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Biomedical subjects

L Möller

Publications and source records attributed to L Möller.

51 records · Page 3Linked to original sources
PubMed1993

Human sperm motility is affected by plasticizers and diesel particle extracts.

In order to test various drugs and possibly hazardous compounds on living cells in vitro a system with human spermatozoa was employed. A population of human spermatozoa was transferred into a defined medium by a swim-up procedure or by separation on a Percoll gradient. Such a population is rather homogenous with respect to motility characteristics and was found to be useful for this purpose. Different modes of response were recorded, indicating various effect mechanisms. Effects of various phthalates used as plastic softeners in the production of medical equipment, and extracts from diesel particulate material were recorded. All these compounds interfered with sperm motility in a dose-response fashion. Immediate effects of phthalates were modest, but upon prolonged exposure effects became more evident. Sperm motility was more affected by diethyl-hexyl and dibutyl phthalates. Significant effects were noted for the different phthalates with regard both to percent motility and to some of the various qualities of motility, such as velocity, linearity and amplitude of the track. Thus, the pattern of response considering the motion variables was not the same with the different phthalates. With regard to the effects on sperm motion di-n-octyl phthalate seemed to be the least toxic, followed by dibutyl phthalate. The initial effects of diesel particulate extracts were moderate and mainly restricted to percent motile sperm but upon exposure for 18 hr the effects became more pronounced for all the movement variables.

Adult↗
PubMed1993

Nitrated polycyclic aromatic hydrocarbons: a risk assessment for the urban citizen.

Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) are formed during incomplete combustion. Sources include emissions from vehicles (mainly diesel vehicles), heating, smoking, certain types of food processing, and incomplete combustion in general. Nitro-PAHs are direct-acting mutagens, and a number of them have been shown to be carcinogens. 2-Nitrofluorene (NF) represents a model substance for the nitro-PAHs. An attempt has been made to calculate the human cancer risk due to exposure to nitro-PAHs by two different models. In the first model, genotoxic lesions were transferred to units of Gray (gamma-irradiation), and in the second model a mega study (24,000 animals) on the carcinogenicity of one metabolite of NF was used to elucidate the risk. Gamma-irradiation of the rat liver gave rise to preneoplastic foci in a dose-dependent manner, which was statistically significant. The Gray-equivalents of chemically (NF) induced foci were calculated, and from the human nitro-PAH exposure, expressed in Sievert, a human risk estimate was calculated. In the second model, an extrapolation from laboratory animals to man was performed because tumor data on 2-acetylaminofluorene (AAF), a major metabolite of NF, were available in the literature. The tumor dose-response data on AAF was linear for tested lifetime doses. The results of both models agreed, with a risk range of 0.15-49 x 10(-6) on human cancer risk for an urban citizen.

Animals↗
PubMed1990

2-Nitrofluorene metabolism in the rat lung. Pharmacokinetic and metabolic effects of beta-naphthoflavone treatment.

Absorption, metabolism and DNA binding of 2-nitrofluorene (NF) was studied in isolated, perfused and ventilated rat lungs and in lung microsomal incubations. Comparisons were made between control animals and animals treated with beta-naphthoflavone (BNF), a 2,3,7,8-tetrachlorodibenzo(rho)dioxin (TCDD) receptor ligand and inducer of cytochrome P450IA1. Clearance of NF increased significantly in the isolated, perfused and ventilated lungs after BNF dosage, from 0.55 +/- 0.06 ml/min to 2.37 +/- 0.62 ml/min (P less than 0.05, n = 5-6). As a consequence of this, the mean residence time (MRT) for NF decreased when NF was dosed directly to the perfusion buffer, from 213 +/- 23 min (n = 6) to 48 +/- 9 min (n = 6), and after intratracheal dosage from 289 +/- 101 min (n = 5) to 135 +/- 72 min (n = 5). Irreversible binding of NF metabolites to DNA increased 2-fold after treatment with BNF when NF was dosed to the lung perfusion buffer. Treatment with BNF increased the rate of lung microsomal NF metabolism significantly, from 54 +/- 5 to 106 +/- 11 pmol/min/mg protein (P less than 0.05, n = 6-12). Formation of the monohydroxylated metabolite X-OHNF was inhibited in vitro by addition of alpha-naphthoflavone (50 microM), by 89 and 98% with lung microsomal fractions from control and BNF-treated rats respectively. In contrast, proadifen (50 microM) preferentially inhibited formation of 9-OHNF, by 42 and 33% in incubations with lung microsomal fractions from control and BNF-treated animals. Anti-P450IIB1-IgG inhibited formation of 9-OHNF by 96 and 45% with lung microsomes from control and BNF-treated rats respectively. Formation of X-OHNF was unaffected by addition of anti-P-450IIB1-IgG in both cases. These results show that both constitutive and inducible microsomal rat lung enzymes metabolize NF. A constitutive enzyme, most likely cytochrome P450IIB1, catalyzes metabolic attack on NF with high preference for the 9-position. A BNF-inducible microsomal enzyme, most likely cytochrome P450IA1, catalyzes hydroxylation of NF both in the 9-position and in other positions. Increased metabolic clearance, metabolism and DNA binding of NF after BNF treatment suggest that the level and specificity of cytochrome P450 isozymes may be important determinants for toxicity and availability of NF in the rat lung.

