RESUMO
Beam alignment is an important practical aspect of the application of squeezed states of light. Misalignments in the detection of squeezed light result in a reduction of the observable squeezing level. In the case of squeezed vacuum fields that contain only very few photons, special measures must be taken in order to sense and control the alignment of the essentially dark beam. The GEO 600 gravitational wave detector employs a squeezed vacuum source to improve its detection sensitivity beyond the limits set by classical quantum shot noise. Here, we present our design and implementation of an alignment sensing and control scheme that ensures continuous optimal alignment of the squeezed vacuum field at GEO 600 on long time scales in the presence of free-swinging optics. This first demonstration of a squeezed light automatic alignment system will be of particular interest for future long-term applications of squeezed vacuum states of light.
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Quantum noise will be the dominant noise source for the advanced laser interferometric gravitational wave detectors currently under construction. Squeezing-enhanced laser interferometers have been recently demonstrated as a viable technique to reduce quantum noise. We propose two new methods of generating an error signal for matching the longitudinal phase of squeezed vacuum states of light to the phase of the laser interferometer output field. Both provide a superior signal to the one used in previous demonstrations of squeezing applied to a gravitational-wave detector. We demonstrate that the new signals are less sensitive to misalignments and higher order modes, and result in an improved stability of the squeezing level. The new signals also offer the potential of reducing the overall rms phase noise and optical losses, each of which would contribute to achieving a higher level of squeezing. The new error signals are a pivotal development towards realizing the goal of 6 dB and more of squeezing in advanced detectors and beyond.
RESUMO
We report on the first long-term application of squeezed vacuum states of light to improve the shot-noise-limited sensitivity of a gravitational-wave observatory. In particular, squeezed vacuum was applied to the German-British detector GEO 600 during a period of three months from June to August 2011, when GEO 600 was performing an observational run together with the French-Italian Virgo detector. In a second period, the squeezing application continued for about 11 months from November 2011 to October 2012. During this time, squeezed vacuum was applied for 90.2% (205.2 days total) of the time that science-quality data were acquired with GEO 600. A sensitivity increase from squeezed vacuum application was observed broadband above 400 Hz. The time average of gain in sensitivity was 26% (2.0 dB), determined in the frequency band from 3.7 to 4.0 kHz. This corresponds to a factor of 2 increase in the observed volume of the Universe for sources in the kHz region (e.g., supernovae, magnetars). We introduce three new techniques to enable the long-term application of squeezed light, and show that the glitch rate of the detector did not increase from squeezing application. Squeezed vacuum states of light have arrived as a permanent application, capable of increasing the astrophysical reach of gravitational-wave detectors.
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Control noise is a limiting factor in the low-frequency performance of the Advanced Laser Interferometer Gravitational-Wave Observatory (LIGO). In this paper, we model the effects of using new sensors called Homodyne Quadrature Interferometers (HoQIs) to control the suspension resonances. We show that if we were to use HoQIs, instead of the standard shadow sensors, we could suppress resonance peaks up to tenfold more while simultaneously reducing the noise injected by the damping system. Through a cascade of effects, this will reduce the resonant cross-coupling of the suspensions, allow for improved stability for feed-forward control, and result in improved sensitivity of the detectors in the 10-20 Hz band. This analysis shows that improved local sensors, such as HoQIs, should be used in current and future detectors to improve low-frequency performance.
RESUMO
This paper presents an analysis of the transient behavior of the Advanced LIGO (Laser Interferometer Gravitational-wave Observatory) suspensions used to seismically isolate the optics. We have characterized the transients in the longitudinal motion of the quadruple suspensions during Advanced LIGO's first observing run. Propagation of transients between stages is consistent with modeled transfer functions, such that transient motion originating at the top of the suspension chain is significantly reduced in amplitude at the test mass. We find that there are transients seen by the longitudinal motion monitors of quadruple suspensions, but they are not significantly correlated with transient motion above the noise floor in the gravitational wave strain data, and therefore do not present a dominant source of background noise in the searches for transient gravitational wave signals. Using the suspension transfer functions, we compared the transients in a week of gravitational wave strain data with transients from a quadruple suspension. Of the strain transients between 10 and 60 Hz, 84% are loud enough that they would have appeared above the sensor noise in the top stage quadruple suspension monitors if they had originated at that stage at the same frequencies. We find no significant temporal correlation with the suspension transients in that stage, so we can rule out suspension motion originating at the top stage as the cause of those transients. However, only 3.2% of the gravitational wave strain transients are loud enough that they would have been seen by the second stage suspension sensors, and none of them are above the sensor noise levels of the penultimate stage. Therefore, we cannot eliminate the possibility of transient noise in the detectors originating in the intermediate stages of the suspension below the sensing noise.
