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Biomedical subjects

H Bartsch

Publications and source records attributed to H Bartsch.

461 records · Page 26Linked to original sources
PubMedDate not supplied

Validation and application of a rapid in vitro assay for assessing the estrogenic potency of halogenated phenolic chemicals.

The E-Screen assay serves as an in vitro tool for the detection of estrogenic activity of chemicals and extracts of environmental samples. Based on the induction of proliferation in human estrogen receptor-positive MCF-7 breast cancer cells we could substantially simplify the assay. As one important step of validation we applied the modified assay for testing nine known xenoestrogens. We could confirm the results of other groups assuring the reproducibility of the E-Screen assay. The results provide evidence that the E-Screen assay is suitable for determination of estradiol equivalency factors (EEFs) for environmental estrogens to rank their estrogenic potency relative to the natural estrogen 17 beta-estradiol. Further, we used the optimized proliferation test to screen nine halogenated phenolic compounds for their possible estrogenic potency. Three widely applied chemicals expressed a weak receptor-mediated estrogenic activity: the flame retardant Tetrabromo-Bisphenol-A, the disinfectant 4-chloro-3-methylphenol, and the herbicide educt 4-chloro-2-methylphenol. Their estrogenic potencies were five to six orders of magnitude lower than that of 17 beta-estradiol.

Biological Assay↗
PubMedDate not supplied

Analysis of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine in rat and human tissues by alkaline hydrolysis and gas chromatography/electron capture mass spectrometry: validation by comparison with 32P-postlabeling.

A sensitive and specific method has been developed to measure levels of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) adducted to DNA in tissues. The method is based on alkaline hydrolysis of PhIP from DNA, followed by organic solvent extraction, derivatization to form the electron-capturing bis(pentafluorobenzyl) derivative, and analysis by gas chromatography/electron capture mass spectrometry (GC/MS) using a deuterium-labeled internal standard. The method can detect PhIP-DNA adducts at levels down to 0.03 fmol of PhIP/micrograms of DNA (1 PhIP adduct/10(8) normal nucleotides) for a 100 micrograms sample of DNA. The method is reproducible for sample sizes ranging up to at least 1000 micrograms of DNA. A series of 20 DNA samples from 5 tissues of rats treated with a single oral dose of PhIP were analyzed both by alkaline hydrolysis-GC/MS and by 32P-postlabeling. Results from the two methods were highly correlated (r2 = 0.83), with adduct levels determined by alkaline hydrolysis-GC/MS averaging about 60% of the levels determined by 32P-postlabeling. A pilot survey of 24 individual human tissue DNA samples, including pancreas (n = 12), colon mucosa (n = 6), and urinary bladder epithelium (n = 6), was carried out by alkaline hydrolysis-GC/MS and 32P-postlabeling. Both methods provided evidence for PhIP-DNA adducts in two of the colon samples, but not in the samples from human pancreas or urinary bladder.

Animals↗
PubMedDate not supplied

New ultrasensitive 32P-postlabelling method for the analysis of 3,N4-etheno-2'-deoxycytidine in human urine.

Etheno-DNA adducts are generated from exogenous carcinogens such as vinyl chloride and urethane and also from endogenous lipid peroxidation products such as trans-4-hydroxy-2-nonenal (HNE). The present authors and others have established that 1,N6-ethenodeoxyadenosine (epsilondA) and 3,N4-ethenodeoxycytidine (epsilondC) are present in human urine and could be explored as biomarkers for monitoring whole-body oxidative stress. The present study reports on a new ultrasensitive 32P-postlabelling/thin-layer chromatography (TLC) method for the analysis of epsilondC as deoxynucleoside in human urine. The urine samples were purified and enriched on a solid-phase silica C-18 column followed by a semi-preparative reverse-phase high-performance liquid chromatography. The purified sample was labelled with a multisubstrate deoxyribonucleoside kinase from Drosophila melanogaster (Dm-dNK) in the presence of 5'-bromo-2'-deoxyuridine (BrdU) as internal standard. The absolute sensitivity of the method was 0.1 fmol epsilondC detectable in 500 microl of human urine. The analysis of human urine samples from 15 healthy volunteers revealed a mean epsilondC level of 2.49+/-1.76 (SD) fmol micromol-1 creatinine (range 0.66-6.42). By this non-invasive method, epsilondC in human urine could be explored as a biomarker for oxidative stress-related human diseases.

