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A Bergman

Publications and source records attributed to A Bergman.

At least 73 records · Page 4Linked to original sources
PubMed1998

In vitro inhibition of thyroid hormone sulfation by polychlorobiphenylols: isozyme specificity and inhibition kinetics.

It was recently demonstrated by our laboratory that hydroxylated metabolites of polychlorinated biphenyls (PCB-OHs) are inhibitors of thyroid hormone sulfation. In this study, a more detailed investigation on sulfotransferase isozyme specificity and the kinetics of inhibition was performed. Thyroid hormone sulfation was determined using 3,3'-diiodothyronine (T2) as a substrate, and various sources of sulfotransferase (SULT) enzyme were used; e.g., female and male rat liver cytosol, male brain cytosol and cytosolic preparations of V79 cells transfected with rat SULT1C1, and human SULT1A1 and human SULT1A3. The inhibition pattern and IC50 values were very similar for male and female rat liver and rSULT1C1 and hSULT1A1. PCB-OHs were not able to inhibit the T2 sulfotransferase activity using hSULT1A3. Metabolite 3-hydroxy-2,3',4,4',5-pentachlorobiphenyl did not inhibit T2 sulfotransferase activity in male brain cytosol, while it was a very potent inhibitor in male and female rat liver cytosol. IC50 values for the tested PCB-OHs were not different with either T2 or 3,3',5-triiodothyronine (T3) as substrate, supporting the hypothesis that T2 is the preferred iodothyronine substrate for the sulfotransferases catalyzing the sulfation of the active hormone T3. The Lineweaver-Burk plot obtained with rat liver cytosol and T2 suggested that the nature of the T2 sulfation inhibition by 4-hydroxy-2',3,3',4',5-pentachlorobiphenyl is competitive. Finally, it was demonstrated that tested hydroxylated polychlorinated dibenzo-p-dioxins and biphenyls were, albeit poorly, sulfated by sulfotransferases as measured by the production of 35S-labeled metabolites.

Animals↗
PubMed1998

Waiting with and without recombination: the time to production of a double mutant.

R.A. Fisher and H.J. Muller argued in the 1930s that a major evolutionary advantage of recombination is that it allows favorable mutations to be combined within an individual even when they first appear in different individuals. This effect is evaluated in a two-locus, two-allele model by calculating the average waiting time until a new genotypic combination first appears in a haploid population. Three approximations are developed and compared with Monte Carlo simulations of the Wright-Fisher process of random genetic drift in a finite population. First, a crude method, based on the deterministic accumulation of single mutants, produces a waiting time of 1/square root of N mu(2) with no recombination and [formula: see text] with recombination between the two loci, where mu is the mutation rate, N is the haploid population size, and R is the recombination rate. Second, the waiting time is calculated as the expected value of a heterogeneous geometric distribution obtained from a branching process approximation. This gives accurate estimates for small values of N mu large. The estimates for small values of N mu are considerably lower than the simulated values. Finally, diffusion analysis of the Wright-Fisher process provides accurate estimates for N mu small, and the time scales of the diffusion process show a difference between R = 0 and for R >> 0 of the same order of magnitude as seen in the deterministic analysis. In the absence of recombination, accurate approximations to the waiting time are obtained by using the branching process for high N mu and the diffusion approximation for low N mu. For low N mu the waiting time is well approximated by 1/the square root of 8N2 mu(3). With R >> 0, the following dependence on N mu is observed: For N mu > 1 the waiting time is virtually independent of recombination and is well described by the branching process approximation. For N mu approximately equal to 1 the waiting time is well described by a simplified diffusion approximation that assumes symmetry in the frequencies of single mutants. For N mu << 1 the waiting time is well described by the diffusion approximation allowing asymmetry in the frequencies of single mutants. Recombination lowers the waiting time until a new genotypic combination first appears, but the effect is small compared to that of the mutation rate and population size. For large N mu, recombination has a negligible effect, and its effect is strongest for small N mu, in which case the waiting time approaches a fixed fraction of the waiting time for R = 0. Free recombination lowers the waiting time to about 45% of the waiting time for absolute linkage for small N mu. Selection has little effect on the importance of recombination in general.