RESUMO
Male C57BL/6N mice were administered a single ip injection of 30 mg of N-methyl-N-nitrosourea (MNU)/kg of body weight. Additional groups were treated similarly every 3 hours for the next 24 hours. Adenocarcinomas of the small intestine were the major treatment-related tumors, with the total incidence being 38% at 250 days after injection. There was a significant circadian variation for tumor induction; the maximum number of intestinal tumors (approximately equal to 55%) tended to occur when the MNU was administered during the middle of the light period (6:00 to 18:00), while the tumor incidence was at a minimum (approximately equal to 10%) when the MNU was given in the middle of the dark phase (18:00 to 6:00). These data are discussed in relation to DNA synthesis and repair and MNU-induced cellular toxicity.
Assuntos
Ritmo Circadiano , Neoplasias Intestinais/induzido quimicamente , Metilnitrosoureia/toxicidade , Adenocarcinoma/induzido quimicamente , Animais , DNA/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Intestino Delgado , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Male and female Sprague-Dawley rats were treated by gastric intubation either 1, 2, 3, or 4 times at biweekly intervals with 10-mg/kg doses of the hepatocarcinogen of N-[ring-3H]-hydroxy-2-acetylaminofluorene. Then either 1 or 14 days following the last treatment, the concentrations of 2-aminofluorene and 2-acetylaminofluorene adducts in liver and kidney DNA were established. 2-Acetylaminofluorene adducts were found in male rat liver DNA only. The C-8-acetylated adduct, N-(deoxyguanosin-8-yl)-2-acetylaminofluorene, was detected only on the day following treatment at a concentration between 1.0 and 2.4 pmol/mg DNA. A second acetylated adduct, 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene, was found at both 1 and 14 days after treatment and, as a result, increased in concentration with repeated doses, from 0.2 pmol/mg DNA after one dose to 2.8 pmol/mg DNA after four treatments. The major adduct detected in male rat liver and the only adduct found in female rat liver and in kidney from either sex was N-(deoxyguanosin-8-yl)-2-aminofluorene. This adduct was slowly lost from the DNA and therefore increased in concentration with repetitive treatments as follows: male liver, 4.0 to 9.4 pmol/mg DNA; female liver, 11.4 to 30.6 pmol/mg DNA; male kidney, 1.1 to 1.8 pmol/mg DNA; and female kidney, 1.8 to 17.7 pmol/mg DNA. These data indicate that certain DNA adducts can accumulate in both target and non-target tissues and therefore suggest that persistence of DNA adducts per se is not sufficient for tumor induction.
