bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of prenatal propranolol exposure on development of the postnatal rat heart
Authors: Harmon James R. , Delongchamp Robert R. , Kimmel Gary L. , Webb Peggy J. 
Published: February 2006

AbstractMaternal propranolol (PRO) treatment has previously been associated with adverse effects on the fetus and neonate. In the present study, pregnant rats were treated with PRO (25 or 50 mg/kg/day s.c.) on gestation days 8–20 to assess its possible effects on the developing heart. Maternal weight gain and pup weight on postnatal day (PND) 1 were reduced in a dose‐dependent manner; litter size was unaffected. Pup body weight and heart weight both showed a dose‐related decrease at all ages tested (PNDs 5/6, 8/9, 15/16, and 22/23). Since heart protein, but not DNA, was similarly reduced, the decrease seen in heart weight most likely reflects a decrease in cell size instead of cell number. Basal ornithine decarboxylase (ODC), an enzyme associated with growth and development, was unaffected by maternal PRO treatment. Insulin and isoproterenol stimulation of ODC, suggested markers for testing the function of the sympathetic pathway to the heart and of the heart's ODC response system, respectively, also showed no PRO‐related response. In conclusion, prenatal PRO exposure resulted in reduced body weight, heart weight, and heart protein, but had little effect on heart DNA or ODC activity. Since PRO treatment also reduced maternal weight gain, the adverse effects seen in the pups may be due to generalized PRO toxicity. The results suggest that when high PRO doses were used clinically, the careful monitoring of maternal weight gain during pregnancy might be useful in predicting adverse fetal effects.
Influence of the nature and the dose of the initiator on the development of premalignant and malignant lesions in rat hepatocarcinogenesis
Authors: Préat V. , de Gerlache J. , Lans M. , Taper H. , Roberfroid M. 
Published: February 2006

AbstractUsing a triphasic protocol recently described to induce malignant tumors in rat liver, the question has been asked whether both the nature and the dose of the initiator influence the carcinogenic process. Two nitrosamines (diethylnitrosamine DEN and N‐nitrosomorpholine NNM) have been used to initiate that process.With regard to the premalignant stages appearing in the liver up to 19 weeks after initiation, there is a dose‐dependent relationship between the dose of initiator and both the percentage of the parenchyma occupied by and the number of GGT+ lesions. DEN is always more potent than equivalent doses of NNM.With regard to malignant tumors appearing within the period of observation (up to 44 weeks), the two highest doses (100 and 200 mg/kg) of DEN appear to be the only carcinogenic treatments. Cancer incidence (percentage of rats bearing histologically characterized malignant tumor) is the same after both treatments, but the tumor yield (number of tumors per rat bearing macroscopic tumors) is higher (± 2 ×) after 200 mg/kg than after 100 mg/kg.
Deoxycytidine reverses inhibition of morphogenesis by thymidine in young chick blastoderm
Authors: Zagris Nikolas 
Published: February 2006

AbstractExogenous thymidine affects morphogenesis of the early chick blastoderm possibly by depleting the deoxycytidine triphosphate pool. The aim of this study is to determine whether the inhibitory action of thymidine on early chick blastoderm morphogenesis is alleviated by the removal of thymidine and/or treatment with deoxycytidine.Chick blastoderms at the full hypoblast stage develop abnormally in egg albumen containing 1.23 × 10−3 M thymidine. Development is normal when deoxycytidine is included simultaneously in the culture medium with thymidine at equimolar concentrations. Blastoderms were cultured in egg albumen containing 15 μCi/ml thymidine [methyl‐3H] or 10 μCi/ml deoxycytidine [5‐3H], and 1.2 × 10−3 M 2′ ‐deoxycytidine or 1.23 × 10−3 M thymidine, respectively. The culture was interrupted at timed intervals, and the amount of radioactivity associated with DNA was determined. Exogenous deoxycytidine in the culture medium caused a noticeable increase in the incorporation of 3H‐thymidine, while exogenous thymidine markedly inhibited the uptake and incorporation of 3H‐deoxycytidine into DNA of blastoderms.Thymidine does not inhibit the expansion of blastoderm, the migration of cells for formation of the primitive streak (PS), and the induction of axial tissues, but it interferes with the organization of these tissues to form the embryonic axis. Blastoderms show slight signs of recovery when thymidine is removed. Deoxycytidine counteracts the action of thymidine and seems to be a rate‐limiting factor in normal differentiation of the early chick blastoderm.
Mutagenic and cytotoxic potencies of a series of anthracycline derivatives as measured by HIS+ reversion, 8‐azaguanine resistance and direct plating cytotoxicity tests in Salmonella typhimurium
Authors: Thomas Harvey F. 
Published: February 2006

