G. Talaska - Academia.edu (original) (raw)
Papers by G. Talaska
European Urology Supplements, 2013
Proceedings of the …, 1996
Encyclopedia of Toxicology, 2014
2-Naphthylamine (2NA, CAS # 91-59-8) was used in as an intermediate in the dye industry and in th... more 2-Naphthylamine (2NA, CAS # 91-59-8) was used in as an intermediate in the dye industry and in the rubber industry. 2NA is frequently produced when nitrogenous organic materials are burned or heated. Tobacco smoke, heated cooking oil, and many other smokes contain 2NA as well as other aromatic amines. 2NA is among the most potent human urinary bladder carcinogens. It is well absorbed by all routes
The levels of covalently bound arylamine-hemoglobin and DNA adduct formation were used as dosimet... more The levels of covalently bound arylamine-hemoglobin and DNA adduct formation were used as dosimeters to measure the effect of acetylator genotype and sex on the metabolic conversion of the carcinogen, 2-aminofluorene, to reactive intermediates. A single high dose of 2-aminofluorene (60 mg/kg b.wt. i.p.) was administered to male and female homozygous rapid (Patr/Patr) acetylator hamsters (MHA/SsLaK) and homozygous slow (Pats/Pats) acetylator hamsters (Bio. 82.73/H). By using 32P-postlabeling assay methodology, a sole nonacetylated DNA adduct, which cochromatographed with authentic N-(deoxyguanosin-8-yl)-2-aminofluorene was detected at 3, 6, 12, 18 or 24 hr postdosing in liver and urinary bladder DNA of both rapid and slow acetylator hamsters. The highest levels were detected at 18 hr post 2-aminofluorene injection at which time the average levels of hepatic 2-aminofluorene-DNA adducts were similar between male and female rapid and slow acetylators. By comparison, the levels of 2-amin...
Cahiers de Nutrition et de Diététique, 2013
Polycyclic Aromatic Compounds, 2004
Passive or environmental tobacco smoke (ETS) exposure has been associated with an increased risk ... more Passive or environmental tobacco smoke (ETS) exposure has been associated with an increased risk of lung cancer of approximately 1.3- to 1.6-fold. Sidestream smoke contains higher concentrations of 4-aminobiphenyl and other urinary bladder cancer-causing aromatic amines than does mainstream smoke. However, there is very limited data regarding the impact of ETS on the urinary bladder, another site of tobacco-related tumors in humans. This study was conducted to determine if ETS exposure can be assessed using biomarkers of internal and effective carcinogen dose. Urine samples from 39 women, 21 spouses of smokers, and 18 spouses of nonsmokers were obtained and the levels of urinary 1-hydroxypyrene and total DNA adduct levels in exfoliated urothelial cells were determined. Increases in both 1HP and DNA adduct levels were detected in the wives of current smokers. However, these increases were not statistically significant at the p < .05 level. Measurable differences in mean levels of 1HP, without an outlier, were obtained with a 1.4-fold increase in spouses of smokers. DNA adduct levels in exfoliated urothelial cells were 2.5 times higher in the same persons. These data indicate that there are measurable differences approaching statistical significance between the two smoking groups using a relatively small number of individuals. Biomarkers integrating exposure over a longer period and responding to cumulative dose (i.e., DNA adducts), may be more sensitive when measuring the low exposure levels of ETS.
International Archives of Occupational and Environmental Health, 1993
N-Heterocyclic aromatics (NHA) are widely occurring environmental pollutants formed during the py... more N-Heterocyclic aromatics (NHA) are widely occurring environmental pollutants formed during the pyrolysis of nitrogen-containing organic chemicals. NHA are found in significant amounts in tobacco condensates, synthetic fuels, gasoline engine exhaust, and effluents from the heating of coal. Dibenz[a,j]acridine (DBA) is an example of NHA. The potency of many carcinogenic compounds is related, at least in part, to the efficiency of their biological activation. We undertook studies to determine which initial metabolites of DBA lead to the formation of high levels of carcinogen-DNA adducts in vivo. DBA and its metabolites, trans-DBA-1,2-dihydrodiol (DBA-1,2-DHD), trans-DBA-3,4-dihydrodiol (DBA-3,4-DHD), and trans-DBA-5,6-dihydrodiol (DBA-5,6-DHD), were applied to the skin of mice. DNA was isolated using enzyme-solvent extraction method. DNA was 32P-postlabeled under conditions of limiting [32P]ATP. In skin, DBA produced two distinct adducts. The same two adducts were seen when DBA-3,4-DHD was applied. In addition the total adduct level elicited by DBA-3,4-DHD was higher than that of parent compound. Two adducts were seen when DBA-5,6DHD was applied, but these were very different from adducts seen with DBA. These results suggested that activation of DBA to DNA-binding compounds in skin includes initial formation of DBA-3,4-DHD. The data support development of biomarkers for the exposure and effect of this compound, and also suggest that specific metabolic susceptibility markers might be able to predict populations at increased risk.
