• 한국환경성돌연변이발암원학회지
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• 제22권4호
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• pp.303-311
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• 2002

This study evaluated the concentrations of urinary metabolites of polycyclic aromatic hydrocarbons (PAHs) in industrial waste incineration workers. The effect of genetic polymorphisms of xenobiotic metabolism enzymes on urinary concentration of PAH metabolites was assessed. And, aromatic DNA adduct levels were also determined in total white blood cells. Fifty employees were recruited from a company handling industrial wastes located in Ansan, Korea: non-exposed group (n=21), exposed group (n=29). Sixteen ambient PAHs were determined by GC/MSD (NIOSH method) from personal breathing zone samples of nine subjects near incinerators. Urinary 1-hydroxypyrene glucuronide (1-OHPG), a major pyrene metabolite, was assayed by synchronous fluorescence spectroscopy after immunoaffinity purification using monoclonal antibody 8E11 (SFS/IAC). Multiplex PCR was used for genotyping for GSTMI/TI and PCR-RFLP for genotyping of CYP1A1 (MspI and Ile/Val). PAH-DNA adducts in peripheral blood WBC were measured by the nuclease P1-enhanced postlabeling assay. Smoking habit, demographic and occupational information were collected by self-administered questionnaire. The range of total ambient PAH levels were 0.00-7.00 mg/㎥ (mean 3.31). Urinary 1-OHPG levels were significantly higher in workers handling industrial wastes than in those with presumed lower exposure to PAHs (p=0.006, by Kruskal-Wallis test). There was a statistically significant dose-response increase in 1-OHPG levels with the number of cigarettes consumed per day (Pearson correlation coefficient=0.686, p<0.001). Urinary 1-OHPG levels in occupationally exposed smoking workers were highest compared with non-occupationally exposed smokers (p=0.053, by Kruskal-Wallis test). Smoking and GSTMI genotype were significant predictors for log-transformed 1-OHPG by multiple regression analysis (overall model R²=0.565, p<0.001), whereas smoking was the only significant predictor for log-transformed aromatic DNA adducts (overall model R²=0.249, p=0.201). Aromatic DNA adducts was also a significantly correlation between log transferred urinary 1-OHPG levels (pearson's correlation coefficient=0.307, p=0.04). However, the partial correlation coefficient adjusting for Age, Sex, and cigarette consumption was not significant (r=0.154, p=0.169). The significant association exists only in individuals with the GSTMI null genotype (pearsons correlation coefficient=0.516, p=0.010; partial correlation coefficient adjusting for age, sex, and cigarette consumption, r=0.363, p=0.038). Our results suggest that the significant increase in urinary 1-OHPG in the exposed workers is due to higher prevalence of smokers among them, and that the association between urinary PAH metabolites and aromatic DNA adducts in workers of industrial waste handling may be modulated by GSTMI genotype. There results remain to be confirmed in future larger studies.

• BMB Reports
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• 제36권1호
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• pp.1-11
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• 2003

The causative role of polycyclic aromatic hydrocarbons (PAH) in human carcinogenesis is undisputed. Measurements of PAH-DNA adduct levels in easily accessible white blood cells therefore represent useful early endpoints in exposure intervention of chemoprevention studies. The successful applicability of DNA adducts as early endpoints depends on several criteria:i.adduct levels in easily accessible surrogate tissues should reflect adduct levels in target-tissues, ii. toxicokinetics and the temporal relevance should be properly defined.iii. sources of inter- and intra-individual variability must be known and controllable, and finally iv. adduct analyses must have advantages as compared to other markers of PAH-exposure. In general, higher DNA adduct levels or a higher proportion of subjects with detectable DNA adduct levels were found in exposed individuals as compared with non-exposed subjects, but saturation may occur at high exposures. Furthermore, DNA adduct levels varied according to changes in exposure, for example smoking cessation resulted in lower DNA adduct levels and adduct levels paralleled seasonal variations of air-pollution. Intra-individual variation during continuous exposure was low over a short period of time (weeks), but varied significantly when longer time periods (months) were investigated. Inter-individual variation is currently only partly explained by genetic polymorphisms in genes involved in PAH-metabolism and deserves further investigation. DNA adduct measurement may have three advantages over traditional exposure assessment: i. they can smooth the extreme variability in exposure which is typical for environmental toxicants and may integrate exposure over a longer period of time. Therefore, DNA adduct assessment may reduce the monitoring effort. ii. Biological monitoring of DNA adducts accounts for all exposure routes. iii. DNA adducts may account for inter-individual differences in uptake, elimination, distribution, metabolism and repair amongst exposed individuals. In conclusion, there is now a sufficiently large scientific basis to justify the application of DNA adduct measurement as biomarkers in exposure assessment and intervention studies. Their use in risk-assessment, however, requires further investigation.