Absorption↗
PubMed1989

The air pollutant 2-nitrofluorene as initiator and promoter in a liver model for chemical carcinogenesis.

2-Nitrofluorene (NF), a model substance for nitrated polycyclic aromatic hydrocarbons, is present in exhaust from diesel- and petrol-driven vehicles, in exhaust from kerosene heaters, and in urban air and river sediments. Therefore the possible consequences of human exposure are important to elucidate. In the present study the initiating and promoting activity of NF was studied in a liver model for chemical carcinogenesis in the rat. Furthermore, the in vivo metabolism and formation of genotoxic metabolites of NF were investigated. NF was found to be a moderate initiator and a weak promoter when compared to diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) respectively, both of which are potent carcinogens. Animals given NF excreted more urinary mutagenicity when compared to animals given AAF or DEN.

2-Acetylaminofluorene↗
PubMed1989

Distribution and regulation of 5 alpha-androstane-3 beta,17 beta-diol hydroxylase in the rat central nervous system.

5 alpha-Androstane-3 beta,17 beta-diol hydroxylase (3 beta-diol OHase), a form of cytochrome P-450 whose main function is thought to be the elimination of dihydrotestosterone (DHT) from its target tissues, was found in the central nervous system (CNS) of both male and female rats at a level which is at least 300-fold higher than any other P-450 catalyzed steroid hydroxylase in the brain. In order to gain some insight into the physiological function of this enzyme we have studied its distribution throughout the CNS as well as the effects of age and hormonal manipulations of rats. We have also partially purified the enzyme from the brain and compared it with the 3 beta-diol OHase in the prostate. 3 beta-Diol OHase activity was distributed throughout the CNS of adult male and female rats with levels between 70-153 nmol products formed/g tissue.h. The products were identified as 5 alpha-androstane-3 beta,7 beta,17 beta-triol,5 alpha-androstane-3 beta,6 alpha,17 beta-triol and 5 alpha-androstane-3 beta,7 alpha,17 beta-triol. The ratio of these three triols was 1:9:3. Catalytic activity was not affected by castration or adrenalectomy of male rats, or during late pregnancy or lactation in females. In the brains of 14-day-old fetuses and 2-day-old rats, the level of 3 beta-diol OHase was 30% of that of adults and it increased to adult levels by day 28. Cytochrome P-450 was partially purified from microsomes of whole brain, hypothalamus, and prostate and 3 beta-diol OHase activity reconstituted. On the basis of the ratios of the three triols formed from 3 beta-diol, it can be concluded that the 3 beta-diol OHase in the brain is similar to that in the prostate. From a comparison of the turnover numbers in reconstituted systems with P-450 prepared from the prostate, brain, and hypothalamus, it can be estimated that up to 50% of the P-450 in the hypothalamus and 10% in whole brain is 3 beta-diol OHase. Supportive evidence for this relative distribution of 3 beta-diol OHase in the hypothalamus was obtained by comparing the sodium dodecyl sulfate electrophoretic profiles of P-450 obtained from the hypothalamus and prostate microsomes.

Adrenalectomy↗
PubMed1988

Age dependent expression of cytochrome P-450b and metabolism of the potent carcinogen 2-nitrofluorene in the rat lung.

Northern and Western blot analyses, and analyses of microsomal metabolism of the carcinogen 2-nitrofluorene (NF) were conducted with the aim of studying age dependent cytochrome P-450b levels in the rat lung. The level of P-450b homologous mRNA and corresponding protein is very low in lungs from fetal and newborn rats. The levels then increase between 3 and 4 weeks of age, and reach adult levels at 6-8 weeks. No sex differences were detected with regard to lung P-450b mRNA levels or catalytical activities. Lung microsomal metabolism of NF increased in parallel with the accumulation of P-450b homologous mRNA and microsomal cytochrome P-450b protein concentration. Formation of the major metabolite, and potent mutagen, 9-hydroxy-2-nitrofluorene (9-OHNF) was significantly inhibited by addition of polyclonal anti-P-450b-IgG, and by addition of the inhibitor proadifen to incubations with lung microsomal protein. It is postulated that the observed, profound age-related differences in level and activity of lung cytochrome P-450b are likely to affect both availability and the ratio of metabolic detoxification and activation of chemical carcinogens deposited in the lung.

2-Acetylaminofluorene↗
PubMed1988

The role of the intestinal microflora in the formation of mutagenic metabolites from the carcinogenic air pollutant 2-nitrofluorene.