etd.ohiolink.edu
... To my dissertation advisor, committee chair, and dear friend, Glenn Talaska, many thanks to y... more ... To my dissertation advisor, committee chair, and dear friend, Glenn Talaska, many thanks to you. ... your belief in me. All of you are my inspiration. To my godchildren (Danyelle, Daniel, and Brandon), remaining family and many friends in Cincinnati and Louisville, thanks ...
Environmental Health Perspectives, 1993
Detdion of cawnogen-DNA adducts inDNA from exfoliated urodelis from an _asand hums aqeosed to pot... more Detdion of cawnogen-DNA adducts inDNA from exfoliated urodelis from an _asand hums aqeosed to potential environmental carcinsgeu3 is described. In an animal model, 4-aminobiphenyl-DNA adducts were detected, and the shape of the dose-response curve was related to the levels of 4-amnobiphenyl-hemoglobin adducts. In a human study, five distnct addct were two tonine tumes higherin nokers thma in in e Thea c onffouradduct measures with smoking was corroborated by nt corrlations with kvelsof4-amnobiplhenyl-hemoglobln adducts, type and number of cigarettes smoked, and/or urinary mutagenicity. One adduct seemed chromatographicaly simla to N-(deox "npmwdn-yl)-4-aminoipbenyl. This adduct showed the strongest correlatn with 4-aminobiphenyl-hemoglobin adduct levels. These data suggest that noninvsive techniquescan be appliedto the study ofcarcinogen-DNA adducts in the target organ of humans at risk for urinary bladder cancer.
![Research paper thumbnail of Benzo[a]pyrene coated ferric oxide and aluminum oxide particles: uptake, metabolism and DNA binding in hamster pulmonary alveolar macrophages and tracheal epithelial cells in vitro [published erratum appears in Carcinogenesis 1997 May;18(5):1123]](https://attachments.academia-assets.com/78373209/thumbnails/1.jpg)
](Carcinogenesis, 1997
B[a]PϪFe 2 O 3 relative to B[a]P-coated Al 2 O 3 can be due to: (i) the enhancement of B[a]P meta... more B[a]PϪFe 2 O 3 relative to B[a]P-coated Al 2 O 3 can be due to: (i) the enhancement of B[a]P metabolism in AM by Fe 2 O 3 Ferric oxide (Fe 2 O 3) and aluminum oxide (Al 2 O 3) particles are widely encountered in occupational settings. Benzo[a] associated with the increased uptake of B[a]P; and (ii) augmentation of DNA adduct formation in epithelial cells. pyrene (B[a]P), a well-characterized environmental carcinogen, is frequently adsorbed onto particles. It has been shown that B[a]P-coated Fe 2 O 3 particles (B[a]PϪ Fe 2 O 3) significantly increased lung tumors in the hamster Introduction in contrast to B[a]P-coated Al 2 O 3 (B[a]PϪAl 2 O 3) or B[a]P Polycyclic aromatic hydrocarbons (PAHs*) are generated alone. In order to determine the genotoxic effects of these through incomplete combustion, cigarette smoke and industrial particles on the metabolism of B[a]P, pulmonary alveolar processes (1,2). It has been shown that most PAHs in the macrophages (AM) from male Syrian golden hamsters were environment are associated with particles (3,4). Particles in incubated with 5 µg (19.8 nmol) B[a]P-coated respirable size the atmosphere serve as condensation nuclei for environmental (99% Ͻ5 µm) Fe 2 O 3 and Al 2 O 3 particles with loads from PAHs and can increase their stability by preventing photo-0.5 to 2.0 mg. Intracellular uptake of B[a]P by AM at 24 h oxidative degradation of chemicals (5). Iron oxide (Fe 2 O 3) and was higher with B[a]PϪFe 2 O 3 than that of B[a]P alone aluminum oxide (Al 2 O 3) are particles commonly encountered (P Ͻ 0.05) or B[a]PϪAl 2 O 3 (P Ͻ 0.05). Total B[a]P metain occupational settings where PAHs are also present. bolism was significantly greater in AM exposed to B[a]P-Data from animal experiments indicate that Fe 2 O 3 or Al 2 O 3 