Biological Evolution↗
PubMed1998

Microsatellite behavior with range constraints: parameter estimation and improved distances for use in phylogenetic reconstruction.

A symmetric stepwise mutation model with reflecting boundaries is employed to evaluate microsatellite evolution under range constraints. Methods of estimating range constraints and mutation rates under the assumptions of the model are developed. Least squares procedures are employed to improve molecular distance estimation for use in phylogenetic reconstruction in the case where range constraints and mutation rates vary across loci. The bias and accuracy of these methods are evaluated using computer simulations, and they are compared to previously existing methods which do not assume range constraints. Range constraints are seen to have a substantial impact on phylogenetic conclusions based on molecular distances, particularly for more divergent taxa. Results indicate that if range constraints are in effect, the methods developed here should be used in both the preliminary planning and final analysis of phylogenetic studies employing microsatellites. It is also seen that in order to make accurate phylogenetic inferences under range constraints, a larger number of loci are required than in their absence.

Bias↗
PubMed1998

In vitro inhibition of thyroid hormone sulfation by hydroxylated metabolites of halogenated aromatic hydrocarbons.

Earlier studies in our laboratory showed that hydroxylated metabolites of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) competitively inhibit thyroxine (T4) binding to transthyretin (TTR) and type I deiodinase (D1) activity. In this study, we investigated the possible inhibitory effects of hydroxylated metabolites of polyhalogenated aromatic hydrocarbons (PHAHs) on iodothyronine sulfotransferase activity. Rat liver cytosol was used as a source of sulfotransferase enzyme in an in vitro assay with 125I-labeled 3,3'-diiodothyronine (T2) as a model substrate. Increasing amounts of hydroxylated PCBs, PCDDs, or PCDFs or extracts from incubation mixtures of PHAHs and induced liver microsomes were added as potential inhibitors of T2 sulfotransferase activity. Hydroxylated metabolites of PCBs, PCDDs, and PCDFs were found to be potent inhibitors of T2 sulfotransferase activity in vitro with IC50 values in the low micromolar range (0.2-3.8 microM). The most potent inhibitor of T2 sulfotransferase activity in our experiments was the PCB metabolite 3-hydroxy-2,3',4, 4',5-pentachlorobiphenyl with an IC50 value of 0.2 microM. A hydroxyl group in the para or meta position appeared to be an important structural requirement for T2 sulfotransferase inhibition by PCB metabolites. Ortho hydroxy PCBs were much less potent, and none of the parent PHAHs was capable of inhibiting T2 sulfotransferase activity. In addition, the formation of T2 sulfotransferase-inhibiting metabolites of individual brominated diphenyl ethers and nitrofen as well as from some commercial PHAH mixtures (e.g., Bromkal, Clophen A50, and Aroclor 1254) was also demonstrated. These results indicate that hydroxylated PHAHs are potent inhibitors of thyroid hormone sulfation. Since thyroid hormone sulfation may play an important role in regulating free hormone levels in the fetus, and PCB metabolites are known to accumulate in fetal tissues after maternal exposure to PCBs, these observations may have implications for fetal thyroid hormone homeostasis and development.

Animals↗
PubMed1998

The efficacy of FP 736-04 in experimental liver cirrhosis.

PURPOSE: To determine whether the uptake of FP 736-04, a hepatocyte-specific CT contrast agent, is influenced by cirrhotic changes in the liver. MATERIAL AND METHODS: Liver cirrhosis was induced by bile duct ligation (BDL) in Sprague-Dawley rats. Seventy-four animals were divided into three groups comprising: rats with acute BDL; rats with chronic BDL; and normal controls. CT was performed after i.v. infusion of FP 736-04 or saline at a dose of 2 ml/kg b.w., and the mean attenuation in the liver and spleen was measured. The livers from the chronic BDL group were taken for histopathological examination and the extent of the disease was graded according to an arbitrary scale. RESULTS AND CONCLUSION: There was a significant reduction of the native liver attenuation in both chronic and acute BDL groups as compared with the normal controls. FP 736-04 was taken up by the liver parenchyma with a similar degree of enhancement in all three groups.

