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Biomedical subjects

K Hemminki

Publications and source records attributed to K Hemminki.

At least 271 records · Page 15Linked to original sources
PubMed1994

Comparison of TLC- and HPLC-32P-postlabelling assay for cisplatin-DNA adducts.

Calf thymus DNA, treated with the antitumour agent cis-diamminedichloroplatinum(II) (cisplatin), was enzymatically digested with deoxyribonuclease I, snake venom phosphodiesterase and prostatic acid phosphatase. As a result the adducts were released with an unmodified nucleotide at their 5'-side. The adducts were postlabelled with [gamma-32P]ATP and separated by thin-layer chromatography (TLC) and HPLC with on-line detection of 32P. One of the standards, platinated d(TGG), could be analysed with a recovery of 31% with both the TLC and the HPLC separation systems, when the amount of adduct was between 0.5 and 100 fmol. In the case of platinated DNA the linear part of the concentration curve was from 100 fmol down to the lowest amount of adducts measured, 3.2 fmol, with the TLC system and between 8 and 40 fmol with the HPLC system. The recoveries of the adducts were 28% and 16% respectively.

Acid Phosphatase↗
PubMed1994

Carcinogen-DNA adducts and gene mutation in foundry workers with low-level exposure to polycyclic aromatic hydrocarbons.

Carcinogen-DNA adducts and somatic gene mutation at the hypoxanthine guanine phosphoribosyl transferase (HPRT) locus were evaluated in peripheral leukocytes of workers in an iron foundry with exposure to benzo[a]pyrene (B[a]P) and other polycyclic aromatic hydrocarbons (PAHs). During the two year study period, B[a]P exposure declined by approximately 40%, from a maximum of 60 ng/m3 in the first year to < 36 ng/m3 1 year later. A total of 64 persons were sampled in November/December of the two successive study years; 24 of them gave two samples one year apart. The biomarkers included carcinogen-DNA adducts in leukocytes (PAH-DNA measured by an immunoassay, aromatic-DNA by the 32P-postlabeling method) and HPRT mutation in lymphocytes. After adjusting for smoking, levels of PAH-DNA, aromatic-DNA and HPRT mutation frequency (Mf) increased with exposure among the 64 workers sampled during the 2 year period (P < or = 0.05). However, the markers showed a differential response to the change in exposure, consistent with their individual biology. For example, among the 24 workers sampled in both years, carcinogen-DNA adducts (which have a half-life on the order of several months) were markedly reduced from the first to the second year (PAH-DNA, 6.2 versus 2.3/10(8); aromatic-DNA, 2.5 versus 1.4/(8); P < 0.01). HPRT Mf (a longer-lived marker) was somewhat less affected by the decline in exposure (1.3 versus 0.8, P < or = 0.05). Moreover, in the second year several long-term workers had low levels of adducts, but elevated HPRT Mf. Thus, PAH-DNA and HPRT Mf were highly correlated in the first year (n = 17; r = 0.67; P < 0.01), but not in the second year or in the two years combined. However, when analysis was restricted to workers with detectable levels of adducts (who included the more highly exposed workers) the correlation was significant between PAH-DNA and HPRT (n = 17; r = 0.65; P = 0.005). In contrast, aromatic-DNA adducts and HPRT were not correlated in either year. These results suggest a molecular link between somatic gene mutation and PAHs; and they highlight the need in such molecular epidemiologic studies to consider the varying lifetimes of the individual markers.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1994

p53 mutations in larynx cancer.

The objective of this work was an analysis of mutations in the p53 gene detected from fresh tumor samples of larynx cancer patients using single-strand conformation polymorphism (SSCP) and direct DNA sequencing of exons 5-8. From 40 patient samples, 15 showed an extra band in SSCP. In 13 samples mutations were detected in exons 5-8. They constituted six transitions and seven transversions, four of them being T to A transversions. Mutations in codons 205 and 248 occurred in two and in codon 246 in three samples. Larynx cancer is strongly associated with tobacco smoking and alcohol consumption. The typical p53 mutations in lung cancer, G to T transversions and G to A and C to T transitions, associated with smoking, accounted for 46% of the mutations detected. Fifty-four per cent of the mutations were detected in a reported hotspot region covering codons 238-248.

