bluuebunny/crossref_metadata_2025_split huggingface dataset:
Implications of multiple mechanisms of carcinogenesis for short‐term testing
Authors: Harper Barbara L. , Morris Debra L. 
Published: February 2006

AbstractThe attempt has been made recently to categorize carcinogens into two mechanistic types based on their mechanism of action: genotoxic (capable of reacting with and damaging DNA) and epigenetic (unable to damage DNA to any detectable extent). By requiring that a given chemical fit into one or the other of these narrowly defined categories for regulatory purposes, we are probably oversimplifying potential biological effects. In fact, based on our limited understanding of carcinogenic mechanisms, this artificial distinction should probably be abandoned in favor of a more precise statement of each chemical's mechanism or relative potency of initiating and promoting effects.Since the standard short‐term tests by which carcinogenicity of chemicals is screened were designed to detect certain chemical classes with active electrophilic intermediates, weak or specialized carcinogens may be missed and may be assumed erroneously to be nongenotoxic. The mechanisms of carcinogenicity for such carcinogens may include particulate deposition, active radical formation, liver toxicity, and hormonal interactions. Not all of these secondary mechanisms depend upon a detectable level of binding to DNA, damage to DNA, or modification of the DNA sequence, even though they may demonstrate other characteristics of a complete carcinogen (that is, irreversibility and lack of a threshold).Certain agents have been labeled as epigenetic. However, a consideration of the literature on sample agents (diethylstilbestrol, asbestos, and urethane) reveals that these are not epigenetic carcinogens despite their being labeled as such.Agents with irreversibility and no threshold have initiating potential and, as such, are genotoxic, whereas carcinogens that are classified as nongenotoxic are largely agents that promote the growth of liver tumors. Even promotion can be a mechanistically specialized phenomenon. For example, some promoters are cytotoxic to the liver, but not all liver toxins are liver tumor promoters or liver carcinogens. Further, the carcinogens commonly labeled as epigenetic might cause a unique specialized genotoxicity not detected by common screening tests routinely used for detecting genotoxicity.If we assume that this unrecognized but necessary initiating potential is mediated by some specialized genotoxicity, extra care must be taken to establish a genuine lack of genotoxicity before an agent can be classified (and regulated) as a promoter (lacking the ability to initiate tumor growth but still enhancing tumor development). There is no question that reversible effects with definite thresholds should be evaluated differently from thos that are irreversible and lack a threshold, but the distinction should be based on their effect and potncy, not on their (often unknown) mechanism of genotoxicity.
Cyclophosphamide teratogenesis: A review
Authors: Mirkes Philip E. 
Published: February 2006

AbstractCyclophosphamide (CP) is one of the best studied teratogens; it produces primarily central nervous system and skeletal anomalies in rats, mice, rabbits, monkeys, and humans. Furthermore, CP is one of the most extensively studied antienoplastic agents. Recent work using in vitro rodent embryo culture has demonstrated that CP must be bioactivated to be teratogenic. This finding extends earlier work showing that CP must be activated to achieve its antineoplastic and mutagenic effects. Activation of CP to its teratogenic, mutagenic, and antineoplastic form is mediated by microsomal cytochrome P‐450 monooxygenases, which convert CP to 4‐hydroxycyclophosphamide (4OHCP). In the absence of detoxification, 40HCP spontaneously breaks down to phosphoramide mustard (PM) and acrolein (AC). PM is the CP metabolite believed to be responsible for the antineoplastic and mutagenic effects of CP, whereas AC is thought to cause the side effects associated with CP chemotherapy. Recent work has shown that the teratogenic effects of CP are mediated by both PM and AC. Although it is far from proven, available evidence supports the hypothesis that DNA is the primary target in terms of the teratogenic, mutagenic, and antineoplastic effects of CP. Although the nature of the DNA lesions produced by CP, which are responsible for its teratogenic, mutagenic, and antineoplastic effects, is not completely understood, cross‐linking of DNA seems to play a critical role in the antineoplastic properties of CP. Preliminary information obtained from embryos exposed to CP metabolites suggests that, although DNA cross‐linking might play a role in CP teratogenesis, metabolite‐induced DNA strand breakage and/or induction of mutations might also play a role. Although insights into the molecular mechanisms underlying CP teratogenesis are just beginning to accumulate, the availability of in vitro embryo culture combined with the modern armamentarium of molecular biology will allow teratologists to probe further the molecular aspects of teratogenesis.
pH‐Induced changes in mitotic and developmental patterns in sea urchin embryogenesis. I. Exposure of embryos
Authors: Pagano Giovanni , Cipollaro Maria , Corsale Giuliana , Esposito Agostino , Ragucci Enrica , Giordano Giovan Giacomo 
Published: February 2006