Animals↗
PubMed1998

Detecting experimental liver metastases at CT with the hepatocyte-specific contrast medium FP 736-03.

PURPOSE: To evaluate the detection of experimental hepatic metastases at CT with the hepatocyte-specific contrast medium FP 736-03. MATERIAL AND METHODS: A nude-rat model of experimental multiple hepatic metastases from a human colonic cancer was used. Three weeks after intraportal tumour cell injection, the CT examination was performed before and after i.v. injection of FP 736-03 at a dose of 0.5 ml/kg b.w. RESULTS: The overall detection rate was determined in a lesion-by-lesion analysis of 87 metastases. Irrespective of metastatic size, the mean detection rate for two viewers was significantly higher at the FP-736-03-enhanced examination (59%) than at the unenhanced CT examination (16%). CONCLUSION: The detection rate increased with the i.v. administration of FP 736-03 at a dose of 0.5 ml/kg b.w. compared with that at unenhanced examination.

Adenocarcinoma↗
PubMed1998

Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones.

The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 microM for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K(m) was 3.5 microM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 microM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.

Adrenal Cortex↗
PubMed1997

Selectivity of electron-donor- and electron-acceptor-bonded silica packing materials for hydrophobic environmental contaminants in polar and non-polar eluents.

Electron-acceptor-bonded stationary phases, 2-(nitrophenyl)ethylsilyl (NPE) and 3-(p-nitrophenoxy)propylsilyl (NPO), and electron-donor-bonded phases, 3-(N-carbazolyl)propylsilyl (CZP), 2-(1-pyrenyl)ethylsilyl (PYE), and 5-coronenylpentylsilyl (COP), were prepared from silica particles and their selectivities were examined in both polar and non-polar solvents for specific isomers of polychlorodibenzo-p-dioxins (PCDDs), hexachloronaphthalenes (HxCNs) and planar and non-planar polychlorobiphenyl (PCB) congeners. Although no single stationary phase was able to separate all the isomer pairs that are coproduced during the synthesis of the PCDDs and HxCNs, pairs can be separated by selecting a suitable stationary phase and solvent. The separation of mixtures of PCDD isomers were found to be most successful with PYE and NPO phases, which yielded the opposite elution orders for each isomer pair that is produced as a mixture. Similar results were obtained for the HxCN isomers that were separated on PYE and CZP phases. The COP phase provided easier separation of non-ortho-substituted and mono-ortho-substituted PCBs from the other PCBs based on the planarity than PYE phase.

Chromatography, High Pressure Liquid↗
PubMed1997

Subchronic toxicity of 2,2',3,3',4,4'-hexachlorobiphenyl in rats.

The subchronic toxicity of 2,2',3,3',4,4'-hexachlorobiphenyl (PCB 128) was investigated in rats following dietary exposure at 0, 0.05, 0.5, 5, or 50 ppm for 13 wk. The growth rate was not affected by treatment and no apparent clinical signs of toxicity were observed. There was a significant increase in liver weight in the 50 ppm females. The liver ethoxyresorufin deethylase (EROD) activity was increased by five- and fourfold in the highest dose males and females, respectively, while aminopyrine demethylase (ADPM) activity was significantly increased only in the highest dose females. Liver vitamin A was significantly reduced in the highest dose females. No other biochemical or hematological effects were observed. Treatment-related histopathological changes were seen in the thyroid and liver, and to a lesser extent in the bone marrow and thymus. Residue data showed a dose-dependent accumulation of PCB 128 in the following tissues: fat, liver, kidney, brain, spleen, and serum, with the highest concentration being found in fat followed by liver and kidney. Based on these data, the no-observable-adverse-effect level of PCB 128 was judged to be 0.5 ppm in diet or 42 micrograms/kg body weight.

