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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 277 (1973), S. 413-428 
    ISSN: 1432-1912
    Keywords: Method ; 14C-Glucose ; 32P-Orthophosphate ; Rat Embryos ; DNA, RNA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Uniformly labelled 14C-glucose and 32P-orthophosphate were applied intravenously to pregnant rats on day 12 of gestation. DNA and RNA were found to be labelled by both of these precursors. 2. Highly purified RNA and DNA were isolated from the embryos and hydrolyzed to mononucleotides and bases, the four nucleotides or bases were separated and the specific activities determined. According to the alkaline hydrolysis, a nearest-neighbour analysis (2′–3′-nucleotides) is achieved in the case of the RNA nucleotides whereas the enzymic hydrolysis of the DNA allows the preparation of 5′-nucleotides. 3. The ribosomal RNA bases were found to be labelled rather equally (≃1.4dpm/nmol) except for Uracil where the specific activity showed a 3 times higher value (≃4 dpm/nmol). 4. The base moieties of the DNA show an almost equal rate of incorporation of 14C-glucose fragments. The 32P-radioactivity found in DNA nucleotides is in the range of the corresponding 14C-data except for that of TMP. In this case a higher rate of 32P was found compared to the 14C-radioactivity.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0738
    Keywords: Methylnitrosourea ; Teratogenicity ; Mice ; Dose-response
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The teratogenic potency of the directly acting alkylating agent methylnitrosourea (MNU) was analysed in mice. Skeletal abnormalities were evaluated after treatment on either day 11 or 12 of pregnancy. Ectrodactyly was the predominant effect after treatment on day 11. Treatment on day 12 triggered especially double-sided microdactyly (method of analysis: measuring digit lengths). Litter variabilities were analysed using a new biometrical procedure. Using probit analysis, dose-response curves were computed from the experimental data obtained and the effective doses were calculated and compared with maternal toxicity. Low dose extrapolation was performed by use of various mathematical models which yielded very similar EDI/100 and EDI/1000 values.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0738
    Keywords: Acyclovir ; Prenatal toxicity ; Rat ; Viru-statics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Pregnant rats were treated during organogenesis with s.c. injections of acyclovir and the embryos were evaluated on day 11.5 of gestation (crown-rump length, somites, protein content, score, abnormalities, histological examination). After eight injections of 50 mg/kg body wt on days 9, 10, and 11 of pregnancy a reduction of the crownrump length was noticed. After 100 mg/kg this effect was more pronounced. With two or three applications of this dose on day 10 specific embryonic abnormalities were visible: the shape of the head was abnormal, the width of the skull had decreased resembling a beak-like visceral cranium. With a single administration of 200 mg/kg on day 10 we found a similar but slightly more pronounced outcome. A drastic change of all variables was obtained after eight injections of 100 mg/kg on days 9, 10, and 11. Comparatively we measured maternal plasma concentrations of acyclovir 1 h after the administration of 50, 100 or 200 mg/kg body wt. After an injection of 50 mg/kg on days 9, 10, and 11 of gestation (three injections/day) the plasma levels ranged from 19.1 to 40.0 mg/l (1 mg/l = 4.44 μM). No cumulation was observed. In contrast, a cumulative effect was detected following a dose of 100 mg/kg. After the first injection of this dose a mean value (± SD) of 60.3±14.7 mg/l (n = 16) was obtained. In this case a third injection increased the mean plasma level to 124.6±16.6 mg/l (n = 5). Further injections, however, led to decreasing levels. One hour after administration of 200 mg/kg body wt acyclovir levels ranged from 120.0 to 163.9 mg/l. We conclude that acyclovir, at doses leading to plasma concentrations well above the therapeutic level in the dam, interferes with the embryonic development in the rat. Acyclovir induces typical gross structural abnormalities which have been first observed using a whole embryo culture system.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0738
