bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complementarity of genotoxic and nongenotoxic predictors of rodent carcinogenicity
Authors: Kitchin Kirk T. , Brown Janice L. , Kulkarni Arun P. 
Published: February 2006

AbstractTwenty‐one chemicals carcinogenic in rodent bioassays were selected for study. The chemicals were administered by gavage in two dose levels to female Sprague‐Dawley rats. The effects of these 21 chemicals on four biochemical assays [hepatic DNA damage by alkaline elution (DD), hepatic ornithine decarboxylase activity (ODC), serum alanine aminotransferase activity (ALT), and hepatic cytochrome P‐450 content (P450)] were determined.Available data from seven cancer predictors published by others [the Ames test (AMES), mutation in Salmonella typhimurium TA 1537 (TA 1537), structural alerts (SA), mutation in mouse lymphoma cells (MOLY), chromosomal aberrations in Chinese hamster ovary cells (ABS), sister chromatid exchange in hamster ovary cells (SCE), and the ke test (ke)] were also compiled for these 21 chemical carcinogens plus 28 carcinogens and 62 noncarcinogens already published by our laboratory. From the resulting 111 (chemicals) by 11 (individual cancer predictors) data matrix, the five operational characteristics (sensitivity, specificity, positive predictivity, negative predictivity, and concordance) of each of the 11 individual cancer predictors (four biochemical parameters of this study and seven cancer predictors of others) are presented.Two examples of complementarity or synergy of composite cancer predictors were found. To obtain maximum concordance it was necessary to combine both genotoxic and nongenotoxic cancer predictors. The composite cancer predictor (DD or [ODC and P450] or [ODC and ALT]) had higher concordance than did any of the four individual cancer predictors from which it was constructed. Similarly, the composite cancer predictor (TA 1537 or DD or [ODC and P450] or [ODC and ALT]) had higher concordance than any of its five individual constituent cancer predictors. Complementarity or synergy has been demonstrated both (1) among genotoxic cancer predictors (DD and TA 1537) and (2) between nongenotoxic (ODC, P450, and ALT) and genotoxic cancer predictors (TA 1537 and DD). ©1993 Wiley‐Liss, Inc.This article is a US Government work and, as suh, is in the public domain in the United States of America.
Teratogenic and reproductive studies of policosanol in the rat and rabbit
Authors: Rodríguez María D. , García Haydee 
Published: February 2006

AbstractThe present studies evaluated the teratogenic potential and reproductive toxicity of Policosanol, a new hypocholesterolemic drug. Policosanol was administered by oral gavage to Sprague‐Dawley rats and New Zealand White rabbits during the period of organogenesis at dosages up to 500 and 1,000 mg/kg/day, respectively. There was no evidence of teratogenicity or any other embryonal toxicity. In a fertility and reproductive study female rats were treated with Policosanol by oral gavage at dosages up to 500 mg/kg/day, 2 weeks prior to mating and throughout mating and pregnancy to day 21 of lactation. Males were given treatment 60 days before and during mating. Reproductive parameters of mothers were normal. There was no evidence that treatment affected the survival, postnatal growth, or behavior of the offspring. No maternal treatment‐related adverse side effects occurred in these studies. It is concluded that Policosanol was not teratogenic in either rats or rabbits, nor did it induce reproductive toxicity in rats. © 1994 Wiley‐Liss, Inc.
Embryotoxic effects of thalidomide derivatives in the non‐human primate Callithrix jacchus. IV. Teratogenicity of μg/kg doses of the EM12 enantiomers
Authors: Heger Wolfgang , Schmahl Hans‐Josef , Klug Stephan , Felies Annegret , Nau Heinz , Merker Hans‐Joachim , Neubert Diether 
Published: February 2006

AbstractThe dose‐response of the teratogenic potency of the thalidomide (Thd) derivative EM12 was evaluated in the common marmoset (Callithrix jacchus). The smallest daily dose found to be effective was 30 μg EM12/kg body wt. This is the lowest dose of a Thd derivative ever reported to induce severe skeletal abnormalities. Ten micrograms EM12/kg body wt may be considered the no‐observed‐adverse‐effect‐level (NOAEL) under the experimental conditions chosen.The teratogenic potencies of the two EM12 enantiomers were tested at 100 μg/kg body wt, the dose which just induces an almost 100% effect in the case of the racemate. The S(−)‐EM12 was found to induce typical severe limb abnormalities such as amelia, phocomelia, and radius aplasia, and none of the exposed fetuses were devoid of skeletal defects. In contrast, only few and minor skeletal defects were observed after application of the R(+) enantiomer. Although a pronounced teratogenic potency of the R(+)‐EM12 can now largely be excluded, these low‐dose studies are not sufficient to completely rule out any teratogenic potential of this enantiomer, since racemisation to small amounts of the S(−) form may occur in vivo.Further studies with Thd derivatives which are unable to racemise are necessary to prove the assumed complete ineffectiveness of the R(+) enantiomers. © 1994 Wiley‐Liss, Inc.
Genotoxic and embryotoxic effects of 5‐bromodeoxyuridine in the chick embryo
Authors: Novotná Božena , Hubálek František , Bednář Vladimír 
Published: February 2006