Animals↗
PubMedDate not supplied

Serial transplants of 7,12-dimethylbenz[a]anthracene-induced mammary tumors in Fischer rats as model system for human breast cancer. 3. Quantitative ultrastructural studies of the pinealocytes and plasma melatonin concentrations in rats bearing an advanced passage of the tumor.

The aim of the present study was to investigate the ultrastructure of pinealocytes and plasma melatonin concentrations in Fischer rats bearing an advanced (14th) passage 7,12-dimethylbenz[a]anthracene-induced mammary tumor. Quantitative ultrastructural analysis of the cell size and relative volumes of various cell organelles as well as the number of dense-core vesicles was performed in pinealocytes of the animals killed either during the daytime (15.00 h) or at night (3.00 h) 1 month after tumor transplantation. No significant differences between control and tumor-bearing animals were observed either during the daytime or at night. However, plasma melatonin concentrations in tumor-bearing rats killed at 3.00 h were suppressed by 35% (p < 0.025) when compared to the control animals killed at the same time.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Serial transplants of DMBA-induced mammary tumors in Fischer rats as model system for human breast cancer. IV. Parallel changes of biopterin and melatonin indicate interactions between the pineal gland and cellular immunity in malignancy.

Nocturnal (23.00-07.00 h) urinary melatonin and total biopterin (tBI; after acidic oxidation of reduced biopterins) were analyzed during the growth of two passages of a mammary tumor line in female F344 Fischer rats. In addition, nocturnal (02.00-03.00 h) peak concentrations of pineal melatonin in plasma were analyzed when tumors had reached comparable average tumor volumes of 25-30 cm3. Since tetrahydrobiopterin (BH4) is produced by murine macrophages in response to interferon-gamma released by activated T lymphocytes, measurements of tBI can serve to estimate the state of cellular immunity. At passage 2, a slow-growing localized carcinosarcoma, tBI showed a progressing increase during tumor growth reaching more than 200% (p < 0.05-0.005) of controls by the end of the experiment. Urinary and plasma melatonin were elevated by 30-50% (p < 0.05) and 42% respectively. At passage 12, a fast-growing metastasizing sarcoma, a depression of about 20-30% was found for tBI (p < 0.05) and urinary melatonin (p < 0.025); plasma melatonin was depleted by 70% (p < 0.005). Parallel changes of both parameters at each tumor passage indicate a close link between the pineal hormone melatonin and cellular immunity. The opposite trends observed at the two passages indicate a clear stimulation of the immune system and the pineal gland at early but inhibition at advanced stages of cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Detection of carcinogen-DNA adducts in exfoliated urothelial cells of cigarette smokers: association with smoking, hemoglobin adducts, and urinary mutagenicity.

The presence of covalent modifications in DNA obtained from exfoliated urothelial cells of smokers and nonsmokers was determined using 32P postlabeling methods. Urine and blood samples were procured from 73 persons. Cells were removed from the urine by filtration. DNA was isolated using an enzyme-solvent extraction method and then coprecipitated with glycogen. Sufficient DNA to detect 1 carcinogen-DNA adduct/10(9) normal nucleotides was obtained from 40 of the 73 samples. DNA was hydrolyzed to 3'-phosphodeoxynucleotides and then 32P postlabeled under conditions of excess [32P]ATP. Carcinogen-DNA adducts were resolved using anion-exchange thin-layer chromatography and visualized by autoradiography; film exposures lasted as long as 7 days. Twelve different carcinogen-DNA adducts and a diagonal zone of radioactivity could be found, but no sample contained all adducts. At least four adducts appeared to be cigarette smoking related. These adducts were from 2 to 20 times higher in the smokers than the nonsmokers. Two carcinogen-DNA adducts were qualitatively very similar to adducts described earlier in a study of human bladder biopsies. One of these corresponded to N-(deoxyguanosin-8-yl)-4-aminobiphenyl. Adducts were correlated significantly with the levels of 4-aminobiphenyl hemoglobin adducts and number of cigarettes smoked. In addition, levels of the putative N-(deoxyguanosin-8-yl)-4-aminobiphenyl adduct and a measure of total adducts were correlated with the mutagenic activity of the individual's urine. These data suggest that noninvasive, biological monitoring techniques can be applied to the study of carcinogen-DNA adducts in humans at high risk for bladder cancer.

Aminobiphenyl Compounds↗
PubMedDate not supplied

Interstrain comparison of hepatic and renal microsomal carcinogen metabolism and liver S9-mediated mutagenicity in DA and Lewis rats phenotyped as poor and extensive metabolizers of debrisoquine.