AbstractThe effects of different pH conditions have been investigated on sea urchin larval development following exposure of embryos to controlled, though changing, decreases or increases of seawater pH. The pH of filtered natural seawater was initially adjusted with 1 N HCl of 1 N KOH and then was altered back to its normal values (8.0–8.2) by the exchange with atmospheric CO2 and subsequent carbonic acid equilibrium. During cultures, pH was regularly monitored.When developing embryos were reared in different pH conditions, larval differentiation was sharply affected by an apparently moderate pH decrease, such as 0.5 pH units. However, even pH decreases as small as 0.2 pH units from the normal value showed reproducible damage to embryogenesis. This damage appeared to be early and irreversible, since the exposure of cleaving embryos resulted in more severe developmental defects than exposure of posthatching blastulae. Moreover, mitotic abnormalities were observed following early exposure of embryos to decreased pH.Increased pH, up to 8.6 (∼ 0.5 pH units above normal value), failed to exert any adverse effect on subsequent development. Moreover, an initial pH increase (8.5–8.7) resulted in the final adjustment of culture pH to 8.1–8.2, thus providing optimal conditions for rearing embryos. Two attempts to stabilize culture pH were performed by decreasing gaseous exchanges or by using Tris as a buffering agent. Both approaches appeared to be impractical, thus ruling out any further attempts.The results point out the hazards of acid contamination in restricted bodies of seawater, leading to apparently “moderate” decreases in pH, which can result in severe damage to some marine organisms, both adult and larval forms.
Teratogen metabolism: Spontaneous decay products of thalidomide and thalidomide analogues are not bioactivated by liver microsomes
Authors: Braun Andrew G. , Weinreb Steven L. 
Published: February 2006

AbstractThalidomide and two analogues, EM87 and EM12, inhibited the attachment of tumor cells to concanavalin A‐coated surfaces only if the drugs were first incubated with hepatic microsomes and cofactors. Most agents that inhibit attachment are demonstrated teratogens. Thalidomide undergoes spontaneous hydrolysis to at least 12 products in saline buffered to a pH of greater than 7. These hydrolysis products did not inhibit attachment nor could they be activated to inhibitory products with hepatic microsomes. Similarly EM12 and EM 87 hydrolysis products were neither inhibitory nor substrates for activation. If the three drugs were incubated in buffered saline, there was a progressive decline in their ability to act as substrates for activation to an inhibitory product. It was possible to remove microsomes from the incubation mixture following drug activation by centrifugation. This microsome‐free mixture inhibited cell attachment. When mouse ovarian tumor (MOT) cells were added to the microsome‐free mixture, attachment was inhibited. However, if the activated drugs were incubated in saline, there was a progressive decline in their ability to inhibit attachment. Decay rates differed for the three compounds. At a pH of 7.4, thalidomide, EM87, and EM12 required 3 h, 1 h and 6 h, respectively, to decay to control levels. These relative rates of decay are consistent with the relative teratogenicity of the three drugs.
Correlations between the degree and type of forebrain malformations and the simultaneous neuro‐oncogenic properties of ethylnitrosourea after diaplacental exposure in rats, alone and in combination with X‐irradiation
Authors: Schmahl W. , Kriegel H. 
Published: February 2006