After a single oral dose of 2-nitro[9-14C]fluorene (NF) to germfree and conventional rats, radioactivity with associated mutagenic activity was rapidly excreted in both urine and feces. The mutagenicity excreted from germfree animals exceeded the mutagenicity excreted from conventional animals. Absence of the microflora resulted in lack of nitroreduction and excreted metabolites from germfree rats were mono- or dihydroxylated nitrofluorenes, as assessed by liquid chromatography/mass spectrometry (LC/MS). These hydroxy-NFs were associated with the high direct-acting mutagenicity that was excreted in germfree animals. Only traces of NF were found in urine from germfree rats and no NF was detected in urine from conventional animals. Thus, in contrast to a number of reports on other mutagenic compounds, these results would tend to indicate that the intestinal microflora causes a reduced excretion of mutagenic metabolites of NF.

Air Pollutants↗
PubMed1988

Correlation between induction of unscheduled DNA synthesis in the liver and excretion of mutagenic metabolites in the urine of rats exposed to the carcinogenic air pollutant 2-nitrofluorene.

The genotoxic effects of 2-nitrofluorene (NF) have been studied in vivo by measuring the induction of DNA repair, i.e. unscheduled DNA synthesis (UDS), in hepatocytes from male rats pretreated by oral gavage with NF. During the NF exposure, urine was collected for 24 h, and its mutagenicity was investigated in the plate incorporation assay, using Salmonella TA98 as tester strain. The urine samples were also used for the identification of excreted metabolites of NF. Rats treated with 2-acetylaminofluorene (AAF) were studied simultaneously. A positive UDS response was observed 12 and 24 h following a single gavage exposure to 12.5, 25 and 50 mg/kg NF, with the response returning to near control levels by 36 h. The positive control AAF induced approximately twice the response observed with NF, and both compounds gave a UDS response that was 2-3 times higher in Wistar rats relative to Sprague-Dawley rats. A potent direct-acting mutagenic effect was observed in urine samples after NF treatment, while AAF exposure only gave rise to a weak mutagenic effect, the NF/AAF ratio being 10/1. The stronger urinary mutagenicity after NF treatment relative to AAF treatment was associated with the presence of hydroxylated NFs. The genotoxic effect observed in the liver after NF treatment is, on the other hand, more likely due to the same AAF metabolites that are also formed after in vivo treatment with AAF.

2-Acetylaminofluorene↗
PubMed1987

Metabolism of the carcinogenic air pollutant 2-nitrofluorene in the isolated perfused rat lung and liver.

The metabolism of 2-nitrofluorene (NF), a model substance for nitrated polycyclic aromatic hydrocarbons, was studied in the isolated perfused rat lung and liver. NF has been identified in urban air and diesel exhaust and occurs in the gas, as well as in the particulate phase. Therefore, it is conceivable that the lung represents one point of entry of this compound into the body. The lung metabolizes NF to hydroxylated NFs, mainly 9-hydroxy-NF, independently of the route of administration (intravascular or intratracheal). After intratracheal administration, NF is rapidly excreted into the perfusate, indicating that other organs might be exposed to unmetabolized NF. The liver excretes NF metabolites as biliary glucuronides. Untreated bile is not mutagenic. However, after beta-glucuronidase treatment of bile, direct-acting mutagens were detected. The mutagenic metabolites in beta-glucuronidase-treated bile were the same as identified in the perfusate of the isolated lung. Since beta-glucuronidase is an enzyme found in the human intestinal microflora, inhalation of NF could result in the liberation of genotoxic metabolites in the colon.

Air Pollutants↗
PubMed1987

Metabolism of the carcinogenic air pollutant 2-nitrofluorene in the rat.

After a single oral dose of 2-nitro [9-14C]fluorene to rats, radioactivity with associated mutagenic activity was rapidly excreted in both urine and faeces, urine being the major excretory route. The major part of the urinary mutagenicity was associated with the unconjugated fraction of metabolites which consisted of a range of hydroxylated acetylaminofluorenes in addition to a number of hydroxylated nitrofluorenes. The formation of hydroxylated acetylaminofluorenes supports the contention that 2-nitrofluorene, in vivo, enters the metabolic pathway of the well-known carcinogen 2-acetylaminofluorene. The single most mutagenic metabolite of 2-nitrofluorene was a hydroxylated nitrofluorene; the formation of this metabolite was markedly increased when the rats had been treated with beta-naphthoflavone. Finally, an alternative pathway is discussed for the formation of 1- and 3-hydroxyacetylaminofluorenes.

2-Acetylaminofluorene↗
PubMed1986

Liquid chromatographic-mass spectrometric analysis of 2-nitrofluorene and its derivatives.

Liquid chromatography-mass spectrometry (LC-MS) with a nebuliser and a moving belt was used to characterise 2-nitrofluorene, its metabolites and related compounds. In total, 13 different compounds were analysed. The LC-MS interface did not affect the chromatographic performance achieved by high performance liquid chromatography (HPLC). The method allowed determination of the positions of the hydroxyl groups in different hydroxylated 2-acetylaminofluorene derivatives. The LC-MS procedure generated acceptable mass spectra with as small amounts of substance as 65 ng. The dose-response curves from the HPLC-detector and the ion-source in the LC-MS were parallel and linear.

Chromatography, High Pressure Liquid↗