    Keywords: Acetoxymethyl-methylnitrosamine ; Teratogen ; Sidepreference ; Limb bud culture ; DNA alkylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 1. The alkylating agent acetoxymethyl-methylnitro-samine (DMN-OAc) triggers preferential left-sided paw defects in mice following IP administration on either day 11 or 12 of pregnancy. Predominantly, ectrodactyly and hypoplasia of the left paws were found. 2. In an organ culture system, using limb buds of 11-day-old mouse embryos, differentiation is severly impaired following addition of 2 μM DMN-OAc to the culture medium. Left and right limbs are equally affected. In contrast, when DMN-OAc is administered in vivo to the dams with subsequent culturing of the limb buds, growth and differentiation of the left limb buds is more affected when compared to the right. 3. Furthermore, DNA alkylation experiments were performed: in vitro, following addition of (14C)-DMN-OAc (2.3 μM) to the culture medium, the DNA alkylation rate of the limb bud DNA is determined. In vivo, following IP administration of 10 mg/kg DMN-OAc to the dams on day 11 of pregnancy, the extent of DNA alkylation of whole-embryo DNA is similar. However, the DNA alkylation rate of separately pooled left and right limb buds exhibits a two-fold difference according to the different teratogenic susceptibility. The results obtained with both in vivo and in vitro systems are consistent with the thesis that a certain amount of DNA alkylation in the tissue of the embryos is the initial step of alkylating agent-induced teratogenicity.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0738
    Keywords: Acyclovir ; Embryotoxicity ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Following three s.c. injections of acyclovir (100 mg acyclovir/kg) into rats on day 10 of pregnancy 19 litters were evaluated on day 21 of gestation and the effects were compared to the results obtained from controls (nine litters) which received the vehicle (0.1 N NaOH) only. The following results were obtained (treated group versus control group): 1) Implantations/litter: 11.2±1.3 versus 10.2±1.1; 2) resorptions/implantations: 27.7% versus 2.2%; 3) number of viable fetuses evaluated: 154 versus 90; 4) fetuses with anomalies of the skull: 78% versus 12%; 5) fetuses with anomalies of the vertebral column: 38% versus 13%; 6) gross-structural anomalies predominantly affected the skull and tail. The most frequently registered defects were: os tympanicum (smaller): 23%, os tympanicum (missing): 23%; missing tail: 7%; protruding tongue (15%); none of these defects were seen in the control fetuses. Postnatally we observed a high mortality rate among the offspring. From a total of 85 newborn (nine litters) we obtained 73 viable offspring (9.1±3.4); 81% of them had tail alterations. In the control group of eight litters (9.4±2.3) no tail alterations occurred. On day 21 postnatally 40 viable offspring were alive (mortality rate: 38.8%). Nearly all of these animals had visible alterations at multiple sites of their bodies; most frequently observed were: tail impairment, closed eyes, dragging hind-limbs, and urogenital alterations (e.g. testicular atrophy). These studies show for the first time that prenatal treatment with acyclovir induces gross-structural defects which persist postnatally. With the usually applied precautions during therapeutic use in pregnant women, the teratogenic potency of acyclovir seems to be small; however, acyclovir does have a teratogenic potential.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0738
    Keywords: 2,3,70,8-Tetrachlorodibenzo-p-dioxin (TCDD) ; Paternally-mediated prenatal toxicity ; Teratogenicity ; Peri-postnatal toxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 μg/kg body wt; maintenance dose: 5 μg/kg body wt, once weekly) and TCDD-75 (initial dose: 75 μg/kg body wt; maintenance dose: 15 μg/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25=5.1%, controls=2.6%), and incompletely ossified ossa zygomatica (TCDD-25=1.8%, controls=0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25=1.3%, controls=0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls=0.6%). There was no difference in postnatal mortality (TCDD-25=1.3%, controls=1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0738
    Keywords: Methylnitrosourea ; DNA adduct formation ; Mice ; Embryo
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Formation of DNA adducts in 11-day-old mouse embryos was studied by measuring the initial alkylation rates of the methylated purine bases 7-methylguanine, O6-methylguanine, and 3-methyladenine. In the first part of the studies the adduct rates were measured in the teratogenic dose range (ED10-ED90, 2.7–5.6 mg/kg). These results were compared with similar data obtained from studies with ethylmethanesulfonate and acetoxymethyl-methylnitrosamine. For the three investigated substances a correlation was found between the initial adduct rate of O6-alkylguanine in the DNA of the embryos and the teratogenic potency. In the second part of the study the rate of adduct formation was measured in the sub-teratogenic dose range. These data will be used for molecular dosimetry in a risk assessment of low doses.
    Type of Medium: Electronic Resource
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