AbstractSingle and combined treatments were performed in rats on day 13 of gestation with either ENU or ENU subsequent to various X‐irradiation doses between 0.5 and 1.5 Gy. At this time of gestation, developmental anomalies of the brain are still inducible by any of these treatments, in addition to neurocarcinogenic effects after ENU alone or in combination with X‐irradiation. We looked for correlations between the degree of brain malformations still detectable in the adult animals and the simultaneous occurrence of brain tumors. These evaluations were based on a histopathological analysis regarding the type and degree of malformation residues, as well as the type and distribution pattern of the tumors (especially regarding gliomas) within the forebrain.Both after ENU and X‐irradiation plus ENU‐treatment, the occurrence of glioma in the offspring was positively correlated with the degree of brain dysplasia. This effect was not only restricted to the total glioma incidence but also confirmed by the higher glioma multiplicity in major dysplastic brains. Additionally, gliomas were preferentially located within the subependymal layer, which simultaneously was most severely affected by the teratogenic effects after prenatal treatment.Although forebrain dysplasia generally presents a significant predisposition for glioma inducibility, this oncogenic event is apparently strictly inversely related to a certain type of forebrain malformation, namely the occurrence of heterotopic neuronal nodules within the telencephalic roof. They emerge from “rosettes,” which are typical radiation lesions occurring only after doses above 1.0 Gy. In none of the forebrains which still revealed rosette‐residues in later life could a simultaneous occurrence of gliomas be observed. This explains not only the substantial decrease of glioma incidence after combined treatment with 1.0 and 1.5 Gy X‐irradiation doses, but also the consistent glioma multiplicity despite the decrease of frequency.
Effects of anticonvulsant drugs on brain cultures from chick embryos: A comparison with cultures from embryos treated in ovo
Authors: Sedowofia S. K. A. , Clayton R. M. 
Published: February 2006

AbstractThe effects of anticonvulsant drugs phenytoin, phenobarbitone, and sodium valproate on neurons and glia from embryonic chicken brain have been tested. These effects have been compared with those produced in neuronal and glial cultures established from embryos that were injected with the drugs in ovo. Choline acetyl transferase activity and accumulation of γ‐aminobutyric acid were measured in neuronal cultures, and carbonic anhydrase and 2,′3′‐cyclic nucleotide 3′ phosphohydrolase activities were measured in glial cultures. Similarities have been observed in the morphological and biochemical changes brought about by the in vitro and in vivo treatment with the drugs. The use of in vitro cell culture systems for screening drugs for potential behavioural teratogenic effects is discussed.
Erythrocytes‐mediated metabolic activation of cyclophosphamide in yeast mutagenicity test
Authors: Paolini Moreno , Forti Giorgio Cantelli , Corsi Claudio , Galli Alvaro , Bronzetti Giorgio 
Published: February 2006

AbstractThe degree of conversion of cyclophosphamide (CP) into mutagenic intermediates was studied using mouse erythrocytes as the metabolic activation system. The amount of mutagenic intermediates produced was measured indirectly in terms of induced frequencies of mitotic recombination, mitotic gene conversion, and reverse mutation in the diploid D7 strain of Saccharomyces cerevisiae. In the absence of S9 microsomal fraction or erythrocytes, CP did not induce any genetic response. In the presence of erythrocytes, on the other hand, CP clearly induced increases in the three genetic endpoints. The responses, however, were lower than those observed with the S9 activation system. The activating principle seems to be the oxyhemoglobin. In fact, neither p‐nitroanisole O‐demethylase activity nor genotoxic responses performed with red‐blood cells from uninduced and PB‐induced mice indicate that (possible) water‐soluble forms of cytochrome P‐450 were responsible for the activation of CP by erythrocytes.
Genotoxic classification of anticancer drugs
Authors: Matney Thomas S. , Nguyen Tot V. , Connor Thomas H. , Theiss Jeffrey C. , Dana William J. 
Published: February 2006

AbstractThe effects of bacterial DNA excision repair on the mutagenic and lethal actions of 17 injectable anticancer drugs have been used to classify them into three levels of potential risk to medical personnel who are involved in their preparation and administration.
Hyperthermia and other factors increasing sensitivity of Euglena to mutagens and carcinogens
Authors: Mačor Marian , Ebringer Libor , Siekel Peter 
Published: February 2006

AbstractThe effects of different factors (temperature, light, enzymic activation) on the ability of selected mutagens and carcinogens to induce hereditary bleaching of Euglena gracilis were investigated. In the resting medium, the elevation of incubation temperature from 25°C to 37°C increased significantly the effect of all compounds tested on the frequency of bleached mutants of E. gracilis. The effect of light is not so unambiguous. While nitrosoguanidine (NG) exhibited practically the same bleaching activity both in the light and dark, the mutagenic effect of sodium azide (SA), nitrovin (NV), nitrosoethylurea (NEU), and benzo(a)pyrene (BP) was decreased in light. On the other hand, the light increased the bleaching activity of 5‐nitro‐2‐furylacrylic acid (NFAA) significantly. The activation mixture S9 increased bleaching effect of NFAA and BP, whereas other mutagens were partially (NG and SA) or completely (NV and NEU) inactivated.
Comparative enzymatic acetylation of carnitine and choline by human placenta syncytiotrophoblast membrane vesicles
Authors: Jarmer Scott , Shoaf Antony R. , Harbison Raymond D. 
Published: February 2006