coated Fe 2 O 3 at 1.0 and 1.5 mg than in the AM exposed to alone are incapable of inducing tracheal bronchiogenic carcin-B[a]pϪal 2 O 3 (0.5, 1.0 and 1.5 mg) (P Ͻ 0.05) or B[a]P alone oma in the hamster. However, when Fe 2 O 3 is combined with (P Ͻ 0.05). Similar significant differences for Fe 2 O 3 relative benzo[a]pyrene (B[a]P), the incidence of lung tumors was to Al 2 O 3 and B[a]P alone were also apparent for total increased significantly compared with treatment of B[a]P alone dihydrodiols, quinones and phenolic metabolites. Co-admin-(6,7). The increased lung cancer rate was not observed when istration of 5 µg α-naphthoflavone (α-NF, an inhibitor of B[a]P was co-administered with Al 2 O 3 (7). Results from cytochrome P-4501A1 and P-4501A2) and 10 Ϫ3 M cyclostudies of co-exposure of B[a]P and carbon black (8), flyash hexene oxide (CO, an inhibitor of epoxide hydrolase) signi-(9), asbestos (10), iron oxide (11-13) and crude air particulates ficantly reduced B[a]P metabolism in B[a]PϪFe 2 O 3 (P Ͻ (12), indicate that the alteration of B[a]P metabolism may 0.05) and B[a]PϪAl 2 O 3 (P Ͻ 0.05) treated groups relative to play an important role in long-term particle-associated pulmon-B[a]P alone. AM were co-cultured with hamster tracheal ary diseases. epithelial cells (HTE) and treated as described above for Cytochrome P-450 enzymes have been shown to play the metabolism studies to assess the DNA binding of B[a]P metamajor role in metabolic activation of B[a]P (14). 7R,8S,9S,10Rbolites in the target cells, using 32 P-postlabeling techniques. epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(ϩ)-anti-BPDE], Two adducts were observed that had chromatographic one of the B[a]P metabolites produced by cytochrome P-450 behavior similar to 7R,8S,9S-trihydroxy-10R-(N 2-deoxyactivation, has been shown to be more mutagenic in mammalian guanosyl-3Ј-phosphate)-7,8,9,10-tetrahydrobenzo[a]pyrene cells and more tumorigenic in animals than the isomers, (ϩ) [(ϩ)-anti-BPDE-dG, adduct 1, major adduct representand (-)-syn-BPDE and (Ϫ)-anti-BPDE (15,16). DNA adducts ing 70-80% of total adducts] and 7S,8R,9R-triare regarded as an internal dosimeter of carcinogen exposure hydroxy-10S-(N 2-deoxyguanosyl-3Ј-phosphate)-7,8,9,10because they reflect the net effect of competing metabolic tetrahydrobenzo[a]pyrene [(Ϫ)-anti-BPDE-dG, adduct 2, activation, detoxification and the action of DNA repair prorepresenting 20-30% of total adducts]. B[a]PϪFe 2 O 3 treatcesses (17). Data from in vitro and in vivo experiments have ment enhanced the levels of the two B[a]PϪDNA adducts in demonstrated the positive correlation between persistence of adduct formation and cellular transformation or tumor induc-*Abbreviations: PAH, polycyclic aromatic hydrocarbons; Fe 2 O 3 , ferric tion (18,19). oxide; Al 2 O 3 , aluminum oxide; B[a]P, benzo[a]pyrene; AM, pulmonary One of the key functions of pulmonary alveolar macrophages alveolar macrophages; HTE, hamster tracheal epithelial cells; HPLC, (AM) is to maintain the sterility of pulmonary alveoli. Particles high performance liquid chromatography; α-NF, α-naphthoflavone; CO, cyclohexene oxide; (ϩ)-anti-BPDE-dG, 7R,8S,9S-trihydroxy-10R-(N 2-deoxy-are not only phagocytozed but may also undergo gradual guanosyl-3Ј-phosphate)-7,8,9,10-tetrahydrobenzo[a]pyrene; (Ϫ)-anti-BPDEdissolution due to the phagolysosomes of AM (20). A fraction dG; 7S,8R,9R-trihydroxy-10S-(N 2-deoxyguanosyl-3Ј-phosphate)-7,8,9,10-tetraof adsorbed PAHs are metabolized by AM and these metabolites hydrobenzo[a]pyrene, B[a]PϪFe 2 O 3 , B[a]P coated ferric oxide; may be released into the surrounding tissues (21,22). Inhaled B[a]PϪAl 2 O 3 , B[a]P coated aluminum oxide; RAL, relative adducted labeling.
