Search PubMed⌕ Search

Biomedical subjects

M Jaeger

Publications and source records attributed to M Jaeger.

At least 37 records · Page 2Linked to original sources
PubMed1997

Benzidine-DNA adduct levels in human peripheral white blood cells significantly correlate with levels in exfoliated urothelial cells.

In a cross-sectional study of 33 workers exposed to benzidine and benzidine dyes and 15 non-exposed controls, we previously reported that exposure status and internal dose of benzidine metabolites were strongly correlated with the levels of specific benzidine-DNA adducts in exfoliated urothelial cells. We also evaluated DNA adduct levels in peripheral white blood cells (WBC) of a subset of 18 exposed workers and 7 controls selected to represent a wide range of adducts in exfoliated urothelial cells. Samples were coded and then DNA was analyzed using 32P-postlabeling, along with n-butanol extraction. One adduct, which co-chromatographed with a synthetic N-(3'-phospho-deoxyguanosin-8-yl)-N'-acetylbenzidine standard, predominated in those samples with adducts present. The median level (range) of this adduct in WBC DNA was 194.4 (3.2-975) RAL x 10(9) in exposed workers and 1.4 (0.1-6.4) in the control subjects (p = 0.0002, Wilcoxon Rank Sum Test). There was a striking correlation between WBC and exfoliated urothelial cell adduct levels (Pearson r = 0.84, p < 0.001) among exposed subjects. In addition, the sum of urinary benzidine, N-acetylbenzidine and N,N'-diacetylbenzidine correlated with the levels of this adduct in both tissues. This is the first study in humans to show a relationship for a specific carcinogen adduct in a surrogate tissue and in urothelial cells, the target for urinary bladder cancer.

Adult↗
PubMed1997

Chronic, topical administration of 4-aminobiphenyl induces tissue-specific DNA adducts in mice.

While current human exposure to 4-aminobiphenyl (4-ABP) is mainly through inhalation, historically, occupational exposure occurred most often through the skin. 4-ABP targets the urinary bladder in humans, dogs, and rats and the liver and urinary bladder in mice. This study examines the time course of DNA adduct levels in mouse target tissues, liver and urinary bladder, and nontarget tissues, lung and skin, after repeated dermal exposure to subcarcinogenic doses of 4-ABP. It was found that, in female mice dermally treated with 50 nmol of 4-ABP twice weekly for 21 weeks, DNA adduct levels measured by 32P-postlabeling increased over time in target and nontarget tissues, but the greatest rate of accumulation occurred in urinary bladder. At 21 weeks liver, urinary bladder, and skin reached their highest median adduct levels of 55, 82, and 58, respectively. Median adduct levels in lung reached a maximum of 3.2 at 3 weeks of exposure. An adduct which had similar chromatographic properties to a standard previously identified as N-(deoxyguanosin-8-yl)-4-aminobiphenyl was the primary adduct detected in all tissues. There were significant correlations in adduct levels between liver and urinary bladder and liver and skin, but not between skin and urinary bladder. These data suggest that urinary bladder adducts are the result of hepatic and not dermal activation. However, adducts were detected at relatively high levels in skin but not in lung, suggesting that skin may have the metabolic capacity to activate 4-ABP when it is applied topically.

Administration, Cutaneous↗
PubMed1997

Carpal bone maturation during childhood and adolescence: assessment by quantitative computed tomography. Preliminary results.

The aim of our study was to measure the volume of each carpal bone during childhood and adolescence by image processing from computed tomography (CT) scans, and to analyze the relationship between the eight carpal bones. Thirteen CT scans were performed in nine normal prepubertal, peripubertal and post-pubertal children, six boys and three girls, aged 5-14 years. Each scan was processed in order to extract the carpal bones. The volume was computed for each bone. There was a significant correlation between carpal bone volume and age (0.55 < r < 0.79), and a very strong correlation between the volume of a given carpal bone and the volume of all the others, whatever the age (0.87 < r < 0.99, p < 0.01). Image processing is a potentially useful method for assessing bone maturation. The constant ratio between carpal bone volumes indicates that these bones interact with each other in wrist bone maturation.

Adolescent↗
PubMed1997

Urinary mutagenicity as a biomarker in workers exposed to benzidine: correlation with urinary metabolites and urothelial DNA adducts.