Assuntos
2-Acetilaminofluoreno/análogos & derivados , DNA/metabolismo , Hidroxiacetilaminofluoreno/metabolismo , Rim/metabolismo , Fígado/metabolismo , Animais , Feminino , Hidroxiacetilaminofluoreno/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Masculino , Neoplasias Experimentais/induzido quimicamente , Ratos , Ratos Endogâmicos , Sulfurtransferases/análiseRESUMO
The N-hydroxy derivatives of 1- and 2-naphthylamine (NA) are directly carcinogenic at sites of application. In this study, the carcinogenicity of these two compounds at s.c. injection sites was compared with their relative rates of absorption, with the extent and persistence of their binding to protein, RNA, and DNA in the skin-subcutis, and with acute histopathological changes observed after local application. Male Sprague-Dawley rats were given injections of the N-hydroxy derivatives in the right rear leg at 16 mumol/dose. When administered twice weekly for 12 weeks, N-hydroxy-1-NA caused a 100% incidence (30 of 30) of poorly differentiated sarcomas at the injection site. N-Hydroxy-2-NA administered in a similar manner resulted in a low yield of tumors (7%; 2 of 30). Injection of N-hydroxy-1-NA once weekly for 12 weeks or twice weekly for 6 weeks also induced a high incidence of sarcomas (93 to 97%), but the time to tumor formation was significantly longer (p less than 0.0001) than in animals treated twice weekly for 12 weeks. The tumors were classified as malignant fibrous histiocytomas. Possible antagonistic or synergistic effects between the two compounds were also investigated. A sequential 6-week treatment with each of the N-hydroxy derivatives did not alter the expected tumor yields. However, alternating injections over 12 weeks caused a significant lengthening in the time to tumor formation (p less than 0.05). N-Hydroxy-1-NA bound covalently to protein, RNA, and DNA to a much greater extent than did N-hydroxy-2-NA. Protein binding with both derivatives decreased by 80 to 90% by 7 days after treatment. RNA binding in N-hydroxy-1-NA-treated rats markedly decreased, while N-hydroxy-2-NA-bound residues diminished only slightly. During this period, the extent of DNA binding with both derivatives remained fairly constant. When N-hydroxy-2-NA was injected 3 days after N-hydroxy-1-NA, there was a marked reduction in the apparent levels of N-hydroxy-1-NA bound to RNA and DNA. The greater tumorigenicity of N-hydroxy-1-NA versus N-hydroxy-2-NA correlated with its greater extent of macromolecular binding. Examination of acute histopathological changes occurring after single injections of N-hydroxy-1-NA and/or N-hydroxy-2-NA indicated that both compounds caused extensive necrosis in tissues at the injection site.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
1-Naftilamina/toxicidade , 2-Naftilamina/toxicidade , Carcinógenos/toxicidade , Naftalenos/toxicidade , Sarcoma/induzido quimicamente , 1-Naftilamina/análogos & derivados , 1-Naftilamina/metabolismo , 2-Naftilamina/análogos & derivados , 2-Naftilamina/metabolismo , Animais , Interações Medicamentosas , Cinética , Masculino , Necrose , Ratos , Ratos Endogâmicos , Sarcoma/patologia , Pele/patologia , Relação Estrutura-Atividade , TrítioRESUMO
6-Nitrochrysene (NC) and 6-aminochrysene (AC) have been shown to be potent lung and liver carcinogens when administered in multiple i.p. doses to preweanling mice. 1,6-Dinitropyrene has been shown to be a strong hepatocarcinogen but a weak lung carcinogen in this same bioassay. We have examined carcinogen-DNA adduct profiles in the target tissues of preweanling male CD-1 mice following administration of single or multiple doses of these compounds. Depending on the tissue and the dosing schedule, the total level of DNA modification in animals dosed with [3H]NC was 2- to 9-fold higher than in animals dosed with [3H]AC. Regardless of the dosing schedule, DNA isolated from the lungs and livers of both [3H]NC- and [3H]AC-treated preweanling male mice contained a single major and chromatographically identical adduct. This major adduct, which accounted for as much as 90% of the total carcinogen-DNA adducts in enzymatic hydrolysates from treated animals, was chromatographically distinct from the major C8-purine-substituted adducts formed from the reaction of N-hydroxy-AC with calf thymus DNA. In contrast to the results obtained with NC and AC, the major carcinogen-DNA adduct formed in the livers of mice treated with [3H]-1,6-dinitropyrene was found to cochromatograph with 1-N-(deoxyguanosin-8-yl)amino-6-nitropyrene, a product derived from N-hydroxy-1-amino-6-nitropyrene. Since NC and its nitro-reduced derivative, AC, yielded an identical carcinogen-DNA adduct in vivo and this adduct was not derived from N-hydroxy-AC, we conclude that the metabolic activation of NC in the neonatal mouse must involve some previously undescribed combination of ring-oxidation and nitro-reduction pathways. This activation pathway could be an important factor in determining the potency of NC and AC as carcinogens in this bioassay system.
