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Biomedical subjects

M Sorsa

Publications and source records attributed to M Sorsa.

At least 37 records · Page 2Linked to original sources
PubMed1995

Influence of GSTM1 genotype on sister chromatid exchange induction by styrene-7,8-oxide and 1,2-epoxy-3-butene in cultured human lymphocytes.

Glutathione S-transferase M1 (GSTM1), catalyzing the conjugation of various reactive molecules with glutathione (GSH), shows genetic polymorphism in humans. Almost half of all Caucasians lack the GSTM1 gene, being theoretically at a higher risk from the toxic effects of substrates for GSTM1. The purpose of the present study was to investigate whether the GSTM1 genotype of lymphocyte donors influences the in vitro induction of sister chromatid exchanges (SCEs) by styrene-7,8-oxide (SO) and 1,2-epoxy-3-butene (MEB), the epoxide metabolites of styrene and butadiene respectively and potential substrates for GSTM1. SCEs induced after a 48 h treatment (started 24 h after culture initiation) by two different concentrations of SO (50 and 150 microM) and MEB (50 and 250 microM) were analyzed in cultured (72 h) lymphocytes of six GSTM1 null (gene deleted) and six GSTM1-positive (gene present) donors. Both SO and MEB were found to clearly increase SCEs. The GSTM1 genotype had no influence on SCE induction by SO. In contrast, MEB produced a higher level of SCEs among the GSTM1 null than GSTM1-positive samples. At 250 microM MEB, the GSTM1 null donors showed 31% more induced SCEs (on average seven more SCEs per cell) than the GSTM1-positive donors (P = 0.02, acetone treatment as the reference). Furthermore, the GSTM1 null genotype was associated with a slight decrease in mitotic index and replication index, regardless of the treatment. The results suggest that GSTM1-mediated GSH conjugation is an important detoxification pathway for MEB, but not for SO, in cultured human lymphocytes.

Adult↗
PubMed1995

Role of GSTT1 and GSTM1 genotypes in determining individual sensitivity to sister chromatid exchange induction by diepoxybutane in cultured human lymphocytes.

The individual genotoxic response of cultured human lymphocytes to diepoxybutane (DEB), an epoxide metabolite of 1,3-butadiene, shows a bimodal distribution. Blood donors can be classified as either DEB-sensitive or DEB-resistant on the basis of the frequency of sister chromatid exchanges (SCEs) induced by DEB in whole-blood lymphocyte cultures. The genetic basis of this phenomenon has thusfar been unknown. To investigate if differences in the ability of individuals to detoxify DEB could explain the bimodal response, sister chromatid exchanges (SCEs) induced by a 48-h treatment with DEB (2 and 5 microM) were analyzed in whole-blood lymphocyte cultures of 20 human donors with known genotypes of two polymorphic glutathione S-transferases (GSTs), GSTT1 and GSTM1. Both polymorphisms include a homozygous null genotype lacking the respective GST gene and isozyme. The mean frequency of SCEs/cell was 1.6 times higher among GSTT1 null donors (n = 8) than GSTT1 positive donors (n = 12) at both 2 microM DEB (mean 67.3 versus 40.9) and 5 microM DEB (mean 123.2 versus 77.5), with no overlapping in DEB-induced individual SCE frequencies between the two genotypes. Thus, all DEB-sensitive individuals were of the GSTT1 null genotype, while all DEB-resistant persons had a detectable GSTT1 gene. A significant (P < 0.05) negative correlation (r = -0.65 at 5 microM, r = -0.56 at 2 microM) was obtained in the GSTT1 positive donors between DEB-induced individual SCE frequency and RBC GSTT1 activity, measured by formaldehyde formation from dichloromethane; the GSTT1 null individuals showed no GSTT1 activity. At 5 microM DEB, the lymphocyte cultures of the GSTT1 null donors also had a significantly decreased replication index, indicating an impact of GSTT1 genotype on the cytotoxicity of DEB. No influence on DEB-induced SCEs or cytotoxic effects was observed for GSTM1 genotype. It is concluded that sensitivity to in vitro SCE induction by DEB is explained by the lack of GSTT1.

Adult↗
PubMed1995

Individual susceptibility and prevention of occupational diseases: scientific and ethical issues.