AbstractHis+ reversion at multiple his− loci, 8‐azaguanine resistance, and a previously reported direct plating cytotoxicity test were used to measure the genotoxic potencies of a series of anthracycline derivatives in Salmonella typhimurium. N‐demethylated amino sugar monosaccharide anthracyclines reverted most his−tester strains and were positive with 8‐azaguanine selection. Reversion of strain TA98 was the most sensitive end point for measuring the mutagenic activity of the N‐demethylated anthracyclines. N,N‐dimethyl amino sugar derivatives of Adriamycin and daunomycin were negative as measured by His+ reversion in tester strain TA98, but generated positive responses in tester strain TA102 that were equal to or greater than those of the demethylated parent coumpounds. Similarly, N,N‐dimethyl amino sugar derivatives of pyrromycinone and 1‐deoxypyrromycinone had no mutagenic activity as measured by His+ reversion except in tester strains TA102 and TA104. These later compounds also gave positive responses with 8‐azaguanine selection. In view of these results, the importance of amino sugar dialkylation and anthracycline mechanisms of mutagenesis are discussed.
Uptake by cells of nucleic acids promoted by compounds sharing the pleiotropic effects of poly(ethylene glycol)
Authors: Klebe Robert J. , Hanson Danelle P. , Harris June V. , Bentley Kevin L. 
Published: February 2006

AbstractPoly(ethylene glycol) (PEG) is a member of a group of membrane active compounds that have pleiotropic effects on cells, eg, promotion of cell fusion, induction of erythroleukemia cell differentiation, and protection of cells from freezing damage. Since PEG has recently been shown to be an efficient promoter of genetic transformation in bacteria, yeast, and mammalian cells, studies were carried out to determine whether other PEG‐related compounds could also promote genetic transformation. In this study, 24 compounds, which behave like PEG in other biological systems, are shown to promote transfection of human cells with isolated poliovirus RNA. That PEG and other commercially important compounds promote transfection indicates that such compounds may represent a biohazard to man.
Antimutagenic effects of natural and synthetic hormonal steroids
Authors: Wilpart Myriam , Speder Anne , Ninane Pascale , Roberfroid Marcel 
Published: February 2006

AbstractAmong the steroid molecules, bile acids have been shown to have either a co‐ or an antimutagenic activity toward various direct and indirect acting mutagens in the Ames test. The present report extends such observations to other steroids having hormonal activity. The main effect of the active hormones is an inhibition of the genotoxicity of both direct and indirect acting mutagens. This effect is strictly structure‐related. Moreover, both ethinyl oestradiol and mestranol, which are synthetic derivatives of β‐oestradiol largely used in contraceptive pills, are strong inhibitors of the mutagenicity, acting at nanomolar concentrations.The present article emphasizes the possible role of compounds with steroid structure as modulators of genotoxicity.
The effects of maternal murine cytomegalovirus infection on the mouse conceptus at different gestational stages
Authors: Huang Yuan‐Shen , Chernoff Neil , Kavlock Robert J. , Kawanishi Clinton Y. 
Published: February 2006

AbstractThe effects of murine cytomegalovirus (MCMV) on the prenatal development of the CD‐1 mouse were investigated. Two sets of experiments were performed. In the first, mice were inoculated with different doses of MCMV on gestational day 7, and in the second, pregnant animals were inoculated with a subacute injection dose at different gestational stages. The effects of maternal infection on pregnancy in terms of maternal sickness, embryo lethality, date of parturition, litter size, postnatal death, and pups' body weight on d 1 and d 3 postpartum were investigated. High‐dose MCMV infection on d 7 of pregnancy resulted in a significant increase in early embryo resorption and also in a reduction of the neonatal body weight of surviving pups. Two gestational stages were identified as being especially susceptible to MCMV infection. Most embryonic death as indicated by resorption rates was found after treatment on d 9, whereas perinatal death was most frequent when treatment was done on d 13 of gestation. Still births and neonatal death within 24 h of birth were found commonly in this latter group, which also showed the most pronounced growth retardation. The phenomenon of delay in time of parturition was noted and found to be most significant in groups of animals that were inoculated on d 3 or d 13. This investigation suggests that the effects of MCMV on the CD‐1 mouse vary greatly with the age of the embryo and the course of the infection.
Cell number and size in selected organs of fetuses of rats malnourished and exposed to nitrofen
Authors: Zeman Frances J. , Heng Helen , Hoogenboom Elizabeth R. , Kavlock Robert J. , Mahboob Soltanali 
Published: February 2006