Urinary mutagenicity has been used in occupational and epidemiological studies for over two decades as a cost-effective, general biomarker of exposure to genotoxic agents. However, few studies have compared urinary mutagenicity to additional biomarkers determined among low- and high-exposed groups. To address this issue, we evaluated the relationship between urinary mutagenicity and other types of biomarkers in a cross-sectional study involving 15 workers exposed to the urinary bladder carcinogen benzidine (BZ, high exposure), 15 workers exposed to BZ-dyes (low exposure), and 13 unexposed controls in Ahmedabad, India. Urinary organics were extracted by C18/methanol and evaluated for mutagenicity in the presence of S9 in the Salmonella strain YG1024, which is a frameshift strain that overproduces acetyltransferase. The results were compared to biomarker data reported recently from the same urine samples (Rothman et al., Proc. Natl Acad. Sci. USA, 93, 5084-5089, 1996) that included a metabolite biomarker (the sum of the urinary levels of BZ + N-acetylbenzidine + N,N'-diacetylbenzidine) and a DNA adduct biomarker [a presumptive N-(3'-phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine (C8dG-ABZ) DNA adduct in exfoliated urothelial cells]. The mean +/- SE urinary mutagenicity (revertants/micromol of creatinine) of the low-exposure (BZ-dye) workers was 8.2 +/- 2.4, which was significantly different from the mean of the controls (2.8 +/- 0.7, P = 0.04) as was that of the mean of the high-exposure (BZ) workers (123.2 +/- 26.1, P < 0.0001). Urinary mutagenicity showed strong, positive correlations with urinary metabolites (r = 0.88, P < 0.0001) and the level of the presumptive C8dG-ABZ urothelial DNA adduct (r = 0.59, P = 0.0006). A strong association was found between tobacco use (bidi smoking) and urinary mutagenicity among the controls (r = 0.68, P = 0.01) but not among the exposed workers (r = 0.18, P = 0.11). This study confirms the ability of a biomarker such as urinary mutagenicity to detect low-dose exposures, identify additional genotoxic exposures among the controls, and correlate strongly with urinary metabolites and DNA adducts in the target tissue (urinary bladder epithelia) in humans.

Benzidines↗
PubMed1997

Acidic urine pH is associated with elevated levels of free urinary benzidine and N-acetylbenzidine and urothelial cell DNA adducts in exposed workers.

We evaluated the influence of urine pH on the proportion of urinary benzidine (BZ) and N-acetylbenzidine present in the free, unconjugated state and on exfoliated urothelial cell DNA adduct levels in 32 workers exposed to BZ in India. Postworkshift urine pH was inversely correlated with the proportions of BZ (r = -0.78; P < 0.0001) and N-acetylbenzidine (r = -0.67; P < 0.0001) present as free compounds. Furthermore, the average of each subject's pre- and postworkshift urine pH was negatively associated with the predominant urothelial DNA adduct (P = 0.0037, adjusted for urinary BZ and metabolites), which has been shown to cochromatograph with a N-(3'-phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine adduct standard. Controlling for internal dose, individuals with urine pH < 6 had 10-fold higher DNA adduct levels compared to subjects with urine pH > or = 7. As reported previously, polymorphisms in NAT1, NAT2, and GSTM1 had no impact on DNA adduct levels. This is the first study to demonstrate that urine pH has a strong influence on the presence of free urinary aromatic amine compounds and on urothelial cell DNA adduct levels in exposed humans. Because there is evidence that acidic urine has a similar influence on aromatic amines derived from cigarette smoke, urine pH, which is influenced by diet, may be an important susceptibility factor for bladder cancer caused by tobacco in the general population.

Analysis of Variance↗
PubMed1996

Chronic, topical exposure to benzo[a]pyrene induces relatively high steady-state levels of DNA adducts in target tissues and alters kinetics of adduct loss.

Carcinogen-DNA adduct measurements may become useful biomarkers of effective dose and/or early effect. However, validation of this biomarker is required at several levels to ensure that human exposure and response are accurately reflected. Important in this regard is an understanding of the relative biomarker levels in target and nontarget organs and the response of the biomarker under the chronic, low-dose conditions to which humans are exposed. We studied the differences between single and chronic topical application of benzo[a]pyrene (BAP) on the accumulation and removal of BAP-DNA adducts in skin, lung, and liver. Animals were treated with BAP at 10, 25, or 50 nMol topically once or twice per week for as long as 15 weeks. Animals were sacrificed either at 24, 48, or 72 hr after the last dose at 1 and 30 treatments, and after 24 hr for all other treatment groups. Adduct levels increased with increasing dose, but the slope of the dose-response was different in each organ. At low doses, accumulation was linear in skin and lung, but at high doses the adduct levels in the lung increased dramatically at the same time when the levels in the skin reached apparent steady state. In the liver adduct, levels were lower than in target tissues and apparent steady-state adduct levels were reached rapidly, the maxima being independent of dose, suggesting that activating metabolism was saturated in this organ. Removal of adducts from skin, the target organ, was more rapid following single treatment than with chronic exposure. This finding is consistent with earlier data, indicating that some areas of the genome are more resistant to repair. Thus, repeated exposure and repair cycles would be more likely to cause an increase in the proportion of carcinogen-DNA adducts in repair-resistant areas of the genome. These findings indicate that single-dose experiments may underestimate the potential for carcinogenicity for compounds that follow this pattern.