Genetic testing of employees is controversial; objections have been raised with regard to privacy, right to work, and the relevance of the tests. A study is being conducted on "the ethical, social, and scientific problems related to the application of genetic screening and genetic monitoring for employees in the context of a European approach to health and safety at work." A conceptual model is proposed of the complex interactions between exposure, acquired and inherited susceptibility, and risk for disease. The validity of tests for determining genotype and phenotype and their relevance for disease must be evaluated critically to provide an objective basis for ethical discussions. The acceptability of such tests is related to a number of issues, which are identified and discussed.

Disease Susceptibility↗
PubMed1995

Age-associated micronuclei containing centromeres and the X chromosome in lymphocytes of women.

Chronological aging of women is clearly associated with an increase in both X-chromosome loss and micronuclei formation in peripheral lymphocytes. It has been suggested that micronucleus formation is an important mechanism of chromosome loss. In the present study, fluorescence in situ hybridization was used to study micronuclei content in two age groups (women below 30 and above 50 years old). A probe for centromeric alphoid consensus sequences (SO-alpha AllCen) and a cloned X-specific centromeric probe (pXBR) were separately used to detect the presence of any chromosomes and the X chromosome, respectively. The presence of centromere-positive micronuclei was significantly higher among the older donors (51.5%) than among the younger donors (34.3%). The X chromosome was highly overrepresented in the micronuclei, the older women showing a higher proportion of X-positive micronuclei (24.0%) than the younger women (14.0%). Assuming that the rest of the centromere-positive micronuclei contained autosomes, a significant age-dependent difference was also noted for micronuclei harboring autosomes (27.5% among the older women and 20.3% among the younger women). These findings suggest that both the X chromosome and autosomes are responsible for the age-dependent increase of micronuclei in women's peripheral lymphocytes.

Adult↗
PubMed1994

Induction of micronuclei in peripheral blood and bone marrow erythrocytes of rats and mice exposed to 1,3-butadiene by inhalation.

Female CB6F1 mice and male Wistar rats were exposed to different concentrations of 1,3-butadiene (1,3-BD) by inhalation. Micronucleus tests using both peripheral blood erythrocytes and femoral marrow cells of these animals were performed. Cells were stained either using conventional acridine orange (AO) staining or supravitally using AO-coated slides. Dose-dependent increases in the frequency of micronuclei (MN) were observed both in blood and in bone marrow cells in mice. 1,3-BD did not, however, increase the frequency of MN in either blood or bone marrow cells of rats at any of the tested concentrations.

Administration, Inhalation↗
PubMed1994

Human cytogenetic biomonitoring of occupational exposure to 1,3-butadiene.

The association of occupational exposure to 1,3-butadiene and chromosomal damage in peripheral blood lymphocytes was studied in 40 workers from two production facilities. Control persons, 30 in all, were chosen from other departments of the same plants, and they were roughly matched for age and smoking habits. The exposure levels to ambient butadiene were measured both by personal sampling using diffuse monitors and by stationary sampling at production and handling sites. Chromosome aberrations (CA), micronuclei (MN) and sister-chromatid exchanges (SCE) in peripheral lymphocytes were analyzed as markers of exposure. Smoking had a slight effect on the frequency of MN, and the mean frequency of SCEs was also higher in smokers than in non-smokers. No effect of smoking, however, was seen in relation to chromosomal aberrations. No exposure related effects were seen in any of the three cytogenetic endpoints in either of the butadiene production plants, representing typical low (below 3 ppm) exposure levels of the butadiene manufacturing industry.

Adult↗
PubMed1994

Analysis of chromosomal aberrations, sister-chromatid exchanges and micronuclei in peripheral lymphocytes of pharmacists before and after working with cytostatic drugs.

The frequencies of chromosome aberrations, SCEs and micronuclei (cytokinesis-block method) in blood lymphocytes were compared among six nonsmoking female pharmacists before and after 1 year of working with cytostatic drugs. All possible precautions were taken to avoid exposure to cytostatics, including proper protective clothing and a monitored, negative-pressured working environment with vertical laminar flow cabinet. As referents, an age-matched group of six nonsmoking female hospital workers not dealing with cytostatics was simultaneously sampled twice with the same time interval. The pharmacists showed a marginally higher mean frequency of SCEs/cell (6.3; P = 0.049) after the working period than 1 year earlier (5.8). On the other hand, the referents, with no obvious exposure, had a higher mean number of cells with chromatid-type aberrations, gaps excluded, in the second sampling (2.0%; P = 0.048) than in the first one (0.5%). In addition, a slight (P = 0.055) trend towards a higher frequency of micronucleated binucleate cells was observed in the second sampling for both the exposed and control subjects. As such findings suggest technical variation in the cytogenetic parameters, the small difference observed in SCEs for the pharmacists between the two samplings was probably not related to the cytostatics exposure. No statistically significant differences were observed for any of the cytogenetic parameters in comparisons between the pharmacists and the referents. The findings suggest that caution should be exercised in comparing results obtained from two different samplings in prospective cytogenetic studies.