… Biomarkers & Prevention
The presence of covalent modifications in DNA obtained from exfoliated urothelial cells of smoker... more 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/109 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 adduds 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)-4aminobiphenyl. 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 adduds in humans at high risk for bladder cancer.
PLOS ONE, Apr 10, 2020
Small extracellular vesicles (sEV) are nano-sized (40–150 nm), membrane-encapsulated vesicles tha... more Small extracellular vesicles (sEV) are nano-sized (40–150 nm), membrane-encapsulated vesicles that are released by essentially all cells into the extracellular space and function as intercellular signaling vectors through the horizontal transfer of biologic molecules, including microRNA (miRNA) and other small non-coding RNA (ncRNA), that can alter the phenotype of recipient cells. sEV are present in essentially all extracellular biofluids, including serum, urine and saliva, and offer a new avenue for discovery and development of novel biomarkers of various disease states and exposures. The objective of this study was to systematically interrogate similarities and differences between sEV ncRNA derived from saliva, serum and urine, as well as cell-free small ncRNA (cf-ncRNA) from serum. Saliva, urine and serum were concomitantly collected from 4 healthy donors to mitigate potential bias that can stem from interpersonal and temporal variability. sEV were isolated from each respective biofluid, along with cf-RNA from serum. sEV were isolated from the respective biofluids via differential ultracentrifugation with a 30% sucrose cushion to minimize protein contamination. Small RNA-sequencing was performed on each sample, and cluster analysis was performed based on ncRNA profiles. While some similarities existed in terms of sEV ncRNA cargo across biofluids, there are also notable differences in ncRNA class and ncRNA secretion, with sEV in each biofluid bearing a unique ncRNA profile, including major differences in composition by ncRNA class. We conclude that sEV ncRNA cargo varies according to biofluid, so thus should be carefully selected and interpreted when designing or contrasting translational or epidemiological studies.
Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of bladder canc... more Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of bladder cancer and with increased bulky DNA adduct levels in several studies, mainly in smokers. We investigated the relation between bulky PAH-DNA adducts in peripheral blood mononuclear cells and bladder cancer in nonsmoking subjects from a large hospital-based casecontrol study in Spain. Additionally, we examined the association between DNA adduct formation and several air pollution proxies. The study comprised 76 nonsmoking cases and 76 individually matched controls by sex, region of residence, age, and smoking status (never, former). To maximize the relevance of the DNA adduct measurement as a proxy of PAH exposure, subjects selected had not changed residence, occupation, and major lifestyle factors during the last 10 years. Bulky DNA adducts were measured using the 32 P-postlabeling technique, nuclease P1 treatment. The percentage of detectable adducts was higher in controls (41%) than in cases (32%) with an odds ratio of 0.75 (95% confidence interval, 0.36-1.58). In an analysis limited to controls, a higher percentage of DNA adducts was found among those whose last residence was in a big city (50%) compared with those living in villages (19%; P = 0.04). No consistent associations were found for other markers of air pollution. In this study, among nonsmokers with stable environmental and lifestyle factors, bulky DNA adducts were not associated with bladder cancer risk. Results do not support an association of bladder cancer risk with low-level exposure to PAHs as measured through the formation of bulky DNA adducts in peripheral mononuclear cells.