AbstractMicrovillous membrane vesicle preparations from the maternal surface of human placental syncytiotrophoblast were examined for the presence of carnitine and choline acetyltransferase activity. Radiometric assay for acetylcholine employed butyronitrile‐tetraphenylboron extraction of the quaternary ions. Acetylcarnitine was assayed by anion exchange chromatography. The data reveal that carnitine is the primary substrate for the vesicle acetyltransferase enzyme(s), whereas choline appears to be a minor substrate. For acetylcarnitine synthesis, the Km is 0.749 mM carnitine and Vmax is 641 pmol·mg protein−1 ·minute−1, respectively; for acetylcholine synthesis, the Km is 0.5 mM choline and Vmax is 53 pmol·mg protein−1·minute−1, respectively. Approximately ten times more acetylated product was formed with carnitine than with choline. The carnitine‐mediated reaction obeyed Michaelis‐Menten kinetics, whereas the choline reaction exhibited anomalous behavior. Vesicle preparations were stable for 21 days at —80°C. Preliminary studies on hypotonically lysed vesicles demonstrate that the acetyltransferase is particulate and is bound to the membrane of the vesicle. These findings demonstrate that carnitine acetyltransferase activity is in the plasmalemma membrane of the syncytiotrophoblast and suggest a role for this enzyme, analogous to the mitochondrial fatty acid shuttle system, in the maternofetal translocation of fatty acyl residues.
Species differences in mutagenicity testing: I. Micronucleus and SCE tests in rats, mice, and Chinese hamsters with aflatoxin B1
Authors: Madle Elisabeth , Korte Anke , Beek Bernd 
Published: February 2006

AbstractThree animal species used in in vivo mutagenicity testing—rats, mice and Chinese hamsters—were compared with respect to their mutagenic response to the mycotoxin aflatoxin B1 (AFB1). The micronucleus test and the SCE test with bone marrow cells were chosen as test methods, employing similar protocols for all species. The mutagenic potential of AFB1 was detected with rats and mice but not with Chinese hamsters. Rats were more susceptible to the mutagenic action of AFB1 than mice with regard to the effective dose. A difference in sensitivity between males and females was evident in rats and mice: male animals exhibited higher induced micronucleus frequencies than females, and a clear SCE‐inducing effect was only detectable in male animals. These results are in agreement with those of in vitro and carcinogenicity studies. They may be due to metabolic differences between the species and sexes, predominantly differences in glutathion conjugation of the reactive AFB1 epoxide and in the formation of the metabolite aflatoxicol. Furthermore, it could be demonstrated that AFB1 seems to be a more potent inducer of micronuclei than of SCE. Since our results obtained with rats and mice were clearly positive, but with the Chinese hamster the mutagenic potential of AFB1 was not detectable with the test systems used, it can be concluded that the choice of an “inappropriate” test species may lead to a false negative judgment on the genotoxic potential of a test compound.
Prenatal exposure to the fungicide dinocap causes behavioral torticollis, ballooning and cleft palate in mice, but not rats or hamsters
Authors: Gray L. Earl , Rogers John M. , Kavlock Robert J. , Ostby Joseph S. , Ferrell Janet M. , Gray Katrina L. 
Published: February 2006

AbstractThe present study is an evaluation of the developmental toxicity of dinocap in three rodent species using an in vivo teratology screen. Our protocol uses postnatal viability, weight gain, and morphological and behavioral development through weaning to assess the developmental toxicity of compounds.Dinocap administered orally on days 7 to 16 of gestation to the CD‐1 mouse resulted in increased postnatal mortality at 25 mg/kg/d (80% in block 1 and 40% in block 2). Many of the treated pups that died during the neonatal period were “ballooned” and had cleft palates. Although there was no treatment related mortality in the 12 mg/kg/d dosage group, 6% (14/226) of these mice and 24% (23/96) of the survivors from the 25 mg/kg/d dosage group displayed torticollis (a twisting of the neck resulting in an abnormal tilting of the head). These tilted‐head mice held the head and forepart of the body tilted constantly to one side, both when resting and walking. The tilt was in either direction but was always constant for a given animal; in different mice, the angle varied considerably from almost 0 to 30°. Some mice circled repeatedly in one direction in the home cage, others bobbed their heads and did back‐flips, while others rolled over, always rolling in the same direction.In the hamster, developmental toxicity was seen at (100 and 200 mg/kg/d) or near (50 mg/kg/d) maternally toxic doses but no behavioral alterations were noted and none of the pups were ballooned.The highest dose of dinocap (100 mglkgld during days 7–20) used in the rat study produced mild maternal toxicity (reduced maternal weight gain from day 3 to 10 of gestation), but did not alter the postnatal development of this species.
Induction of sister chromatid exchange in preimplantation mouse embryos in vitro by 3H‐thymidine or ultraviolet light in combination with caffeine
Authors: Müller W.‐U. , Spindle Akiko 
Published: February 2006