Assuntos
Crisenos/metabolismo , DNA/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Fenantrenos/metabolismo , Pirenos/metabolismo , Animais , Animais Lactentes , Cromatografia Líquida de Alta Pressão , Masculino , Camundongos , Camundongos EndogâmicosRESUMO
The human urinary bladder carcinogen, 4-aminobiphenyl (ABP), is known to undergo hepatic metabolism to an N-hydroxy arylamine and its corresponding N-glucuronide. It has been proposed that these metabolites are both transported through the blood via renal filtration to the urinary bladder lumen where acidic pH can facilitate the hydrolysis of the N-glucuronide and enhance the conversion of N-hydroxy-4-aminobiphenyl (N-OH-ABP) to a reactive electrophile that will form covalent adducts with urothelial DNA. Blood ABP-hemoglobin adducts, which have been used to monitor human exposure to ABP, are believed to be formed by reactions within the erythrocyte involving N-OH-ABP that has entered the circulation from the liver or from reabsorption across the urothelium. To test these hypotheses directly, experimental data were obtained from female beagles given [3H]ABP (p.o., i.v., or intraurethrally). [3H]N-OH-ABP (i.v. or intraurethrally), or [3H]N-OH-ABP N-glucuronide (i.v.). Analyses included determinations of total ABP in whole blood and plasma, ABP-hemoglobin adducts in blood erythrocytes, ABP and N-OH-ABP levels (free and N-glucuronide) in urine, urine pH, frequency of urination (controlled by urethral catheter), rates of reabsorption of ABP and N-OH-ABP across the urothelium, and apparent volumes of distribution in the blood/tissue compartment. The major ABP-DNA adduct, N-(guan-8-yl)-4-aminobiphenyl, was also measured in urothelial and liver DNA using a sensitive immunochemical method. An analog/digital hybrid computer was then utilized to construct a multicompartmental pharmacokinetic model for ABP and its metabolites that separates: (a) absorption; (b) hepatic metabolism and distribution in blood and tissues; (c) ABP-hemoglobin adduct formation; (d) hydrolysis and reabsorption in the urinary bladder lumen; and (e) excretion. Using this model, cumulative exposure of the urothelium to free N-OH-ABP was simulated from the experimental data and used to predict ABP-DNA adduct formation in the urothelium. The results indicated that exposure to N-OH-ABP and subsequent ABP-DNA adduct formation are directly dependent on voiding frequency and to a lesser extent on urine pH. This was primarily due to the finding that, after p.o. dosing of ABP to dogs, the major portion of the total N-OH-ABP entering the bladder lumen was free N-OH-ABP (0.7% of the dose), with much lower amounts as the acid-labile N-glucuronide (0.3% of the dose).(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Compostos de Aminobifenil/metabolismo , Carcinógenos/metabolismo , DNA/metabolismo , Hemoglobinas/metabolismo , Fígado/metabolismo , Bexiga Urinária/metabolismo , Micção , Compostos de Aminobifenil/sangue , Compostos de Aminobifenil/farmacocinética , Compostos de Aminobifenil/urina , Animais , Cães , Feminino , Cinética , Modelos Biológicos , Fatores de Tempo , Distribuição TecidualRESUMO
Tilt-horizontal coupling in inertial sensors limits the performance of active isolation systems such as those used in gravitational wave detectors. Inertial rotation sensors can be used to subtract the tilt component from the signal produced by horizontal inertial sensors, but such techniques are often limited by the sensor noise of the tilt measurement. A different approach is to mechanically filter the tilt transmitted to the horizontal inertial sensor, as discussed in this article. This technique does not require an auxiliary rotation sensor and can produce a lower noise measurement. The concept investigated uses a mechanical suspension to isolate the inertial sensor from input tilt. Modeling and simulations show that such a configuration can be used to adequately attenuate the tilt transmitted to the instrument, while maintaining translation sensitivity in the frequency band of interest. The analysis is supported by experimental results showing that this approach is a viable solution to overcome the tilt problem in the field of active inertial isolation.
RESUMO
2-Amino-5-phenylpyridine (2-APP) is a mutagenic heterocyclic aromatic amine that is formed by pyrolysis of phenylalanine in proteins. Since this mutagen is structurally similar to the multipotent carcinogen, 4-aminobiphenyl (4-ABP), we compared their relative tumorigenic activity in the neonatal male B6C3F1 mouse. After determinations of the maximum tolerated dose (MTD), both aromatic amines were administered i.p. at 2 dose levels (MTD and MTD/2) on days 1, 8, 15 and 22 after birth. Groups were killed at 9 and 12 months and examined for histopathologic changes. No treatment-related neoplastic lesions were observed for 2-APP. In contrast, 4-ABP was strongly carcinogenic and induced a high incidence of multiple hepatocellular adenomas and carcinomas.