JNCI Journal of the …, 1996
Background: In April 1991, an excess of bladder cancer cases among workers employed at a chemical... more Background: In April 1991, an excess of bladder cancer cases among workers employed at a chemical manufacturing facility in Niagara Falls, NY, was reported. This excess was primarily confined to 708 workers who had ever been employed in the rubber chemicals ...
European Urology Supplements, 2013
Proceedings of the …, 1996
Encyclopedia of Toxicology, 2014
2-Naphthylamine (2NA, CAS # 91-59-8) was used in as an intermediate in the dye industry and in th... more 2-Naphthylamine (2NA, CAS # 91-59-8) was used in as an intermediate in the dye industry and in the rubber industry. 2NA is frequently produced when nitrogenous organic materials are burned or heated. Tobacco smoke, heated cooking oil, and many other smokes contain 2NA as well as other aromatic amines. 2NA is among the most potent human urinary bladder carcinogens. It is well absorbed by all routes
The levels of covalently bound arylamine-hemoglobin and DNA adduct formation were used as dosimet... more The levels of covalently bound arylamine-hemoglobin and DNA adduct formation were used as dosimeters to measure the effect of acetylator genotype and sex on the metabolic conversion of the carcinogen, 2-aminofluorene, to reactive intermediates. A single high dose of 2-aminofluorene (60 mg/kg b.wt. i.p.) was administered to male and female homozygous rapid (Patr/Patr) acetylator hamsters (MHA/SsLaK) and homozygous slow (Pats/Pats) acetylator hamsters (Bio. 82.73/H). By using 32P-postlabeling assay methodology, a sole nonacetylated DNA adduct, which cochromatographed with authentic N-(deoxyguanosin-8-yl)-2-aminofluorene was detected at 3, 6, 12, 18 or 24 hr postdosing in liver and urinary bladder DNA of both rapid and slow acetylator hamsters. The highest levels were detected at 18 hr post 2-aminofluorene injection at which time the average levels of hepatic 2-aminofluorene-DNA adducts were similar between male and female rapid and slow acetylators. By comparison, the levels of 2-amin...
Cahiers de Nutrition et de Diététique, 2013
Polycyclic Aromatic Compounds, 2004
Passive or environmental tobacco smoke (ETS) exposure has been associated with an increased risk ... more Passive or environmental tobacco smoke (ETS) exposure has been associated with an increased risk of lung cancer of approximately 1.3- to 1.6-fold. Sidestream smoke contains higher concentrations of 4-aminobiphenyl and other urinary bladder cancer-causing aromatic amines than does mainstream smoke. However, there is very limited data regarding the impact of ETS on the urinary bladder, another site of tobacco-related tumors in humans. This study was conducted to determine if ETS exposure can be assessed using biomarkers of internal and effective carcinogen dose. Urine samples from 39 women, 21 spouses of smokers, and 18 spouses of nonsmokers were obtained and the levels of urinary 1-hydroxypyrene and total DNA adduct levels in exfoliated urothelial cells were determined. Increases in both 1HP and DNA adduct levels were detected in the wives of current smokers. However, these increases were not statistically significant at the p < .05 level. Measurable differences in mean levels of 1HP, without an outlier, were obtained with a 1.4-fold increase in spouses of smokers. DNA adduct levels in exfoliated urothelial cells were 2.5 times higher in the same persons. These data indicate that there are measurable differences approaching statistical significance between the two smoking groups using a relatively small number of individuals. Biomarkers integrating exposure over a longer period and responding to cumulative dose (i.e., DNA adducts), may be more sensitive when measuring the low exposure levels of ETS.