AbstractChick embryos were exposed intra‐amniotically to the thymidine analog bromodeoxyuridine (BrdU) in order to study its embryotoxic and genotoxic effects. Teratogenic effects were observed at doses of BrdU which failed to produce mitotic inhibition, clastogenic effects or any significant increase in sister chromatid exchanges. Clastogenic effects and depressed cell proliferation were observed only at high embryolethal doses. Thus, BrdU‐induced teratogenicity was independent of genotoxic effects manifested at chromosomal level. On the contrary, a significant increase of DNA single strand breaks was detected even 24 hours after the administration of teratogenic dose. BrdU incorporation in the DNA does not appear to prevent embryonic cells from mitotic proliferation. Whether the single strand breaks in DNA would ultimately lead to BrdU‐induced teratogenesis in chick embryos remained undetermined. © 1994 Wiley‐Liss, Inc.
Malformations persist after metamorphosis of Xenopus laevis tadpoles exposed to Ni2+, Co2+, or Cd2+ in FETAX assays
Authors: Plowman Marilyn C. , Grbac‐lvankovic Svetlana , Martin Jennifer , Hopfer Sidney M. , Sunderman F. William 
Published: February 2006

AbstractThis study was performed to determine whether malformations induced in Xenopus laevis embryos by exposures to divalent nickel, cobalt, or cadmium chlorides in FETAX assays persist after the tadpoles undergo metamorphosis to juvenile frogs. Embryos were exposed for four days to EC50 concentrations of Ni2+, Co2+, or Cd2+ under the standard conditions of FETAX assays; thereafter, the exposures were discontinued and the tadpoles were kept in aquaria through metamorphosis. Controls were treated similarly, without exposure to metals. At 13 weeks of age, surviving frogs were killed and examined for malformations. Control and metal‐exposed groups of Xenopus did not differ significantly in their median ages at metamorphosis, mean body weights, or survival at 13 weeks. Overall incidences of malformations found in Ni2+−, Co2+−, or Cd2+−exposed frogs at 13 weeks of age were 55, 40, and 51%, respectively (P <0.01 vs. 3% in controls). The malformations of metal‐exposed frogs included retinal depigmentation, diastematomyelia, scoliosis, kyphosis, phocomelia, sacro‐pelvic and hind‐limb deformities, and dysplasias of the heart, kidney, ovary, and gut. © 1994 Wiley‐Liss, Inc.
Progressive growth of rat bladder carcinomas after exposure to prolonged uracil‐induced urolithiasis
Authors: Shibata Masa‐Aki , Shirai Tomoyuki , Takahashi Satoru , Takesada Yasuko , Iwata Hiroyuki , Okumura Masanao , Fukushima Shoji 
Published: February 2006

AbstractDietary uracil at the 3% level induces urinary bladder tumors in rats through urolithiasis‐dependent mechanical irritation. In the present study, comparison of lesions induced by uracil administration over the different periods of 36 weeks (middle‐term) and up to 103 weeks (long‐term) revealed significant elevation of both incidences and multiplicity of transitional cell carcinomas (TCCs) in the long‐term group. Histopathological assessment in terms of tumor biology further demonstrated significantly higher grading on the basis of the degree of cellular and structural atypia, and greater depth of invasion in the long‐term group. Application of markers for cell proliferation activities including proliferating cell nuclear antigen (PCNA) and silver‐binding nucleolar organizer regions (AgNORs) also revealed significantly elevated AgNOR counts in the long‐term group TCC. AgNOR counts and PCNA rates in TCCs showed relation to the histological grades. Thus the present study demonstrated that prolonged uracil‐induced urolithiasis causes more biologically aggressive bladder carcinomas with invasive potential. Continuous stimulation of cell proliferation presumably has the potential to facilitate multiple genetic alterations leading to development of more malignant carcinomas. However, it should be borne in mind that the difference in bladder cancer development might also be related to the fact that the animals survived longer and that the early lesions therefore had more time to progress to more advanced stages. © 1994 Wiley‐Liss, Inc.
Lack of promoting effect of proline on bile duct cancer development in dimethylnitrosamine‐initiated hamster livers
Authors: Thamavit Witaya , Pairojkul Chawalit , Tiwawech Danai , Shirai Tomoyuki , Ito Nobuyuki 
Published: February 2006