Administration, Topical↗
PubMed1996

Development and application of non-invasive biomarkers for carcinogen-DNA adduct analysis in occupationally exposed populations.

Biological monitoring of exposures to carcinogenic compounds in the workplace can be a valuable adjunct to environmental sampling and occupational medicine. Carcinogen-DNA adduct analysis has promise as a biomarker of effective dose if target organ samples can be obtained non-invasively. We have developed non-invasive techniques using exfoliated urothelial and bronchial cells collected in urine and sputum, respectively. First morning urine samples were collected from 33 workers exposed to benzidine or benzidine-based dyes and controls matched for age, education, and smoking status. Sufficient DNA for 32P-postlabelling analysis was obtained from every sample. Mean levels of a specific DNA adduct (which co-chromatographed with standard characterized by MS) were elevated significantly in the benzidine-exposed workers relative to controls. In addition, workers exposed to benzidine had higher adduct levels than those exposed to benzidine-based dyes. This study demonstrates the usefulness of these non-invasive techniques for exposure/effect assessment. To be useful in occupational studies, biomarkers must also be sensitive to exposure interventions. We have conducted topical application studies of used gasoline engine oils in mice and found that the levels of carcinogen-DNA adducts in skin and lung can be significantly lowered if skin cleaning is conducted in a timely manner. The combination of useful, non-invasive techniques to monitor exposure and effect and industrial hygiene interventions can be used to detect and prevent exposures to a wide range of carcinogens including those found in used gasoline engine oils and jet exhausts.

Animals↗
PubMed1996

The impact of interindividual variation in NAT2 activity on benzidine urinary metabolites and urothelial DNA adducts in exposed workers.

Several epidemiologic studies indicate that NAT2-related slow N-acetylation increases bladder cancer risk among workers exposed to aromatic amines, presumably because N-acetylation is important for the detoxification of these compounds. Previously, we showed that NAT2 polymorphisms did not influence bladder cancer risk among Chinese workers exposed exclusively to benzidine (BZ), suggesting that NAT2 N-acetylation is not a critical detoxifying pathway for this aromatic amine. To evaluate the biologic plausibility of this finding, we carried out a cross-sectional study of 33 workers exposed to BZ and 15 unexposed controls in Ahmedabad, India, to evaluate the presence of BZ-related DNA adducts in exfoliated urothelial cells, the excretion pattern of BZ metabolites, and the impact of NAT2 activity on these outcomes. Four DNA adducts were significantly elevated in exposed workers compared to controls; of these, the predominant adduct cochromatographed with a synthetic N-(3'- phosphodeoxyguanosin-8-yl)-N'-acetylbenzidine standard and was the only adduct that was significantly associated with total BZ urinary metabolites (r = 0.68, P < 0.0001). To our knowledge this is the first report to show that BZ forms DNA adducts in exfoliated urothelial cells of exposed humans and that the predominant adduct formed is N-acetylated, supporting the concept that monofunctional acetylation is an activation, rather than a detoxification, step for BZ. However, because almost all BZ-related metabolites measured in the urine of exposed workers were acetylated among slow, as well as rapid, acetylators (mean +/- SD 95 +/- 1.9% vs. 97 +/- 1.6%, respectively) and NAT2 activity did not affect the levels of any DNA adduct measured, it is unlikely that interindividual variation in NAT2 function is relevant for BZ-associated bladder carcinogenesis.

Adult↗
PubMed1996

Perioperative on-site haemoglobin determination: as accurate as laboratory values?

PURPOSE: This study assessed the accuracy of photometer based haemoglobin (Hb) determination technology (HemoCue) when used by different anaesthetists in situations of rapidly changing Hb values during anaesthesia. METHODS: (Part 1) In the laboratory, repeated measurements were done on 16 split samples of blood using both the Hematology Analyzer (CELL-DYN 3500 System, Abbot Laboratories, San Jose, California) and the photometer. (Part 2) Twelve patients had blood samples drawn from an arterial line for simultaneous Hb determination in the hospital laboratory and by the photometer. At the same time, capillary samples were taken from the patient's earlobe for Hb determination by the photometer. All sample collection and photometer measurements were done by the same operator. (Part 3) The Part 2 protocol was then repeated with different anaesthetists performing both the sampling and the photometer measurements. Statistical comparison was by ANOVA and a two-tailed paired t-test. RESULTS: (Part 1) Samples determined by the photometer and the laboratory were highly correlated (r2 = 1.0, P < 0.001). The average error of each method was similar ( < 4%). (Part 2) Using a 2-tailed paired t-test, the photometer arterial measurements were not different from the laboratory measurements, however the photometer capillary measurements were consistently approximately 8% higher (P = 0.003). (Part 3) When multiple operators performed the sampling there were no differences on arterial or capillary samples (r2 = 0.942, r2 = 0.851 respectively), although the variance was greater. CONCLUSIONS: The HemoCue haemoglobinometer has sufficient accuracy to support treatment decisions regarding blood transfusions.