International Archives of Occupational and Environmental Health, 1993
N-Heterocyclic aromatics (NHA) are widely occurring environmental pollutants formed during the py... more N-Heterocyclic aromatics (NHA) are widely occurring environmental pollutants formed during the pyrolysis of nitrogen-containing organic chemicals. NHA are found in significant amounts in tobacco condensates, synthetic fuels, gasoline engine exhaust, and effluents from the heating of coal. Dibenz[a,j]acridine (DBA) is an example of NHA. The potency of many carcinogenic compounds is related, at least in part, to the efficiency of their biological activation. We undertook studies to determine which initial metabolites of DBA lead to the formation of high levels of carcinogen-DNA adducts in vivo. DBA and its metabolites, trans-DBA-1,2-dihydrodiol (DBA-1,2-DHD), trans-DBA-3,4-dihydrodiol (DBA-3,4-DHD), and trans-DBA-5,6-dihydrodiol (DBA-5,6-DHD), were applied to the skin of mice. DNA was isolated using enzyme-solvent extraction method. DNA was 32P-postlabeled under conditions of limiting [32P]ATP. In skin, DBA produced two distinct adducts. The same two adducts were seen when DBA-3,4-DHD was applied. In addition the total adduct level elicited by DBA-3,4-DHD was higher than that of parent compound. Two adducts were seen when DBA-5,6DHD was applied, but these were very different from adducts seen with DBA. These results suggested that activation of DBA to DNA-binding compounds in skin includes initial formation of DBA-3,4-DHD. The data support development of biomarkers for the exposure and effect of this compound, and also suggest that specific metabolic susceptibility markers might be able to predict populations at increased risk.
etd.ohiolink.edu
... To my dissertation advisor, committee chair, and dear friend, Glenn Talaska, many thanks to y... more ... To my dissertation advisor, committee chair, and dear friend, Glenn Talaska, many thanks to you. ... your belief in me. All of you are my inspiration. To my godchildren (Danyelle, Daniel, and Brandon), remaining family and many friends in Cincinnati and Louisville, thanks ...
Environmental Health Perspectives, 1993
Detdion of cawnogen-DNA adducts inDNA from exfoliated urodelis from an _asand hums aqeosed to pot... more Detdion of cawnogen-DNA adducts inDNA from exfoliated urodelis from an _asand hums aqeosed to potential environmental carcinsgeu3 is described. In an animal model, 4-aminobiphenyl-DNA adducts were detected, and the shape of the dose-response curve was related to the levels of 4-amnobiphenyl-hemoglobin adducts. In a human study, five distnct addct were two tonine tumes higherin nokers thma in in e Thea c onffouradduct measures with smoking was corroborated by nt corrlations with kvelsof4-amnobiplhenyl-hemoglobln adducts, type and number of cigarettes smoked, and/or urinary mutagenicity. One adduct seemed chromatographicaly simla to N-(deox "npmwdn-yl)-4-aminoipbenyl. This adduct showed the strongest correlatn with 4-aminobiphenyl-hemoglobin adduct levels. These data suggest that noninvsive techniquescan be appliedto the study ofcarcinogen-DNA adducts in the target organ of humans at risk for urinary bladder cancer.
Carcinogenesis, 1997
B[a]PϪFe 2 O 3 relative to B[a]P-coated Al 2 O 3 can be due to: (i) the enhancement of B[a]P meta... more B[a]PϪFe 2 O 3 relative to B[a]P-coated Al 2 O 3 can be due to: (i) the enhancement of B[a]P metabolism in AM by Fe 2 O 3 Ferric oxide (Fe 2 O 3) and aluminum oxide (Al 2 O 3) particles are widely encountered in occupational settings. Benzo[a] associated with the increased uptake of B[a]P; and (ii) augmentation of DNA adduct formation in epithelial cells. pyrene (B[a]P), a well-characterized environmental carcinogen, is frequently adsorbed onto particles. It has been shown that B[a]P-coated Fe 2 O 3 particles (B[a]PϪ Fe 2 O 3) significantly increased lung tumors in the hamster Introduction in contrast to B[a]P-coated Al 2 O 3 (B[a]PϪAl 2 O 3) or B[a]P Polycyclic aromatic hydrocarbons (PAHs*) are generated alone. In order to determine the genotoxic effects of these through incomplete combustion, cigarette smoke and industrial particles on the metabolism of B[a]P, pulmonary alveolar processes (1,2). It has been shown that most PAHs in the macrophages (AM) from male Syrian golden hamsters were environment are associated with particles (3,4). Particles in incubated with 5 µg (19.8 