Adult↗
PubMed1993

Analysis of chromosomal aberrations, sister chromatid exchanges and micronuclei among power linesmen with long-term exposure to 50-Hz electromagnetic fields.

Chromosomal aberrations, sister chromatid exchanges (SCEs), replication indices and micronuclei in peripheral blood lymphocytes were analysed among 27 nonsmoking power linesmen with considerable long-term exposure to 50-Hz electromagnetic (EM) fields, and among 27 nonsmoking telephone linesmen serving as a reference group, pairwise matched with the exposed workers for age and geographical region. Blood samples from the two groups were collected, cultured and analysed in parallel. No differences between the groups were observed on analysis of SCEs, replication indices or micronuclei. However, the mean rate of lymphocytes with chromatid-type breaks was higher among the power linesmen (0.96% gaps excluded, 1.41% gaps included) than among the reference group (0.44% and 0.70%, respectively). The excess of aberrant cells was concentrated among those power linesmen who had worked earlier in their life. Although the interpretation is somewhat complicated by the confounding effect of previous smoking, these results suggest that exposure to 50-Hz EM fields is associated with a slight increase in chromatid breaks.

Adult↗
PubMed1993

Maternal smoking induced cotinine levels and genotoxicity in second trimester amniotic fluid.

Cotinine concentrations in amniotic fluid samples from 22 smoking and 37 non-smoking pregnant women and induction of sister-chromatid exchanges (SCE) in Chinese hamster ovary (CHO) cells by samples from 15 smokers and 15 non-smokers were studied as indicators of exposure to potential genotoxic activity during pregnancy. Analysis of cotinine revealed one individual in the non-smoking group with a high cotinine level apparently due to non-reported smoking. The mean cotinine concentration of smokers was 85 ng/ml whereas non-smokers had a concentration of 0.3 ng/ml. According to interview data 16 persons announced some passive exposure to tobacco smoke at home or at work; however this group did not differ from unexposed non-smokers in their amniotic fluid cotinine concentration. SCE inducing activity was tested with and without metabolic activation. The mean SCE frequency in CHO cells induced in the presence of exogenous metabolic activation by concentrated amniotic fluid of heavy smokers (> or = 10 cigarettes/day) was significantly higher (9.7 +/- 0.6 SCE/cell) than among non-smokers (8.9 +/- 0.6 SCE/cell) with metabolic activation. The results show that amniotic fluid cotinine measurements and induction of SCEs in CHO cells can be used to indicate fetal exposure by maternal smoking and support earlier studies suggesting a potential genotoxic hazard to the fetus of heavy smokers.

Adult↗
PubMed1993

Human biological monitoring of occupational genotoxic exposures.

Human biological monitoring is a valuable tool for exposure assessment in groups of persons occupationally exposed to genotoxic agents. If the monitoring activity covers genetic material the term genetic monitoring is used. The methods used for genetic monitoring are either substance specific, e.g. the quantitation of identified DNA-adducts or substance unspecific as is the measurement of DNA-repair. The sample material used for analysis must be well characterized and subject to uniform processing for comparison of the results. Confounding factors of smoking, age and sex must be well controlled for and the biomonitoring results should preferentially be linked with accurate ambient air monitoring. In persons occupationally exposed to styrene the endpoints of DNA-damage and DNA-repair in genetic monitoring are methods of choice in exposure situations above the current Danish (25 ppm) or Finnish (20 ppm) occupational exposure limit value of styrene in ambient air. The consideration of ethical issues in human genetic monitoring is an important but often overlooked aspect. This includes the scientific and preventional relevance of performing a test on individuals, pre- and post study information of donors and confidentiality as well as ownership of the results.

DNA Damage↗
PubMed1993

Micronucleus assay in lymphocytes as a tool to biomonitor human exposure to aneuploidogens and clastogens.