Adult↗
PubMed1994

DNA adducts among personnel servicing and loading diesel vehicles.

The levels of aromatic DNA adducts were compared by the 32P-postlabeling assay between the lymphocytes isolated from bus maintenance and truck terminal workers, using hospital mechanics as a control group. The adduct levels were elevated in all the bus and truck terminal workers. Within the bus maintenance personnel, garage workers had the highest levels of adducts. Within the terminal workers those driving diesel forklifts had the highest adduct levels. The results suggest that diesel exhaust contributes to the level of adducts.

DNA↗
PubMed1994

Aromatic DNA adducts, micronuclei and genetic polymorphism for CYP1A1 and GST1 in chimney sweeps.

Aromatic DNA adducts in total white blood cells, cytochrome P450 (CYP) class 1A1 and glutathione transferase (GST1) class mu genotypes and micronuclei in T- and B-lymphocytes were studied in 69 full-time chimney sweeps and 35 controls, all male subjects. The sweeps had a higher (22%) but statistically non-significant increase in the level of DNA adducts as compared to the controls when all individuals independent of genotype were compared. The non-inducible CYP1A1 genotype, m1/m1, lacking a MspI restriction site at the 3' end of the gene, was associated with significantly higher adduct levels in the sweeps. Among the 26 sweeps with the combined genotype m1/m1 and GST1(-), a statistically significant 60% increase in median adduct levels was observed as compared with those 14 control subjects with the corresponding genotype. Smoking also showed a significant effect on the level of adducts. The effect on DNA adducts by sweeping, smoking and genotype appeared to be additive and independent of each other. DNA adducts in sweeps were moderately but statistically significantly correlated with micronuclei in both T- and B-lymphocytes. The correlation between adduct levels and micronuclei was most marked in T-lymphocytes of individuals lacking the GST1 gene.

Adult↗
PubMed1994

Persistence of O6-guanine DNA adducts in styrene-exposed lamination workers determined by 32P-postlabelling.

A modified 32P-postlabelling method was used for the detection of styrene-specific DNA adducts in lamination workers. The persistence of O6-styrene DNA adducts was studied in DNA from lymphocytes and granulocytes of an exposed and a control group. We compared O6-adduct levels obtained from a sampling prior to vacation, after 2 weeks of vacation and after an additional 1 month of work. In granulocytes, there was no significant difference in adduct levels between the control and the exposed groups in any individual samplings. In lymphocytes of laminators the detected adduct levels were significantly higher (5.4 adducts/10(8) nucleotides) than those in the controls (1.0 adduct/10(8) nucleotides). The 2 week interruption of exposure did not influence the total O6-adduct level (4.9 adducts/10(8) nucleotides in the first sampling versus 5.1 adducts/10(8) nucleotides in the second), indicating very slow removal of the specific O6-styrene adducts from DNA.

Adult↗
PubMed1994

Biological monitoring of exposure to polycyclic aromatic hydrocarbon in an electrode paste plant.

We have compared several biomarkers for polycyclic aromatic hydrocarbon (PAH) exposure among electrode paste plant workers and workers not occupationally exposed to PAH. The PAH exposure was quantitated from samples collected with person-attached sampling devices. The mean particulate PAH exposure level in the plant was 14.4 micrograms/m3. The level of pyrene was significantly correlated with both PAH level and the level of selected carcinogenic PAHs in this type of exposure. The mean concentration of the biomarker 1-hydroxypyrene in the PAH exposed workers' urine was 6.98 mumol of 1-hydroxypyrene per mole of creatinine compared with 0.08 and 0.14 mumol of 1-hydroxypyrene per mole of creatinine in the two reference groups. PAH-DNA adducts were measured in DNA from white blood cells by the ultrasensitive enzyme radioimmunoassay (USERIA) and the 32P-postlabeling technique. Only urinary 1-hydroxypyrene was significantly increased in the PAH-exposed group.

Adult↗
PubMed1994

Laboratory work and pregnancy outcome.