Assuntos
Compostos de Aminobifenil/toxicidade , Aminopiridinas/toxicidade , Carcinógenos , Neoplasias Hepáticas Experimentais/induzido quimicamente , Animais , Animais Recém-Nascidos , Masculino , Camundongos , Camundongos EndogâmicosRESUMO
The tumorigenic activities of four representative heterocyclic amine food pyrolysates, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), were assessed in the neonatal male B6C3F1 mouse and were compared with that of the potent human carcinogen, 4-amino-biphenyl (4-ABP). These aromatic amines were administered by i.p. injection at two dose levels on days 1, 8, and 15 after birth; and the incidence of tumors was examined at 8 and 12 months. Glu-P-1, IQ, PhIP, MeIQx, and 4-ABP each induced a significant incidence of hepatic adenomas, as compared to the solvent-treated (DMSO) control. Hepatocellular carcinomas were also observed with 4-ABP, SO, and MeIQx. Overall tumorigenicity was in the order: 4-ABP greater than Glu-P-1 greater than IQ approximately PhIP greater than MeIQx greater than DMSO. In the neonatal B6C3F1 mouse, these heterocyclic aromatic amines showed potent tumorigenicity after 8 and 12 months at total doses that were 5-10,000-fold less than those employed in standard chronic bioassays.
Assuntos
Compostos de Aminobifenil/toxicidade , Carcinógenos/toxicidade , Imidazóis/toxicidade , Neoplasias Hepáticas Experimentais/induzido quimicamente , Mutagênicos/toxicidade , Quinolinas/toxicidade , Quinoxalinas/toxicidade , Animais , Animais Recém-Nascidos , Testes de Carcinogenicidade , Masculino , CamundongosRESUMO
Hepatic N-oxidation, followed by N-glucuronidation, has been proposed as a route of metabolic activation for arylamine bladder carcinogens. It is postulated that the N-glucuronides are transported to the bladder lumen where they are hydrolyzed under slightly acidic conditions to release direct-acting carcinogenic and mutagenic N-hydroxyarylamines. In this study, 4-aminobiphenyl (ABP), 1-naphthylamine (1-NA), 2-naphthylamine (2-NA), 2-acetylaminofluorene (AAF), 4-nitrobiphenyl (NBP), benzidine (BZ), and N-acetylbenzidine (ABZ) were administered to male beagle dogs (60 mumole/kg), and the bladder epithelium DNA adducts were quantified at various times after treatment. At 24-48 hr after administration, the order of binding to bladder epithelium DNA was: ABP >> AAF > NBP congruent with 2-NA congruent withBZ congruent with ABZ >> 1-NA. The level of DNA modification by ABP remained constant for 7 days, whereas 2-NA and AAF residues decreased by 35% and 80%, respectively. The extent and relative persistence of total DNA binding correlated with the compounds' ability to induce bladder tumors in dogs. ABP, AAF, NBP, 2-NA and ABZ administration resulted in DNA binding sufficient for adduct analysis. Enzymatic hydrolysis of the DNA and examination of the adducts by high pressure liquid chromatography indicated that arylamine substitution at C8 of deoxyguanosine was the dominant product. Additional adducts were detected in animals treated with ABP, NBP, and 2-NA. Furthermore, the profiles of adducts obtained in vivo were remarkably similar to the profiles obtained when the N-hydroxy arylamine metabolites of these carcinogens were reacted with DNA in vitro at pH 5.0. To evaluate the mutagenic potential of these arylamine-DNA adducts, Salmonella typhimurium strains TA 1535 and TA 1538 were incubated with N-hydroxy-2-NA, N-hydroxy-2-aminofluorene (AF), N-hydroxy-ABP, and N-hydroxy-ABZ and the resulting DNA adducts and reversions were quantified. Arylamine-C8-deoxyguanosine substitution was correlated with frameshift reversions induced by these agents, with the lesions showing a relative order of mutagenic efficiency of ABZ>AF congruent with2-NA>ABP. These data suggest that mutagenic N-hydroxyarylamines may be ultimate carcinogens for the bladder epithelium. Furthermore, if one assumes that a mutagenic lesion is important for tumor initiation, then C8-deoxyguanosine substitution by these compounds may be significant for urinary bladder carcinogenesis.