Anesthesia↗
PubMed1996

Carcinogenicity, DNA adduct formation and K-ras activation by 7H-dibenzo[c,g]carbazole in strain A/J mouse lung.

N-Heterocyclic polynuclear aromatic hydrocarbons (NHA) are environmental pollutants formed during the combustion of organic materials. 7-H-Dibenzo[c,g]carbazole (DBC) is a potent carcinogen in lung, liver and skin. We undertook these studies to determine whether tissue specificity for DBC lung carcinogenicity in the strain A/J mouse is mirrored by formation of DBC-DNA adducts in lung tissue and whether these adducts are consistent with mutation patterns in the K-ras gene. Strain A/J mice were given a single i.p. injection of DBC at doses of 0, 5, 10, 20 or 40 mg/kg and levels of DNA adducts in the lung were monitored by 32P-postlabeling on days 1, 3, 5, 7, 14 and 21. The remaining animals were sacrificed 8 months after DBC treatment and lung tumor multiplicity and K-ras mutation patterns in the tumors were determined. The lung tumor response to DBC was dose related, with an average of 4.7 +/- 1.2 tumors/mouse at 5 mg/kg and 48.1 +/- 5.5 tumors/mouse at 40 mg/kg. As many as seven DBC-DNA adducts were observed in the lung. DNA binding levels in the lung were highest at 40 mg/kg, with maximum binding at 5-7 days. At lower dose levels the maximum binding to DNA decreased and shifted to earlier time points. The DBC-DNA adduct in the lung with the highest level of binding at all dose levels was DBC-DNA adduct 3. The majority of DBC-induced mutations in the K-ras gene in the lung were A-->T (80%) transversions in the third base of codon 61, a mutation that has not been previously observed in chemically induced lung tumors in strain A/J mice.

Animals↗
PubMed1996

Polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental compounds: biological markers of exposure and effects.

Lung cancer caused by polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs and related environmental agents is a major problem in industrialized nations. The high case-fatality rate of the disease, even with the best supportive treatment, underscores the importance of primary lung cancer prevention. Development of biomarkers of exposure and effects to PAHs and related compounds is now underway and includes measurement of urinary metabolites of specific PAHs as well as detection of protein and DNA adducts as indicators of effective dose. Validation of these markers in terms of total environmental dose requires that concurrent measures of air levels and potential dermal exposure be made. In addition, the interrelationships between PAH biomarkers must be determined, particularly when levels of the marker in surrogate molecules (e.g., protein) or markers from surrogate tissues (e.g., lymphocyte DNA) are used to assess the risk to the target organ, the lung. Two approaches to biomarker studies will be reviewed in this article: the progress made using blood lymphocytes as surrogates for lung tissues and the progress made developing noninvasive markers of carcinogen-DNA adduct levels in lung-derived cells available in bronchial-alveolar lavage and in sputum. Data are presented from studies in which exfoliated urothelial cells were used as a surrogate tissue to assess exposure to human urinary bladder carcinogens in occupational groups.

Biomarkers↗
PubMed1996

The glutathione S-transferase M1 (GSTM1) null genotype and benzidine-associated bladder cancer, urine mutagenicity, and exfoliated urothelial cell DNA adducts.

Multiple studies in the general population have suggested that subjects with the glutathione S-transferase M1 (GSTM1)-null genotype, who lack functional GSTM1, are at higher risk for bladder cancer. To evaluate the impact of the GSTM1-null genotype on bladder cancer caused by occupational exposure to benzidine and to determine its influence on benzidine metabolism, we carried out three complementary investigations: a case-control study of bladder cancer among workers previously exposed to benzidine in China, a cross-sectional study of urothelial cell DNA adducts and urinary mutagenicity in workers currently exposed to benzidine in India, and a laboratory study of the ability of human GSTM1 to conjugate benzidine and its known metabolites in vitro. There was no overall increase in bladder cancer risk for the GSTM1-null genotype among 38 bladder cancer cases and 43 controls (odds ratio, 1.0; 95% confidence interval, 0.4-2.7), although there was some indication that highly exposed workers with the GSTM1-null genotype were at greater risk of bladder cancer compared to similarly exposed workers without this allele. However, the GSTM1 genotype had no impact on urothelial cell DNA adduct and urinary mutagenicity levels in workers currently exposed to benzidine. Furthermore, human GSTM1 did not conjugate benzidine or its metabolites. These results led us to conclude that the GSTM1-null genotype does not have an impact on bladder cancer caused by benzidine, providing a contrast to its association with elevated bladder cancer risk in the general population.

Benzidines↗