nmol) B[a]P-coated respirable size the atmosphere serve as condensation nuclei for environmental (99% Ͻ5 µm) Fe 2 O 3 and Al 2 O 3 particles with loads from PAHs and can increase their stability by preventing photo-0.5 to 2.0 mg. Intracellular uptake of B[a]P by AM at 24 h oxidative degradation of chemicals (5). Iron oxide (Fe 2 O 3) and was higher with B[a]PϪFe 2 O 3 than that of B[a]P alone aluminum oxide (Al 2 O 3) are particles commonly encountered (P Ͻ 0.05) or B[a]PϪAl 2 O 3 (P Ͻ 0.05). Total B[a]P metain occupational settings where PAHs are also present. bolism was significantly greater in AM exposed to B[a]P-Data from animal experiments indicate that Fe 2 O 3 or Al 2 O 3 coated Fe 2 O 3 at 1.0 and 1.5 mg than in the AM exposed to alone are incapable of inducing tracheal bronchiogenic carcin-B[a]pϪal 2 O 3 (0.5, 1.0 and 1.5 mg) (P Ͻ 0.05) or B[a]P alone oma in the hamster. However, when Fe 2 O 3 is combined with (P Ͻ 0.05). Similar significant differences for Fe 2 O 3 relative benzo[a]pyrene (B[a]P), the incidence of lung tumors was to Al 2 O 3 and B[a]P alone were also apparent for total increased significantly compared with treatment of B[a]P alone dihydrodiols, quinones and phenolic metabolites. Co-admin-(6,7). The increased lung cancer rate was not observed when istration of 5 µg α-naphthoflavone (α-NF, an inhibitor of B[a]P was co-administered with Al 2 O 3 (7). Results from cytochrome P-4501A1 and P-4501A2) and 10 Ϫ3 M cyclostudies of co-exposure of B[a]P and carbon black (8), flyash hexene oxide (CO, an inhibitor of epoxide hydrolase) signi-(9), asbestos (10), iron oxide (11-13) and crude air particulates ficantly reduced B[a]P metabolism in B[a]PϪFe 2 O 3 (P Ͻ (12), indicate that the alteration of B[a]P metabolism may 0.05) and B[a]PϪAl 2 O 3 (P Ͻ 0.05) treated groups relative to play an important role in long-term particle-associated pulmon-B[a]P alone. AM were co-cultured with hamster tracheal ary diseases. epithelial cells (HTE) and treated as described above for Cytochrome P-450 enzymes have been shown to play the metabolism studies to assess the DNA binding of B[a]P metamajor role in metabolic activation of B[a]P (14). 7R,8S,9S,10Rbolites in the target cells, using 32 P-postlabeling techniques. epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(ϩ)-anti-BPDE], Two adducts were observed that had chromatographic one of the B[a]P metabolites produced by cytochrome P-450 behavior similar to 7R,8S,9S-trihydroxy-10R-(N 2-deoxyactivation, has been shown to be more mutagenic in mammalian guanosyl-3Ј-phosphate)-7,8,9,10-tetrahydrobenzo[a]pyrene cells and more tumorigenic in animals than the isomers, (ϩ) [(ϩ)-anti-BPDE-dG, adduct 1, major adduct representand (-)-syn-BPDE and (Ϫ)-anti-BPDE (15,16). DNA adducts ing 70-80% of total adducts] and 7S,8R,9R-triare regarded as an internal dosimeter of carcinogen exposure hydroxy-10S-(N 2-deoxyguanosyl-3Ј-phosphate)-7,8,9,10because they reflect the net effect of competing metabolic tetrahydrobenzo[a]pyrene [(Ϫ)-anti-BPDE-dG, adduct 2, activation, detoxification and the action of DNA repair prorepresenting 20-30% of total adducts]. B[a]PϪFe 2 O 3 treatcesses (17). Data from in vitro and in vivo experiments have ment enhanced the levels of the two B[a]PϪDNA adducts in demonstrated the positive correlation between persistence of adduct formation and cellular transformation or tumor induc-*Abbreviations: PAH, polycyclic aromatic hydrocarbons; Fe 2 O 3 , ferric tion (18,19). oxide; Al 2 O 3 , aluminum oxide; B[a]P, benzo[a]pyrene; AM, pulmonary One of the key functions of pulmonary alveolar macrophages alveolar macrophages; HTE, hamster tracheal epithelial cells; HPLC, (AM) is to maintain the sterility of pulmonary alveoli. Particles high performance liquid chromatography; α-NF, α-naphthoflavone; CO, cyclohexene oxide; (ϩ)-anti-BPDE-dG, 7R,8S,9S-trihydroxy-10R-(N 2-deoxy-are not only phagocytozed but may also undergo gradual guanosyl-3Ј-phosphate)-7,8,9,10-tetrahydrobenzo[a]pyrene; (Ϫ)-anti-BPDEdissolution due to the phagolysosomes of AM (20). A fraction dG; 7S,8R,9R-trihydroxy-10S-(N 2-deoxyguanosyl-3Ј-phosphate)-7,8,9,10-tetraof adsorbed PAHs are metabolized by AM and these metabolites hydrobenzo[a]pyrene, B[a]PϪFe 2 O 3 , B[a]P coated ferric oxide; may be released into the surrounding tissues (21,22). Inhaled B[a]PϪAl 2 O 3 , B[a]P coated aluminum oxide; RAL, relative adducted labeling.