Spontaneous abortions among women working in laboratories, and congenital malformations and birth weights of the children were examined in a retrospective case-referent study. In the spontaneous abortion study there were 535 women (206 cases and 329 referents), and in the malformation study 141 women (36 cases and 105 referents). The analysis of the birth weights concerned 500 women (referents). Significant associations with spontaneous abortion were found for exposure to toluene (odds ratio [OR], 4.7, 95% confidence interval [CI], 1.4 to 15.9), xylene (OR 3.1, CI 1.3 to 7.5) and formalin (OR 3.5, CI 1.1 to 11.2) > or = 3 days a week, adjusted for the covariates. Most of the women exposed to formalin and xylene were working in pathology or histology laboratories. No association with congenital malformation was found.

Abortion, Spontaneous↗
PubMed1994

The detection of increased amounts of the extracellular domain of the epidermal growth factor receptor in serum during carcinogenesis in asbestosis patients.

Overexpression of the epidermal growth factor receptor (EGFr) has been implicated in the pathogenesis of a wide variety of human malignancies and may be related to asbestos-induced carcinogenesis. Overexpression of the EGFr can be detected immunologically by quantitation of the extracellular domain (ECD) in the extracellular fluid in vitro and in serum in vivo. An enzyme-linked immunosorbent assay (ELISA) for the EGFr ECD was used to examine banked serum samples of 38 asbestosis patients who subsequently developed cancer, 72 age-sex-race-smoking-asbestos exposure matched asbestosis controls without cancer, and 20 age-sex-race-smoking matched nonasbestosis noncancer controls. The mean serum level for the EGFr ECD in the cancer cases (636 +/- 299 fmol/ml) was statistically significantly elevated (P < 0.05) in comparison to the mean level in the asbestosis controls (546 +/- 147 fmol/ml) or the nonasbestosis controls (336 +/- 228 fmol/ml). Defining a positive elevation of the serum EGFr ECD as any value more than 2 standard deviations above the nonasbestosis control mean, 7 (18%) of the cancer cases were positive compared to 4 (6%) of the asbestosis controls and one (5%) of the nonasbestosis controls. In addition, all of these cancer cases had positive serum samples prior to the time of disease diagnosis (average = 5.1 years). These results suggest that serum EGFr ECD may be elevated at an early stage of carcinogenesis in some asbestosis patients and that further prospective study of the utility of this biomarker is warranted.

Adult↗
PubMed1994

Cancer risk of air pollution: epidemiological evidence.

Epidemiological studies on the effect of urban air pollution on lung cancer were surveyed. Overall, the studies from many countries point to a smoking-adjusted risk in urban areas over countryside areas that is higher by a factor of up to 1.5. The extent to which urban air pollution contributes to this excess remains unknown. Studies on diesel-exposed occupational groups show that urban air pollution may have a causative role in lung cancer. Model calculations on unit risk factors of known human carcinogens were carried out to rank carcinogens according to their current ambient air concentrations.

Air Pollutants↗
PubMed1993

Smoking-related DNA adducts: 32P-postlabeling analysis of 7-methylguanine in human bronchial and lymphocyte DNA.

7-methylguanine DNA adducts were determined in macroscopically normal bronchial specimens and peripheral blood lymphocytes of 20 patients undergoing pulmonary surgery. A recently developed 32P-postlabeling assay was applied with anion exchange chromatography as an adduct enrichment method. The material consisted of 13 smokers and 7 non-smokers. The mean bronchial 7-methylguanine levels of 11 smokers and 6 non-smokers were 17.3 and 4.7 adducts/10(7) nucleotides. In lymphocyte DNA, the respective mean levels were 11.5 and 2.3 adducts/10(7) nucleotides. The bronchial DNA adduct levels in smokers were statistically higher than those in non-smokers. Among 5 smokers, for whom both bronchial and lymphocyte DNA was available, 7-methylguanine levels correlated in the two tissues (r = 0.77).

Adult↗
PubMed1993

DNA adducts, mutations and cancer.