Assuntos
Aminas/metabolismo , DNA/metabolismo , Mutagênicos , Neoplasias da Bexiga Urinária/induzido quimicamente , Aminas/toxicidade , Animais , Cães , Técnicas In Vitro , Masculino , Testes de Mutagenicidade , Neoplasias Experimentais/induzido quimicamente , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/metabolismoRESUMO
6-Nitrochrysene has previously been shown to be a potent lung and liver carcinogen following i.p. administration to newborn mice and to be metabolically activated to DNA-binding derivatives by nitro-reduction or a combination of nitro-reduction and ring oxidation. In this study, we have examined fecal metabolites and DNA-carcinogen adducts in 5-week-old conventional and germfree Balb/c mice treated with [3H]6-nitrochrysene in order to determine if the metabolic activation pathway(s) for this compound in these mice differs from that observed in preweanling mice. We further evaluated the role of the intestinal microflora on the metabolism and generation of DNA-reactive metabolites in this system. The amount of 6-aminochrysene excreted in the feces of germfree mice within 48 h after treatment with a single i.p. dose of [3H]6-nitrochrysene (0.03 mumol/5 microliters/g body wt) was approximately 25% of that excreted in identically treated conventional mice. However, the levels of carcinogen-DNA adducts in the lungs and livers of conventional and germfree Balb/c mice were similar at the 24 and 48 h time points examined. HPLC analysis of hydrolysates of liver and lung DNA indicated that adducts derived from both N-hydroxy-6-aminochrysene and trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene metabolites were formed in the liver whereas only the latter adduct was detected in the lung. This contrasts with previous findings in preweanling mice where the adduct derived from the trans-1,2-dihydroxy-1,2-dihydro-6-aminochrysene metabolite was the single major adduct detected in both liver and lung DNA. The proportion of adducts derived from N-hydroxy-6-aminochrysene was significantly greater in the liver DNA of germfree mice than in the liver DNA of conventional mice.
Assuntos
Carcinógenos/farmacocinética , Crisenos/farmacocinética , Proteínas de Ligação a DNA/metabolismo , Intestinos/microbiologia , Fenantrenos/farmacocinética , Animais , Biotransformação , Carcinógenos/metabolismo , Cromatografia Líquida de Alta Pressão , Crisenos/metabolismo , Proteínas de Ligação a DNA/análise , Fezes/análise , Inativação Metabólica , Mucosa Intestinal/metabolismo , Intestinos/análise , Fígado/análise , Pulmão/análise , Masculino , Camundongos , Camundongos Endogâmicos BALB C , OxirreduçãoRESUMO
Two-dimensional gel electrophoresis (2DG) has been used to study the changes induced in dog plasma polypeptides by the known urinary bladder carcinogens, 4-aminobiphenyl (4-ABP) and 2-naphthylamine (2-NA). Treatment with 3-aminobiphenyl (3-ABP) and 1-naphthylamine (1-NA), both considered to be non-carcinogenic, were used as controls. The purpose of this study was: (1) to determine whether or not changes that occurred in the plasma protein patterns were specific to 4-ABP and/or other related carcinogenic arylamines; (2) to measure the time course in the changes of the major polypeptides during dosing and their resynthesis during a recovery period; and (3) to determine, by microsequencing, the biochemical identity of the affected proteins. The results indicate that only the most potent carcinogen, 4-ABP, had the effect of suppressing the expression of some proteins, while the other aromatic amines caused no discernible change in the 2DG patterns during a 12-week dosing period. The 4-ABP caused dramatic suppression of two sets of proteins. One set of three spots had an apparent molecular weight of 32.5 kDa, and a pI of 5.8-6.0. The major component in this group was identified as the beta-chain of haptoglobin. Expression of this protein decreased markedly during the first 2 weeks of treatment and recovered slowly after dosing stopped. Since haptoglobin functions to bind with free hemoglobin and facilitates its elimination from the blood stream, these results can be rationalized as a consequence of 4-ABP binding to hemoglobin in the erythrocyte, resulting in cell death and hemolysis. The 4-ABP modified hemoglobin then binds to haptoglobin and this tertiary complex is purged from the blood stream, resulting in the disappearance of free haptoglobin. A second set of spots (mol. wt., 65 kDa; pI, 6.5-6.6) disappeared much faster than the haptoglobin, and recovered more quickly. The major protein is about one-fifth the intensity of haptoglobin and appeared to be N-terminally blocked. Internal microsequencing of four fragments obtained from tryptic cleavage of the major spot of this group showed significant similarity to the serum albumin sequence of several species. This spot group is not the major serum albumin spot, however, since the latter is readily identified as the most abundant spot on the plasma map. During the course of this study, several other polypeptides in the 2DG map of dog plasma were identified and are presented here.