AbstractThe effects of maternal exposure to nitrofen or protein‐energy malnutrition on the number and sizes of cells in selected organs of the fetal rat have been studied. Pregnant rats were fed either an adequate (CON) or protein‐energy deficient diet (PEM) throughout gestation. Each diet group was divided into two subgroups. One subgroup was gavaged with 25 mg nitrofen/kg body weight on gestational days 7–21 and the other, with corn oil carrier only. Fetal liver, kidneys, intestine, heart, lung, and brain were weighed and assayed for DNA, RNA, and protein. Maternal protein deficiency resulted in a reduction in organ weight and total DNA, RNA, and protein in all six organs. Maternal nitrofen exposure resulted in reduced weight and reduced protein in all organs except the brain. Total DNA and RNA were reduced in intestine, heart, and lung, and total RNA was also reduced in the liver following maternal nitrofen exposure. An interaction between diet and toxin affected lung weight, DNA, RNA, and protein, intestinal total protein, and heart DNA. Protein/DNA ratios were reduced in liver, intestine, and brain in the group fed the inadequate diet and in intestine only following nitrofen exposure. The deficient diet resulted in increased RNA/DNA ratio in the fetal liver and heart and a decreased ratio in the kidney and brain. Nitrofen exposure resulted in a lower RNA/DNA ratio in the liver. The data indicate that maternal protein‐energy malnutrition results in smaller organs in the fetuses with fewer cells and containing less protein and RNA. The greater reduction in protein than that expected from the decrease in numbers of cells in the liver, intestine, and brain in fetuses of malnourished dams suggests that cells were also smaller. Effects on RNA/DNA were essentially in the same direction as seen for protein/DNA. In general, the diet deficiency appeared to have a general metabolic effect reducing cell replication that, however, spared the brain. Nitrofen exposure results in an organ‐specific reduction in cell replication in the intestine, heart, and lung. An interaction between restricted diet and nitrofen exposure involves the lung primarily.
Heavy metal inhibition of carnitine acetyltransferase activity in human placental syncytiotrophoblast: Possible site of action of HgCl2, CH3HgCl, and CdCl2
Authors: Shoaf Antony R. , Jarmer Scott , Harbison Raymond D. 
Published: February 2006

AbstractThe effect of the heavy metal toxicants HgCl2, CH3HgCl, and CdCl2 on the acetylating activity of membranous carnitine acetyltransferase (CarAc) in membrane vesicles from the maternal surface of human placental syncytiotrophoblast has been investigated. CarAc was inhibited by inorganic and organic mercury and cadmium. Carnitine acetylation was inhibited by as little as 5 μM mercury, with complete inhibition at 50 μM inorganic and organic mercury. Inhibition by cadmium was incomplete (< 60%) at 500 μM CdCl2. Kinetic studies using Hanes plots revealed a mixed type of inhibition of CarAc by the metals. Cysteine preincubation decreased the amount of inhibition of CarAc by the metals. These results indicate that the inhibition of CarAc by heavy metals occurs by binding of the sulfhydryl on the enzyme by the metals. This interaction may be a mechanism of the heavy metal‐induced fetotoxicity.
Validation of an in vivo developmental toxicity screen in the mouse
Authors: Seidenberg Janice M. , Anderson David G. , Becker Richard A. 
Published: February 2006