AbstractBile duct hyperplasia caused by proline is believed to represent a chemical effect of the liver fluke, Fasciola hepatica, and the resultant cell division might be expected to play a role as a tumor promoter. To investigate the potential promoting effect of proline on bile duct cancer development, Syrian hamsters were therefore divided into 8 treatment groups: dimethylnitrosamine (DMN) + proline intraperitoneally (i.p.); DMN + proline s.c.; DMN + saline i.p.; DMN + saline s.c.; proline i.p.; proline s.c.; saline i.p.; and saline s.c. DMN was injected i.p. at 20 mg/kg to the animals 2 weeks prior to commencement of proline treatment, whereby 1 ml of a 2 M solution was given by i.p. or s.c. injection 3 times a week for 20 weeks. At the end of week 42, assessment of preneoplastic lesion development did not reveal any significant modulating influence of proline on DMN‐initiated lesion development nor did it itself cause persistent bile duct hyperplasia. © 1994 Wiley‐Liss, Inc.
Impact of higher doses of vitamin C in modulating pesticide genotoxicity
Authors: Khan Parimal Kumar , Sinha S. P. 
Published: February 2006

AbstractThe modulatory effect of higher doses of vitamin C (ascorbic acid) on the genotoxicity of the three pesticides (endosulfan, phosphamidon, and mancozeb) was assessed in the in vivo micronucleus test in Swiss albino mice. Concurrent administration of the vitamin in a dose (20 mg/kg bwt/day) equivalent to double the human therapeutic one, along with each of the three pesticides, was most effective as an antimutagen. The therapeutic dose (10 mg/kg bwt/day) was comparatively less so, and the quadruple (40 mg/kg bwt/day) of it did not show any further amelioration. © 1994 Wiley‐Liss, Inc.
Comparison of DNA adduct levels in human placenta from polychlorinated biphenyl exposed women and smokers in which CYP 1A1 levels are similarly elevated
Authors: Gallagher Jane E. , Everson Richard B. , Lewtas Joellen , George Michael , Lucier George W. 
Published: February 2006

AbstractPrevious studies demonstrated that cigarette smoking is associated with high elevations in levels of both cytochrome P450 1A1 (CYP 1A1) and DNA adducts in human placenta. To date, the identity of the smoking related DNA adducts is not known. The DNA adducts identified in placenta of smokers could result from chemicals present in cigarette smoke, substances formed by CYP 1A1 metabolic activation of endogenous compounds, non‐cigarette related exposures or a combination of these processes. Exposure to contaminated rice oil containing large doses of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) also resulted in massive elevation of CYP 1A1 in human placenta but formation of DNA adducts directly from this exposure has not previously been reported. The purpose for comparing the two populations was to test the hypothesis that if CYP 1A1 induction results in the metabolic activation of endogenous compounds, then DNA adducts should also be present in PCB/PCDF exposed tissues exhibiting high CYP 1A1 activity and some of the adducts detected in the placental DNA from smokers may be identified as those derived from the metabolic activation of endogenous compounds. To test this hypothesis, we measured DNA adducts using 32P‐postlabeling to analyze placental DNA from women exposed to PCB/PCDF and from cigarette smokers where levels of CYP 1A1 were similarly elevated. There was no evidence of DNA adducts among specimens obtained from PCB/PCDF exposed individuals. These data suggest that CYP 1A1 induction alone (in the absence of cigarette smoking) does not induce the formation of DNA adducts detectable by this approach, and that smoking related adducts are not a consequence of CYP 1A1 induction mediated activation of endogenous compounds or xenobiotics other than cigarette smoke. ©1993 Wiley‐Liss, Inc.This Article is a US Government work and, as such, is in the public domain in the United States of America.
In utero exposure to caffeine causes delayed neural tube closure in rat embryos
Authors: Wilkinson Jenny M. , Pollard Irina 
Published: February 2006