Assuntos
2-Naftilamina/toxicidade , Aminas/toxicidade , Compostos de Aminobifenil/toxicidade , Proteínas Sanguíneas/metabolismo , Carcinógenos/toxicidade , 2-Naftilamina/administração & dosagem , Sequência de Aminoácidos , Compostos de Aminobifenil/administração & dosagem , Animais , Apolipoproteína A-I/sangue , Biomarcadores , Proteínas Sanguíneas/química , Simulação por Computador , Cães , Eletroforese em Gel Bidimensional , Feminino , Fibrinogênio/metabolismo , Haptoglobinas/química , Haptoglobinas/metabolismo , Humanos , Dados de Sequência Molecular , Peso Molecular , Albumina Sérica/química , Albumina Sérica/metabolismoRESUMO
The distribution and metabolism of the environmental pollutant 1-nitropyrene was studied in C57B1/6N mice following oral or intraperitoneal dosing. When administered by gavage, 1-nitropyrene and its metabolites demonstrated biphasic elimination kinetics from the blood, with half-lives of 0.3 and 1.8 days and a distribution volume of 74 ml. Intraperitoneal administration resulted in similar biphasic elimination, with half-lives of 0.5 and 3 days and a distribution volume of 98 ml. Treating pregnant C57B1/6N (C3H sire) mice by gavage resulted in similar absorption and elimination kinetics of 1-nitropyrene and metabolites, except that the distribution volume increased to 123 ml. 1-Nitropyrene and/or its metabolites (0.7% of the administered dose) crossed the placenta and accumulated in the fetuses and amniotic fluid, with both C-oxidized and nitroreduced metabolites being detected. Suckling neonates accumulated 1-nitropyrene and its metabolites when their dams were administered 1-nitropyrene by gavage. Each neonate received approximately 0.1% of the administered dose and demonstrated the presence of both C-oxidized and nitroreduced metabolites. These results demonstrate that this environmental pollutant is capable of crossing the placenta or mammary tissues to expose the offspring to a potentially genotoxic compound.
Assuntos
Glândulas Mamárias Animais/metabolismo , Mutagênicos/farmacocinética , Placenta/metabolismo , Pirenos/farmacocinética , Administração Oral , Líquido Amniótico/química , Animais , Animais Lactentes , Transporte Biológico , Análise Química do Sangue , Cromatografia Líquida de Alta Pressão , Feminino , Feto/metabolismo , Injeções Intraperitoneais , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos C57BL , Mutagênicos/administração & dosagem , Mutagênicos/toxicidade , Oxirredução , Gravidez , Pirenos/administração & dosagem , Pirenos/toxicidade , Espectrofotometria UltravioletaRESUMO
Fumonisin B1 is a mycotoxin produced by Fusarium moniliforme, a fungus that infects corn and other grains in the U.S. Fumonisin ingestion causes a variety of effects including equine leukoencephalomalacia and porcine pulmonary edema, and has been associated epidemiologically with human esophageal cancer. Fumonisin B1 produces growth inhibition and increased apoptosis in primary human keratinocyte cultures and in HET-1A cells. In order to set the doses for a 2-year tumor bioassay, male and female F344 rats were fed fumonisin B1 (99, 163, 234, and 484 ppm) for 28 days and the organs examined histologically. There was a dose dependent decrease in liver and kidney weights in the rats. The liver weight loss was accompanied by the induction of apoptosis and hepatocellular and bile duct hyperplasia in both sexes, with the female rats being more responsive at lower doses. The induction of tubular epithelial cell apoptosis was the primary response of the kidneys to dietary fumonisin B1. Apoptosis was present at all doses in the kidneys of the male rats, and occurred in the females only at 163, 234, and 484 ppm fumonisin B1. These results demonstrate that fumonisin B1 treatment causes a similar increase in apoptosis both in vivo and in vitro.