AbstractA test system for identifying toxicity, including potential teratogenicity has been developed that is based on growth and viability of embryonic, fetal, and postnatal mice (J. Toxicol Environ Health 10:541–550, 1982). To test the utility of this assay, a series of 55 compounds was administered to timed‐pregnant ICR/SIM mice during organogenesis. The test compounds included known teratogens, known nonteratogens, and equivocal teratogens. They represented a wide variety of classes including pesticides, organic solvents, metals, steroids, nutrients, food additives, antimetabolites, alkylating agents, and pharmaceutical agents. A single dose level, at or near the level producing overt maternal toxicity in preliminary range‐finding studies, was administered by gavage on gestation days 8 through 12. Females were allowed to deliver; litter size and weight on the day of birth and 2 days postpartum were recorded, and stillborns were examined. Dams that had not given birth by gestation days 21 or 22 were killed and their uteri were examined. The results confirmed a strong correlation between reported teratogenic activity and embryo/fetal viability, and/or postnatal growth and viability. The results indicate that this test system is an effective, cost‐efficient means of prioritizing compounds for more detailed teratogenicity testing.
Sirenomelia: Analysis in the cadmium‐ and lead‐treated golden hamster
Authors: Hilbelink Don R. , Kaplan Stanley 
Published: February 2006

AbstractSirenomelia, a fusion of the lower extremities, is believed to result from a median, bilateral symmetric defect of the caudal portion of the embryo at a very early stage in development. Anomalies of the gastrointestinal and urogenital systems are commonly associated with this malformation. Sirenomelia is not an embryolethal condition but typically is incompatible with postnatal life when combined with the associated malformations. In this study, intravenous treatment of hamsters with a combination of cadmium and lead on the morning of the eighth day of gestation resulted in 1.4, 22.2, and 35.6% of the viable fetuses displaying sirenomelia in litters recovered on days 15, 12, and 10 of gestation, respectively. With the exception of several fetuses with exencephaly, most structures cranial to the level of the umbilicus were normal. Caudal abdominal and pelvic structures were severely affected, with agenesis or dysgenesis of the kidneys, bladder, umbilical arteries, and external genitalia frequently noted. The administration of a combination of cadmium and lead has proven to be an effective and consistent means of inducing sirenomelia in the golden hamster.
Enhancement of cytogenetic damage by inhibitors of poly(ADP‐ribose)polymerase in human lymphocytes exposed to antineoplastics in vivo and in vitro
Authors: Mourelatos D. , Kourakis A. , Koliouskas D. E. , Hatzitheodoridou P. , Dozi‐Vassiliades J. 
Published: February 2006

AbstractThe effect of benzamide (B) and 3‐aminobenzamide (3‐AB) on sister chromatid exchanges (SCEs) and cell kinetics induced in vitro by melphalan (MELPH) or thiotepa (THIO) was studied in normal human lymphocytes. The combined treatments with either MELPH or THIO plus B or 3‐AB showed the potentiating ability on SCE rates and the ability to induce cell division delays of the latter chemicals.In a combined in vivo and in vitro study, lymphocytes taken from six cancer patients who had been given cytoxan by injection 2 hr before and then treated with theophylline (THEOPH) or B or 3‐AB in vitro were found to have synergistically increased exchange rates and cell division delays. The frequency of SCEs in the patients own lymphocytes with and without exposure to inhibitor of Poly(ADP‐ribose) polymerase (P(ADPR)polymerase) was determined before the cytostatic therapy and was used as a control for later comparison in each individual case. These results further substantiate the use of this approach for detecting the induction of cytogenetic damage concerning controlled mutagen human exposure in combined in vivo and in vitro studies.Chemically induced cytotoxicity manifested as an alteration (division delay) in cell kinetics and as synergistic DNA damage by cytostatics and inhibitors of P(ADPR)polymerase may be of use in the treatment of human cancer.
The direct‐acting mutagenicity of nitroimidazo[2,1‐b]thiazoles in Salmonella typhimurium
Authors: Hrelia P. , Paolini M. , Biagi G. L. , Cantelli‐Forti G. 
Published: February 2006

AbstractA series of nitroimidazo[2,1‐b]thiazole derivatives was investigated for directacting mutagenic potency with the Salmonella assay. All of the nine derivatives tested were mutagenic. The compounds induced predominantly base displacements resulting in frame‐shift mutations. The mutagenic activity did not require the S9 fraction but was largely dependent on “classical” bacterial nitroreductase. The primary basis of the mutagenic activity of nitroimidazo[2,1‐b]thiazoles appears to be a reduction of the nitro‐function to the corresponding hydroxylamine. Mutagenicity seems to be paralleled by an increase of the nitro groups: dinitroderivatives were more active than nitroderivatives. Other electrophiles and sterically constrained nitro groups could account for differences in genotoxicity.
Malformations induced in cultured rat embryos by enzymically generated active oxygen species
Authors: Jenkinson P. C. , Anderson Diana , Gangolli S. D. 
Published: February 2006