The analysis of micronuclei (MN) in cultured human lymphocytes is, in principle, able to detect exposure to clastogens and aneuploidogens alike. There is, however, no clear evidence from human biomonitoring studies or animal experiments showing that in vivo exposure of resting lymphocytes to an aneuploidogen could actually be expressed as MN in cultured lymphocytes. In vitro, a pulse treatment of human lymphocytes with vinblastine, an aneuploidogen, did result in MN induction even if performed before mitogen stimulation, although a much more pronounced effect was obtained in actively dividing lymphocyte cultures. On the other hand, it is probable that a considerable portion of "spontaneous" MN contain whole chromosomes, their contribution increasing with age. It also seems that cytochalasin B, used for the identification of second cell cycle interphase cells in the MN assay, is able to slightly increase the level of MN with whole chromosomes. If MN harboring chromosome fragments represent a minority of the total MN frequency, there may be difficulties in detecting a weak effect in this fraction of MN against the background of MN with whole chromosomes. This would reduce the sensitivity of the assay in detecting clastogens, unless MN with whole chromosomes and chromosome fragments are distinguished from each other. That a problem may exist in sensitivity is suggested by the difficulty in demonstrating MN induction by smoking, an exposure capable of inducing chromosome aberrations. The sensitivity of the lymphocyte MN assay could be increased by detecting kinetochore or centromere in MN, or by automation, allowing more cells to be analyzed.

Aneuploidy↗
PubMed1993

Chromosome aberrations in peripheral lymphocytes of workers employed in the plywood industry.

Workers employed in sawmills and in the manufacture of plywood are exposed to potentially mutagenic chemical aromatic emissions from wood. However, very little is known about the exposure to these natural wood components. In an attempt to determine whether such exposure could have clastogenic effects, a group of 13 male nonsmoking employees mainly from the beginning of the wood-processing line of three plywood mills and 15 matched nonsmoking referents were studied for chromosome aberrations in blood lymphocytes. A statistically significant elevation of the frequency of cells with chromatid-type breaks (mean 2.1%), as compared with the corresponding frequency of the referents (mean 1.0%), was observed for the lymphocytes of the wood workers. These results lend support to previous studies which suggested that wood-drying fumes may be carcinogenic.

Adult↗
PubMed1993

Genetic toxicity of 1,3-butadiene and styrene.

1,3-Butadiene and styrene (vinyl benzene) are indirect genotoxins, which require metabolic activation to an epoxide form in order to bind covalently to DNA. Styrene 7,8-oxide, the active metabolite of styrene, is a carcinogen in rodents and has been shown to be genotoxic in most in-vitro test systems and at various genetic endpoints. The few studies available on the genotoxicity of styrene 7,8-oxide in vivo have yielded negative or (in mice) weakly positive results. Styrene is not usually genotoxic in vitro in assays employing a microsomal preparation from rat liver for metabolic activation, but positive effects have been obtained when other sources of metabolic activation, such as human erythrocytes, were provided. In vivo, styrene has been found repeatedly to be weakly genotoxic in the assay for sister chromatid exchange, especially in mice. Cytogenetic damage (usually chromosomal aberrations) has been reported in many studies of workers, mainly from the reinforced plastics industry where ambient concentrations of styrene may be high (50-100 ppm), while most negative findings are associated with exposure to lower levels. Butadiene is metabolized to two reactive forms, 1,2-epoxy-3-butene and further to 1,2:3,4-diepoxybutane, both of which are genotoxic in various test systems in vitro. The lowest effective dose of the latter is 1-2 orders of magnitude higher than that of the respective monoepoxide. Butadiene itself has not been tested extensively for genotoxicity in vitro. A species-specific difference in the responses of mice and rats at various cytogenetic end-points is seen in vivo, the lowest effective concentrations in rats being clearly higher than those in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Genotoxic effects and chemical compositions of four creosotes.

Four creosotes used in Finland for impregnating wood were tested in the Ames Salmonella test, the SCE test and the SOS chromotest. Compounds volatile at 37 degrees C were assayed using the taped plate testing protocol. The creosotes were fractionated according to their natural boiling ranges and the fractions were tested in the Ames Salmonella assay. Chemical compositions of creosotes and fractions were determined by high resolution gas chromatography/mass spectrophotometry techniques and by reversed phase high performance liquid chromatography. Mutagenic activities were shown to reside in fractions having the highest boiling point ranges (greater than 290 degrees C). The concentrations of mutagenic polycyclic aromatic hydrocarbons in creosotes and in some of their corresponding distillation fractions, when compared with mutagenic activities, indicated synergistic or antagonistic interactions.

Animals↗