AbstractWe have investigated the effect of caffeine on embryo growth and development. Caffeine (25 mg/kg) was administered on gestation day (g.d.) 8–9 and the embryos examined histologically 24 h after the final dose. The crown‐rump length of caffeine treated embryos (1.92 ± 0.08 mm) was significantly smaller (P<0.001) than the controls (2.91 ± 0.26 mm) as was the circumferential length (caffeine vs. controls, 3.79 ± 0.16 mm vs. 6.03 ± 0.61 mm;P<0.001). Additional measures, such as development of the heart, eye, and limb buds, were also reduced in the caffeine treated embryos. The most striking difference between the control and caffeine treated embryos was the larger proportion of treated embryos with regions of open neural tube. This was most marked in the caudal region of the embryos where 91% of treated embryos had regions of open neural tube compared with 14% of controls. The amount of open neural tube in any individual caffeine treated embryo did not relate to the crown‐rump or circumferential length of that embryo nor was the effect restricted to particular litters. These results indicate that caffeine had a significant effects on embryonic growth and development. © 1994 Wiley‐Liss, Inc.
Electromagnetic fields and brain tumours: A commentary
Authors: Hughes J. T. 
Published: February 2006

AbstractBrain tumours are of different cell types, the commonest being tumours of glia called gliomas. Many etiological factors of gliomas have been suggested and certain industries have been implicated. Several epidemiological studies have linked electromagnetic fields (EMFs) to gliomas. Health effects of EMFs have been studied, both in humans and in experimental animals, mainly with negative findings. Positive experimental evidence linking EMFs to tumours is the effect of EMFs on melatonin production by the pineal gland. Removal of the pineal gland in rats increases the incidence of tumours. Further epidemiological and experimental evidence is required to elucidate this possible link between EMFs and brain tumours. © 1994 Wiley‐Liss, Inc.
Carcinogenicity of policosanol in sprague dawley rats: A 24 month study
Authors: Alemán Celia Luz , Ferreiro Rosa Más , Puig Miriam Noa , Guerra Idania Rodeiro , Ortega Caridad Hernández , Capote Amelia 
Published: February 2006

AbstractThe effects of policosanol (50–500 mg/kg) administered orally for 24 months to Sprague Dawley rats of both sexes were investigated. No differences related to daily clinical observations, weight gain, food consumption, or mortality (survival analysis) between groups were found. Histopathological study showed that the frequency of the occurrence of non‐neoplastic and neoplastic (benign and malignant) lesions was similar in the control and policosanol‐treated groups. The lesions observed in this study were similar to the spontaneous lesions reported in this species in previous studies. Since no drug‐related increase in the occurrence of malignant or benign neoplasms was found, nor acceleration in tumors growth in any specific group was observed, this study shows no evidence of policosanol induced carcinogenicity in this strain of rats. © 1994 Wiley‐Liss, Inc.
Human carcinogenic risk assessment based on hormonal effects in a carcinogenicity study in rats with the antifungal agent, fluconazole
Authors: Paulus G. , Longeart L. , Monro A. M. 
Published: February 2006

AbstractFluconazole is an orally active bis‐triazole antifungal agent that acts by selective inhibition of lanosterol 14α‐demethylase, a key enzyme for maintenance of the fungal cell wall. It is not genotoxic. In a 2 year carcinogenicity study in Sprague‐Dawley rats, fluconazole decreased mammary fibroadenomas in females and adrenal pheochromocytomas in males, and increased hepatic adenomas in males. The pattern of these changes is explicable in terms of a hormonal imbalance, corroborated in other studies with fluconazole in rats by changes in the weights of hormone‐sensitive organs and circulating levels of 17β‐estradiol. The decreases in mammary tumors are probably a consequence of aromatase inhibition by fluconazole at high dose levels. The tumor effects observed in this study are extremely unlikely to be of relevance to humans, since the hormone effects observed in this study do not occur in humans treated with therapeutic dose levels of fluconazole. This study illustrates the importance of seeking a mechanistic interpretation of rodent tumor findings, which may then be assessed for its relevance to the clinical use of a drug. © 1994 Wiley‐Liss, Inc.
Role of protein kinase C in the regulation of gap junctional communication
Authors: Budunova Irina V. , Mittelman Leonid A. , Miloszewska Joanna 
Published: February 2006