AbstractDay 9.5 rat embryos were exposed in culture to xanthine/xanthine oxidase generated active oxygen species. Growth and development were assessed after 46 hr of culture. The treatment induced abnormalities of the neural suture, the severity of which increased in a dose‐related manner with the concentration of substrate or enzyme. Glutathione (10 mM) or catalase (50 μg/ml) either partially or completely abolished the effects of xanthine/xanthine oxidase, whereas the addition of superoxide dismutase (50 μg/ml) or desferrioxamine (1mM) did not reduce the number of malformed embryos. These findings suggest that hydrogen peroxide and/or hydroxyl radicals are responsible for the effects of xanthine and xanthine oxidase.
The heat‐shock response in vivo: Experimental induction during mammalian organogenesis
Authors: German James , Louie Elaine , Banerjee Debendranath 
Published: February 2006

AbstractAccording to the embryonic stress hypothesis of teratogenesis, anatomical malformation can be the consequence of the induction of a heat‐shock response (HSR) in the embryo at some critical stage during the determination or differentiation of organs. This hypothesis states that a teratogen is any agent (i) that is capable of inducing a HSR and (ii) that can reach the developing embryo. As a first step in determining whether the hypothesis is tenable, it was necessary to determine whether the embryo in fact is capable of making the HSR during the period of organogenesis. Pregnant mice were treated with two classical inducers of the HSR, one a physical and the other a chemical agent—namely, hyperthermia and sodium arsenite. The embryos, while still in the living mouse, responded with heat‐shock protein induction, as did control bone marrow.
Hyperthermia as a teratogen: A review of experimental studies and their clinical significance
Authors: Edwards M. J. 
Published: February 2006

AbstractAlthough hyperthermia is teratogenic in birds, all the common laboratory animals, farm animals, and primates and satisfies defined criteria as a teratogen, its study as a human teratogen has been neglected. Homeothermic animals, including humans, can experience body temperature elevations induced by febrile infections, heavy exercise and hot environments which exceed the thresholds (1.5–2.5°C elevation) which are known to cause a syndrome of embryonic resorptions, abortions, and malformations in experimental animals. Hyperthermia is particularly damaging to the central nervous system, and if a threshold exposure occurs at the appropriate stages of embryonic development, exencephaly, anencephaly, encephalocoele, micrencephaly, microphthalmia, neurogenic talipes, and arthrogryposis can be produced in a high proportion of exposed embryos, the incidence and type of defect depending on the species and strain within species, the stage of development, and the severity of hyperthermic exposure. Other defects which can be induced experimentally include exomphalos, hypoplasia of toes and teeth, renal agenesis, vertebral anomalies, maxillary hypoplasia, facial clefting, cataract, coloboma, and heart and vascular defects. Proliferating cells are particularly sensitive to temperature elevations, resulting in arrest of mitotic activity and immediate death of cells in mitosis with threshold elevations (1.5–2.5°C) and delayed death of cells probably in S phase with higher elevations (3.5°C). In general, lower temperature elevations (2.5°C) require longer durations of elevation to cause defects than a simple spike at a higher elevation (4.5°C). The death of cells is largely confined to the brain and in the day 21 guinea pig embryo to the alar regions of the brain. Cell death probably accounts for most of the defects in the central nervous system, but microvascular disturbances leading to leakage, oedema and haemorrhage, placental necrosis, and infarction are other known effects of hyperthermia; and these are probably involved in the pathogenesis of many defects of the heart, limbs, kidneys, and body wall. Recent experiments have demonstrated protection of rat embryos in culture against a known teratogenic exposure by a brief nonteratogenic exposure given at least 15 min earlier. This protection is associated with the synthesis of heat‐shock proteins, and temporary arrest of the cell proliferative cycle. Hyperthermia appears to be capable of causing congenital defects in all species and may act alone or synergistically with other agents. With minimally teratogenic doses of heat plus arsenic, lead, or vitamin A, the combined responses with heat have been clearly augmented compared with the additive responses of single treatments. The contribution of hyperthermia to abortions is well documented, and its effect on human birth defects needs careful evaluation.