Adipose Tissue↗
PubMed1997

Effects of four organohalogen environmental contaminants on cytochrome P450 forms that catalyze 4- and 2-hydroxylation of estradiol in the rat liver.

The four environmental pollutants studied (3,3',4,4',5-pentachlorobiphenyl, 2,2',4,4'-tetrabromodiphenyl ether, Tris-(p-chlorophenyl)methanol, and 3,4,5-trichloroguaiacol) were all found to induce a significant increase in 4-hydroxylation of estradiol activity in male rat liver microsomes. However, only 3,3',4,4',5-pentachlorobiphenyl was found to significantly increase 4- and 2-hydroxylation of estradiol in female rat liver microsomes. 4-Hydroxylation has been suggested to be responsible for the development of estrogen-dependent tumors and, therefore, it cannot be excluded that these pollutants can be a risk for the development of estrogen-dependent tumors in humans and wildlife.

Animals↗
PubMed1997

Hydroxylated polychlorinated biphenyl metabolites are anti-estrogenic in a stably transfected human breast adenocarcinoma (MCF7) cell line.

Hydroxylated metabolites of polychlorinated biphenyls (OHCBs) have been identified in blood of marine mammals, fish-eating birds, and humans at concentrations in some cases exceeding those of the unmetabolized polychlorinated biphenyls (PCBs). OHCBs have been associated with inhibition of vitamin A and thyroxin transport, estrogenicity in a mouse uterotrophic assay, and feminization of male turtle sexual development. OHCBs, representing both environmentally derived and laboratory exposure-derived metabolites, were tested in an in vitro bioassay utilizing an estrogen-responsive human breast adenocarcinoma cell line (MCF7-LUC) stably transfected with a luciferase reporter gene linked to estrogen responsive elements. OHCB activity was tested at three different media concentrations of 17beta-estradiol (E2), comparing the concentration-response curves using charcoal-stripped medium (0.0009 nM E2), and two physiologically relevant E2 concentrations (0.1 and 1.0 nM E2). Eleven of 13 OHCBs tested were anti-estrogenic. Evidence for an estrogen receptor mediated mechanism of action was apparent for only two OHCBs-4-OH-2',3,3',4',5,5'-Cl6-biphenyl and 4,4'-(OH)2-3,3',5,5'-Cl4-biphenyl. These two have not been identified in environmental samples. The remaining OHCBs exhibited "anti-estrogenicity" that was related to their effect on cell viability and, therefore, cannot be described as exhibiting "hormone disruption" solely by an estrogen receptor mediated mechanism. OHCB anti-estrogenic activity was eliminated in the presence of E2 concentrations normally found in humans, except for 4,4'(OH)2-3,3',5,5'-Cl4-biphenyl. 4-OH-2',3',4',5'-Cl4-biphenyl and 4-OH-2',4',6'-Cl3-biphenyl were partial estrogen agonists, exhibiting weak estrogenicity in the presence of 0.0009 nM E2 and weak anti-estrogenicity in the presence of 0.1 and 1 nM E2. Human metabolites of PCBs were not estrogenic in MCF7 cells.

Adenocarcinoma↗
PubMed1997

Effects of tris(4-chlorophenyl)methanol on the rat following short-term oral exposure.

The systemic toxicity of tris(4-chlorophenyl)methanol (TCPM) was studied in male and female rats following 4 weeks dietary exposure dosed at 1, 10 and 100 ppm. An increased spleen to body weight ratio was observed in males at 10 and 100 ppm and in females at 100 ppm. An increased liver to body weight ratio was detected in both sexes at 100 ppm. Dose-related increases in hepatic Phase-I (AH, APDM, EROD and PROD) and Phase-II (UDPGT, GST) enzyme activities were observed generally at 10 and 100 ppm, with the elevation in PROD activity being the most marked. Increased urinary ascorbic acid was detected in both males and females after 1 week of treatment at 100 ppm and after 4 weeks of treatment at 10 and 100 ppm. At 10 and 100 ppm, elevated % lymphocytes were found in males, and higher white blood cell and lymphocyte counts were observed in females. In the liver, mild to moderate cytoplasmic changes consistent with proliferation of smooth endoplasmic reticulum were present in rats of both sexes at 10 and 100 ppm, and increased number of hepatocytes undergoing apoptosis were observed in male rats at 100 ppm. Mild splenic changes consisting of sinus hyperplasia in males and females at 100 ppm and mantle zone atrophy in males at 100 ppm were also observed. It was concluded that TCPM at a dietary concentration of 10 ppm (equivalent to 1.2 mg/kg/day) produced systemic changes in rats that included various hepatic effects, increased splenic weight, and modulations in white blood cells and lymphocyte counts.