Anyone having lectured on DNA adducts is likely to be familiar with the first question after the presentation: 'What is the relationship of DNA adducts and cancer?'. Although there are a number of reviews on the topic (1-5), my personal response, instead of going into lengthy circumstantial argumentation and hand-waving, has been a quotation from Mortimer Mendelson: 'I wouldn't like to have my DNA messed up'. In this commentary I will indulge in this still circumstantial argumentation. The reason being that never before has it appeared to be so easy, or less difficult, to entertain the question. Hopefully this effort will spare colleagues confronting the same question some time. At the same time I will take the opportunity to describe developments in the identification of DNA adducts. A vivid history of the development of ideas on chemical causes of cancer has been published by Lawley.

Animals↗
PubMed1993

32P-postlabeling of DNA adducts of styrene-exposed lamination workers.

Lamination workers are exposed to high concentrations of styrene. A postlabeling method was developed for the detection of styrene-specific DNA adducts of the workers. To synthesize a standard, styrene oxide was reacted with 2'-deoxyguanosine 3'-monophosphate (dGMP) and the O6-dGMP-adduct was isolated and characterized. The human samples were assayed by the nuclease P1 version of the 32P-postlabeling technique, using magnet transfer of the adducts in chromatography. The human samples were spiked with the standards to ensure identification and quantitation. In lamination workers the O6-adducts, adjusted for adduct recovery, were detected at a level of 5 adducts/10(8) nucleotides, over five times the level in the controls.

Chromatography, Thin Layer↗
PubMed1993

Seasonal variation of aromatic DNA adducts in human lymphocytes and granulocytes.

DNA adducts were measured by 32P-postlabelling in lymphocytes and granulocytes of 75 healthy men exposed occupationally and environmentally to high concentrations of aromatic compounds in the ambient air. Volunteers enrolled in the study were men working at the coke batteries and nonoccupationally exposed inhabitants of Silesia, a highly industrialized region in southern Poland. Blood samples were drawn twice: in February and September 1992. Seasonal variations in the levels of DNA adducts were found only in lymphocytes: 3.6- and 8.7-fold in the occupationally and environmentally exposed groups respectively. In smokers the seasonal variation was as large as 12.8-fold in the environmentally exposed group. No seasonal variations were observed in granulocytes. The observed seasonal variation in the level of aromatic DNA adducts coincided with winter/summer differences in the concentrations of benzo[a]pyrene in the ambient air of Silesia. The study recommends the application of lymphocytes for adduct studies in chronic exposures and provides evidence on the repair of aromatic adducts in lymphocytes.

Benzo(a)pyrene↗
PubMed1993

Carcinogenic chemicals in the occupational environment.

A survey of occupational carcinogens by the Institute of Occupational Health, Finland shows that more than 100,000 workers are exposed to carcinogenic substances. The most common exposures are silica, wood dust, tobacco smoke and lead compounds. Based on biological monitoring of workers over the years it appears that overall lead exposure has decreased but exposure to styrene, trichloroethylene and tetrachloroethylene has decreased only slightly or remained constant. The biological monitoring data are based on samples sent by the workplaces on their initiative presenting no scientifically selected sampling. Thus due caution is needed in the interpretation of the trends.

Carcinogens, Environmental↗
PubMed1993

Analysis of cigarette-smoke-induced DNA adducts by butanol extraction and nuclease P1-enhanced 32P-postlabeling in human lymphocytes and granulocytes.

In an earlier study, we analyzed the aromatic DNA adducts separated from lymphocytes and granulocytes of smokers and nonsmokers using the nuclease P1-enhanced 32P-postlabeling assay. Here we compare the butanol extraction and nuclease P1-enhanced procedure on the same kind of samples. The DNA adducts of 42 per 10(8) nucleotides from smokers' lymphocytes were statistically higher (p < 0.05) than those of 11 from nonsmokers', when analyzed by the nuclease P1 treatment, but not by the 1-butanol extraction. The radioactivity obtained from the DNA digests on the TLC plates was lower in butanol-treated DNA samples when compared to those of nuclease P1 digestion. Lymphocytes appear to be a suitable test tissue for determining aromatic carcinogen exposure when detecting smoking-related DNA adducts by the nuclease P1-enhanced 32P-postlabeling analysis.

Butanols↗