Lewis (extensive metabolizers) and DA (poor metabolizers) rat strains show genetic polymorphism for the gene regulating debrisoquine 4-hydroxylation in a manner analogous to human drug polymorphism and show also a different toxicological response to aflatoxin B1. In order to investigate the underlying mechanism(s) of the different drug-metabolizing capacities, the in vitro metabolism and liver S9-mediated mutagenicity of several drugs and carcinogens were studied in female Lewis and DA rat strains, using untreated, 3-methylcholanthrene-treated, and phenobarbital-treated animals. S9-mediated mutagenicity of aflatoxin B1 and hepatic and renal ochratoxin A 4-hydroxylase activity were much lower in DA rats; however, the activity of a number of other hepatic and renal drug-metabolizing enzymes did not show any interstrain difference. Slight strain differences were found in the inducibility of several hepatic drug-metabolizing enzymes, except for ochratoxin A 4-hydroxylase activity; the latter was inducible only by 3-methylcholanthrene in the DA strain and appeared to be linked genetically with other Ah locus-associated monooxygenases. Our data suggest that ochratoxin A 4-hydroxylase activity, which is low in the DA strain, is catalyzed by a cytochrome P-450 isozyme different from that responsible for debrisoquine 4-hydroxylation. Our results provide some insight into why the two metabolic oxidation phenotypes show different susceptibility to cancer induction and to the toxicity of certain environmental carcinogens, such as aflatoxin B1 and ochratoxin A.

2-Acetylaminofluorene↗
PubMedDate not supplied

In vivo nitrosoproline formation and other risk factors in Costa Rican children from high- and low-risk areas for gastric cancer.

The hypothesis that intragastric synthesis of N-nitroso compounds (NOC) in early life could play a role in gastric carcinogenesis was tested by applying the N-nitrosoproline (NPRO) test to about 50 children living in high- and low-risk areas for stomach cancer in Costa Rica. The median values of excretion of NPRO and the sum of three nitrosamino acids (micrograms/12 h urine) were 10-20% of those in adults from other geographical high-risk areas for stomach cancer. The urinary NPRO level after proline intake was higher in children from the high-risk area (P < 0.04) and markedly reduced after ingestion of ascorbic acid together with proline (P < 0.05). NPRO levels on the day of proline intake were highly correlated with levels of nitrate excretion (P < 0.001). Mean levels of total NOC in an aqueous (pH 2) extract of cooked beans from the high- and low-risk areas were similar. Acid-catalyzed nitrosation of the extract increased the total NOC concentration up to 1000-fold, but there was no difference between samples from the two areas. About 10% of bean extracts from both areas showed weak direct-acting genotoxicity in Escherichia coli; after acid-catalyzed nitrosation, all samples were genotoxic at similar levels. The diet of children in the low-risk area satisfied recommended levels of intake of energy and most nutrients except riboflavin and retinol equivalents. Diets from the high-risk area were deficient in energy intake and all nutrients except protein and vitamin C.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Urinary excretion of nitrosamino acids and nitrate by inhabitants of high- and low-risk areas for nasopharyngeal carcinoma in southern China.

The hypothesis that endogenous synthesis of nitrosamines from dietary precursors is a risk factor for nasopharyngeal carcinoma (NPC) in China was tested by applying the nitrosoproline (NPRO) test to subjects living in high- and low-risk districts for NPC in Zangwu county, Guangxi region, in southern China. Samples of 12-h urine were collected from 77 subjects: (a) before any treatment; (b) after ingestion of proline; and (c) after ingestion of proline together with vitamin C. NPRO, other nitrosamino acids, and nitrate were measured as indices of exposure to preformed and endogenously formed nitrosamines or their precursors. The NPRO level after proline intake was significantly increased in subjects from the high-risk area (P = 0.012) and markedly reduced after ingestion of ascorbic acid (P = 0.007), but such an effect was not seen in subjects from the low-risk area. Levels of N-nitrosothiazolidine-4-carboxylic acid and the sum of nitrosamino acids in subjects in the high-risk area were significantly reduced by ascorbic acid (P < 0.01) but were not reduced in subjects from the low-risk area. The urinary nitrate level was about twice as high in subjects from the high-risk area. In subjects from high- and low-risk areas combined, NPRO levels in any of the three dose groups were highly correlated with nitrate levels (P = 0.0001). These results demonstrate a higher potential for endogenous nitrosation in subjects living in the high-risk area of NPC and suggest the occurrence of nitrosation inhibitors in the diet consumed in the low-risk area.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