinogenic action. Using in vitro transformation, we report for the first time that ozone (6 ppm for 10 min) acts in additive fashion with ultraviolet light (4 J/m2) to produce enhanced levels of transformation in hamster embryo cells and mouse C3H/10T‐1/2 cells as compared to rats induced by each of the agents alone.The results underscore the hazard of ozone as a toxic pollutant which may have putative carcinogenic effects and interact with other environmental carcinogens.
Toxic and DNA‐damaging activities of the fungicides mancozeb and thiram (TMTD) on human lymphocytes in vitro
Authors: Perocco Paolo , Alessandra Santucci M. , Campani Anna Gasperi , Forti Giorgio Cantelli 
Published: February 2006

AbstractThe cytotoxic and mutagenic effects of the fungicides mancozeb and thiram were studied using human peripheral blood lymphocytes cultured in vitro with or without an S‐9 mix microsomal metabolizing system. The results obtained suggested that the chemicals caused dose‐dependent inhibition of thymidine uptake and unscheduled DNA synthesis on both resting and proliferating lymphocytes in the absence of the S‐9 mix. In the presence of the S‐9 mix, only thiram showed mutagenic activity by eliciting unscheduled DNA synthesis and a significantly higher frequency of sister chromatid exchanges than did controls.
Effects of quinoline and 8‐hydroxyquinoline on mouse bone marrow erythrocytes as measured by the micronucleus assay
Authors: Hamoud M. A. , Ong T. , Petersen M. , Nath J. 
Published: February 2006

AbstractBoth quinoline and 8‐hydroxyquinoline (HOQ) were tested for their genotoxicity in CD1 male mice by using a bone marrow micronucleus assay. Mice were intraperitoneally treated in single injections with three dose levels (25, 50, and 100 mg/kg) of each chemical with corn oil as solvent vehicle. Bone marrow was sampled at 24, 48, and 72 h postinjection. Quinoline resulted in a significant dose‐related increase in the number of micronucleated polychromatic erythrocytes (MPCE) at the 24 h sampling time for all doses tested. The high dose (100 mg/kg) and the medium dose (50 mg/kg) also induced statistically significant increases (P < .05) in the number of MPCEs at 48 h interval. The ratios of polychromatic to normochromatic erythrocytes at the 24 h sampling time were lower for the treated than the control animals. Although HOQ resulted in some increases in the number of MPCEs over the control, this compound induced a statistically significant increase in the number of micronucleated normochromatic erythrocytes (MNCEs) at all three doses following 24 h treatment. Both low and medium doses also induced a higher incidence of MNCEs at the 48 and 72 h sampling times. No data were available for the high dose at these times. The cytotoxic effect of this compound was expressed as low PCE/NCE ratios with all doses at 24 h after injection and as a high mortality rate in animals treated with the high dose (100 mg/kg).
Developmental toxicity screen: Results of rat studies with diethylhexyl phthalate and ethylene glycol monomethyl ether
Authors: Morrissey Richard E. , Harris Martha W. , Schwetz Bernard A. 
Published: February 2006

AbstractThe purpose of these investigations was to develop a protocol for an in vivo developmental toxicity screen (DETS) that would provide sufficient data to determine whether to 1) do a full developmental toxicity evaluation without additional range‐finding studies, or, depending on the results, to 2) do no further testing of a chemical. In order to evaluate this screen, we compared results obtained by using the DETS protocol with results of previously conducted developmental toxicity evaluations of diethylhexyl phthalate (DEHP) and ethylene glycol monomethylether (EGME). Five groups (n ± 17) of F344 rats were treated on days 6–15 of gestation by dosed feed (DEHP levels = 0, 0.5, 1.0, 1.5, 2.0%) or gavage (EGME doses = 0, 12.5, 25, 50, 100 mg/kg/day). One half of the rats in these studies were killed on day 16 of gestation, and the remaining animals were allowed to deliver litters which were killed on day 4. EGME caused only a small decrease in maternal weight gain during treatment (100 mg/kg group) that was accompanied by a decrease in gravid uterine weight. The percentage of resorptions was increased in the 50 and 100 mg/kg groups. The number of live pups was decreased in the 25, 50, and 100 mg/kg groups, and litter weight and postnatal survival were decreased in the 100 mg/kg group. These results are consistent with those reported in developmental toxicity studies on EGME conducted by the inhalation and dermal routes. With DEHP, there were treatment‐related reductions in maternal body weight and weight gain. There was also a nonstatistical increase in percentage of resorptions per litter that was also observed, but at relatively high levels, in a definitive study in which F344 dams were treated on days 0–20 of gestation. The results of studies on these two chemicals compare well with published results and would have led to the selection of proper dose levels for subsequent FDA segment 2 studies.