AbstractPreimplantation mouse embryos were exposed in vitro to 3H‐thymidine (25, 100, or 250 Bq/ml) or ultraviolet (UV) light (1.35 or 4.05 J/m2), either alone or in combination with caffeine (1 mM with 3H‐thymidine and 0.5 mM with UV light). Exposure to 3H‐thymidine lasted for 2 days, from the two‐cell stage to the late morula/early blastocyst stage, and UV radiation was applied acutely at the late morula/early blastocyst stage. The effects were quantified by the sister chromatid exchange (SCE) assay. All three agents induced SCEs when used singly. 3H‐thymidine was effective in inducing SCEs only at 250 Bq/ml, whereas UV light was effective at both fluences. Although caffeine did not induce SCEs when it was added before exposure to bromodeoxyuridine (BrdUrd), which is used to visualize SCEs, it did induce SCEs when present during the entire culture period (3H‐thymidine experiments) or during incubation in BrdUrd (UV experiments). Caffeine markedly enhanced the SCE‐inducing effect of UV light but did not influence the effect of 3H‐thymidine.
Cardiovascular defects in rat embryos cultured on serum from rats chronically exposed to phenytoin
Authors: Clapper Margie L. , Clark Michael E. , Klein Norman W. , Kurtz Perry J. , Carlton Betsy D. , Chhabra Rajendra S. 
Published: February 2006

AbstractHeadfold‐stage rat embyros were cultured for 48 hours on serum from rats chronically exposed to phenytoin for periods as long as from conception until 11 months of age. Serum from phenytoin‐exposed rats caused approximately 50% of the cultured rat embryos to develop cardiovascular defects as compared to 12% for controls. These morphological abnormalities included hemorrhaging of blood vessels within the embryo, pericardial edema, and absence of yolk sac circulation. Neither serum glucose nor phosphate levels nor serum osmolality were appreciably affected by phenytoin treatment. However, serum protein concentration was reduced in rats exposed to phenytoin as compared to controls. An absence of the serum protein hemopexin was associated with the reduction in serum protein levels but did not appear to be responsible for the observed cardiovascular defects.
Effect of prenatal imipramine exposure on development of the postnatal rat heart and brain
Authors: Harmon James R. , Webb Peggy J. , Kimmel Gary L. , Delongchamp Robert R. 
Published: February 2006

AbstractImipramine (IMI) was administered s.c. at 0, 5, or 10 mg/kg/day to pregnant rats on gestation days 8–20 to assess possible alterations in postnatal heart and brain development. Maternal weight gain was significantly reduced in a dose‐response manner, but litter size and pup weight on postnatal day (PND) 1 were unaffected. On PND 1, litters were culled to 10 pups for analysis on PNDs 4/5, 7/8, 14/15, and 21/22. Pup body weight was not affected at any age measured, but heart weight was significantly reduced at 10 mg/kg IMI on PNDs 4/5 and 7/8. Brain weight was increased in a dose‐related pattern on PNDs 4/5 and 7/8 and was significantly higher at 5 mg/kg IMI on PND 14/15. No significant effect was observed in heart or brain protein and DNA content or in cardiac beta‐adrenergic receptor concentration. Prenatal IMI exposure had no effect on basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development, but basal brain ODC was lower at 5 mg/kg IMI at all ages measured. Cardiac ODC stimulation by insulin was unaffected by prenatal exposure to IMI, but isoproterenol‐stimulated ODC was increased on PND 21/22 at 5 mg/kg IMI. In conclusion, the IMI‐related changes in several parameters suggest that when maternal IMI treatment is used, alterations in postnatal heart and brain development must be considered as possible outcomes.