AbstractWe have examined the effect of protein kinase (PKC) depletion in SV40‐transformed Djungarian hamster fibroblasts (DM15 cells) on the level of gap junction permeability, C×43 electrophoretic mobility, and cell sensitivity to different uncoupling stimuli. After 24 hr exposure to 12‐O‐tetradecanoyl‐phorbol‐13‐acetate (TPA), the total PKC activity in DM15 cells was reduced to 20–25% in comparison with intact cells. In PKC‐depleted cells the level of dye coupling was 30–40% higher than in the same untreated cultures. Western blot analysis revealed multiple forms of the gap junction protein connexin 43, which correspond to known phosphorylated and dephosphorylated forms of this protein. No decrease in the level of connexin 43 phosphorylation after PKC depletion was observed. TPA (10−7 g/ml), mezerein (10−7 g/ml), teleocidin (10−8 g/ml), Ca‐ionophore A23187 (10−6 g/ml), insecticide 1,1,1‐trichloro‐2,2‐bis‐(p‐chlorphenyl)‐ethane (DDT) (10−4 g/ml), and nigericin (10−5 M in hydrolysate lactalbumin solution, pH 6.3) induced a four‐to six‐fold decrease in the number of recipient cells in the dye‐coupling assay. PKC‐depleted cells became almost completely resistant to the uncoupling effect of mezerein, teleocidin, and A23187, as well as to new exposure to TPA, and became partially resistant to the effect of DDT. Nigericin inhibited intercellular communication between PKC‐depleted cells to the same extent as between control cells. Thus, in the cell system studied, PKC plays a certain role in maintaining the basal level of gap junction permeability and has an important significance as a mediator of the uncoupling effects of such substances as TPA, mezerein, teleocidin, and Ca2+. © 1994 Wiley‐Liss, Inc.
Differences in teratogenic and toxic properties of alcohol dehydrogenase inhibitors pyrazole and 4‐methylpyrazole in Drosophila melanogaster: I. ADH allozymes in variable genetic backgrounds
Authors: Eisses Karel Th. 
Published: February 2006

AbstractPyrazole and 4‐methylpyrazole (4‐MP) are effective inhibitors of alcohol dehydrogenase (ADH) activity in mammals both in vivo and in vitro. 4‐MP has a tenfold higher inhibition specificity compared with pyrazole. Pyrazole proved a teratogenic compound in Drosophila melanogaster. Treatment of third instar larvae of D. melanogaster with pyrazole, in contrast with 4‐MP, produced an increase in the number of dorsocentral and scutellar macrochaetae and wing‐notches in the adult fly. A large difference in the penetrance of terata in males and females was observed. Similar effects were observed in flies lacking ADH molecules. The teratogenicity of pyrazole must be due to disturbance of processes other than ADH inhibition. Synergistic effects were observed between pyrazole and methoxyacetic acid (MAA), an in vitro inhibitor of sarcosine dehydrogenase activity. Each of these compounds, when fed to early third instar larvae, produced terata resembling the Notch mutant of D. melanogaster. © 1995 Wiley‐Liss, Inc.
Chemical skin carcinogenesis is prevented in mice by the induced expression of a TGF‐β related transgene
Authors: Blessing Manfred , Nanney Lillian B. , King Lloyd E. , Hogan Brigid L. M. 
Published: February 2006

AbstractSkin papillomas and squamous cell carcinomas (SCCs) are induced in mice by tumor initiation with a carcinogen followed by tumor promotion with the phorbol ester 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). These usually arise from preneoplastic lesions characterized by epidermal proliferation and hyperplasia, dermal edema, and inflammation. To evaluate the role of polypeptide growth factors in chemically induced skin carcinogenesis, we used transgenic mice carrying the cDNA for a TGF‐β related molecule, bone morphogenetic protein‐4 (BMP‐4), under the control of the regulatory elements of the cytokeratin IV* gene in a skin carcinogenesis protocol.Control non‐transgenic littermates and BMP‐4 transgenic mice were treated with a single dose of a carcinogen, N‐methyl‐N′‐nitrosoguanidine (MNNG), and biweekly with the tumor promoter TPA for 9 months. In control littermates TPA induced epidermal hyperproliferation, atypia with “dark” cells, and dermal inflammation, resulting in papillomas and SCCs in 13 of 26 animals tested. In BMP‐4 transgenic mice, TPA treatment induced the expression of the BMP‐4 transgene in interfollicular epidermis but only minimal epidermal thickening, hyperproliferation, and inflammation were noted after the initial dose of TPA. Furthermore, the mitotic indices in transgenic epidermis after 9 months of TPA treatment were significantly lower than the corresponding indices from untreated transgenic epidermis. Consequently, none of the 22 transgenic animals tested developed papillomas or SCCs. In conclusion, we have shown that the TPA induced expression of the BMP‐4 transgene blocks proliferation and inflammation in skin, steps that are critical to the subsequent formation of papillomas and SCCs and we characterized an inducible promotersystem which expresses polypeptides in interfollicular epidermis after exogenous stimulation. © 1995 Wiley‐Liss, Inc.