… Biomarkers & Prevention
The presence of covalent modifications in DNA obtained from exfoliated urothelial cells of smoker... more 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/109 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 adduds 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)-4aminobiphenyl. 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 adduds in humans at high risk for bladder cancer.
PLOS ONE, Apr 10, 2020
Small extracellular vesicles (sEV) are nano-sized (40–150 nm), membrane-encapsulated vesicles tha... more Small extracellular vesicles (sEV) are nano-sized (40–150 nm), membrane-encapsulated vesicles that are released by essentially all cells into the extracellular space and function as intercellular signaling vectors through the horizontal transfer of biologic molecules, including microRNA (miRNA) and other small non-coding RNA (ncRNA), that can alter the phenotype of recipient cells. sEV are present in essentially all extracellular biofluids, including serum, urine and saliva, and offer a new avenue for discovery and development of novel biomarkers of various disease states and exposures. The objective of this study was to systematically interrogate similarities and differences between sEV ncRNA derived from saliva, serum and urine, as well as cell-free small ncRNA (cf-ncRNA) from serum. Saliva, urine and serum were concomitantly collected from 4 healthy donors to mitigate potential bias that can stem from interpersonal and temporal variability. sEV were isolated from each respective biofluid, along with cf-RNA from serum. sEV were isolated from the respective biofluids via differential ultracentrifugation with a 30% sucrose cushion to minimize protein contamination. Small RNA-sequencing was performed on each sample, and cluster analysis was performed based on ncRNA profiles. While some similarities existed in terms of sEV ncRNA cargo across biofluids, there are also notable differences in ncRNA class and ncRNA secretion, with sEV in each biofluid bearing a unique ncRNA profile, including major differences in composition by ncRNA class. We conclude that sEV ncRNA cargo varies according to biofluid, so thus should be carefully selected and interpreted when designing or contrasting translational or epidemiological studies.
Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of bladder canc... more Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of bladder cancer and with increased bulky DNA adduct levels in several studies, mainly in smokers. We investigated the relation between bulky PAH-DNA adducts in peripheral blood mononuclear cells and bladder cancer in nonsmoking subjects from a large hospital-based casecontrol study in Spain. Additionally, we examined the association between DNA adduct formation and several air pollution proxies. The study comprised 76 nonsmoking cases and 76 individually matched controls by sex, region of residence, age, and smoking status (never, former). To maximize the relevance of the DNA adduct measurement as a proxy of PAH exposure, subjects selected had not changed residence, occupation, and major lifestyle factors during the last 10 years. Bulky DNA adducts were measured using the 32 P-postlabeling technique, nuclease P1 treatment. The percentage of detectable adducts was higher in controls (41%) than in cases (32%) with an odds ratio of 0.75 (95% confidence interval, 0.36-1.58). In an analysis limited to controls, a higher percentage of DNA adducts was found among those whose last residence was in a big city (50%) compared with those living in villages (19%; P = 0.04). No consistent associations were found for other markers of air pollution. In this study, among nonsmokers with stable environmental and lifestyle factors, bulky DNA adducts were not associated with bladder cancer risk. Results do not support an association of bladder cancer risk with low-level exposure to PAHs as measured through the formation of bulky DNA adducts in peripheral mononuclear cells.
JNCI Journal of the …, 1996
Background: In April 1991, an excess of bladder cancer cases among workers employed at a chemical... more Background: In April 1991, an excess of bladder cancer cases among workers employed at a chemical manufacturing facility in Niagara Falls, NY, was reported. This excess was primarily confined to 708 workers who had ever been employed in the rubber chemicals ...