Administration, Oral↗
PubMed1997

Relationship between contrast enhancement and diagnostic accuracy with the liver-specific CT contrast medium FP 736-04 in an experimental model of liver metastases.

RATIONALE AND OBJECTIVES: The authors sought to establish the optimal level of liver enhancement at computed tomography (CT) with a hepatocyte-specific contrast medium in an experimental model of liver metastases. MATERIALS AND METHODS: Anesthetized nude rats (n = 18) injected intraportally with cells from human colonic adenocarcinoma and Sprague-Dawley rats (n = 11) without metastases were used. A fractional intravenous infusion of contrast material was given in escalating doses up to a total of 4.0 mL per kilogram of body weight. Mean attenuation of the liver was calculated for each accumulated dose, and the overall detection rate was determined on a lesion-by-lesion basis. Sensitivity, specificity, and positive and negative predictive values were also established for each dose. RESULTS: Liver metastases were diagnosed with increasing reliability for enhancement values of up to 30.0 HU +/- 5.2 (mean +/- standard deviation), which corresponded to a dose of 0.5 mL/kg. CONCLUSION: In this model, optimal reliability in the diagnosis of liver metastases with CT was achieved at an enhancement value of approximately 30 HU.

Adenocarcinoma↗
PubMed1997

An iodinated lipid emulsion for CT of the liver. Comparison with iohexol in the detection of experimental hepatic metastases.

PURPOSE: The iodinated hepatocyte-specific lipid emulsion FP 736-03 for CT of the liver was tested against the conventional water-soluble contrast agent iohexol. MATERIAL AND METHODS: A nude rat model of experimental multiple hepatic metastases from a human colonic cancer was used. The animals were examined 3 weeks after intraportal tumor cell injection. Native examination, and iohexol- and FP-736-03-enhanced CT were performed. The detection rate was determined on a lesion-by-lesion basis. Metastatic diameters measured on CT images were compared with corresponding macroscopic serial liver specimens. RESULTS: In a lesion-by-lesion analysis of 140 metastases, the detection rates for 2 viewers were 16.4% and 30.7% for native examination, 12.9% and 17.9% for iohexol-enhanced CT, and 53.6% and 72.1% for FP-736-03-enhanced CT, respectively. The detection rates tended to increase with lesion diameter. CONCLUSION: The hepatocyte-specific contrast medium FP 736-03 improved the detection rate significantly in comparison with both native and iohexol-enhanced CT.

Animals↗
PubMed1997

CT of experimental hepatoma using the hepatocyte-specific lipid emulsion FP 736-03.

PURPOSE: The aim of the study was to investigate whether moderately to well differentiated hepatocellular carcinomas (HCC) possess the same ability to take up a new lipid emulsion contrast medium, FP 736-03, as do hepatocytes. MATERIAL AND METHODS: A rat model of an experimental HCC was used. CT was performed before and after an i.v. bolus injection of 1.0 ml FP 736-03/kg b.w. Attenuation values of normal liver parenchyma and tumour tissue were measured over time. RESULTS: The contrast medium was taken up by the normal liver parenchyma but not by the tumour tissue for which the attenuation remained virtually constant over the observation period. CONCLUSION: The study demonstrated that FP 736-03 was not taken up by the HCC, thus producing a high lesion-to-liver contrast.

Animals↗