• 한국산업보건학회지
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• 제8권2호
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• pp.289-295
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• 1998

Used gasoline engine oils(UGEO) are carcinogenic in long term studies and capable of increasing the number of carcinogen-DNA adducts in short term studies when dermally applied to mice. The carcinogenic risk of UGEO has been attributed to the concentration of polycyclic aromatic hydrocarbons(PAH) which accumulate in the lubricating system during the combustion of gasoline. When dermally exposed to UGEO, the use of hand cleanser was commonly recommended for removing it. But generally workers who dermally exposed oils, use kerosene as cleaner which make skin trouble. During this study, female mice aged 4-6 weeks were utilized to evaluate the efficiency of kerosene, as solvent-based cleanser, following dermal exposure to UGEO. DNA adduct were detected at skin and lung tissues by using the $^{32}P$-postlabeling method. Washing with cleansers were done at two different interval times following dermal application of UGEO. The total DNA adducts in skin and lung tissues were statistically significantly increased in positive control groups, and of which the total adduct level in skin tissues was statistically significant higher than those in lung tissues(p=0.005). When washing kerosene, the DNA adduct level in skin tissues was statistically significantly decreased(p=0.0001). But DNA adducts in lung tissue was statistically increased(p=0.0039), and that washed at 8hr post exposure was more severly increase(p<0.05). The slope of regression between DNA adducts of lung between skin tissues was 1.0802. In conclusion, skin cleaning with kerosene facilitates passage of carcinogens to the lungs of animals dermally treated with used gasoline engine oils(UGEO).

• Journal of Ginseng Research
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• 제35권3호
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• pp.339-343
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• 2011

Polycyclic aromatic hydrocarbons (PAHs) are well known environmental carcinogens. PAH metabolites, especially BaP-7,8- dihydrodiol, 9,10 epoxide, initiate carcinogenesis via high specificity binding to DNA to form DNA adducts. The Korean red ginseng (KRG) from Panax ginseng has been suggested to protect against damages due to PAH exposure but the mechanism is unknown. Therefore, we investigated effects of KRG on PAH exposure using toxicokinetic methods and changes of PAH-induced oxidative damage during a 2 week-clinical trial (n=21 healthy young female, $23.71{\pm}2.43$ years). To analyze antioxidative effects of KRG, we measured changes in the levels of urinary malondialdehyde (MDA) before and after KRG treatment. We observed a significant positive association between levels of urinary MDA and 1-hydroxypyrene, a biomarker of PAH exposures (slope=1.47, p=0.03) and confirmed oxidative stress induced by PAH exposures. A reverse significant correlation between KRG treatment and level of urinary MDA was observed (p=0.03). In summary, results of our clinical trial study suggest that KRG plays a significant role in antioxidative as well as toxicokinetic pathways against PAHs exposure.

• Environmental Analysis Health and Toxicology
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• 제21권4호
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• pp.375-380
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• 2006

Endocrine disrupting chemicals (EDC) have been emphasized due to their threats in human health. Waste incinerator emission has been emphasized as a source of EDC including polychlorinateddibenzofurans(PCDD/F) and other carcinogenic polycyclic aromatic hydrocarbons (PAHs). Urinary 1-hydroxypyrene (1-OHP) has been used as an exposure biomarker for the PAHs. On the other hand, etheno-DNA adducts, e.g. 1, $N^6-ethenodeoxyadenosine({\varepsilon}dA)$, has been developed as an useful effective or response biomarker for carcinogenesis. Thus, I investigated association between urinary 1-OHP and ${\varepsilon}dA$ levels due to distance from an incinerator which was built more 10 years ago in the middle of a farm in P city. I designated the EDC-high and low exposed group due to distance from the incinerator, i.e. within 2.5km and $5.0{\sim}7.5km$ from the incinerator, respectively. The study subjects were age and sex-matched males and females (mean age, $61.3{\pm}9.6$ yrs; total 40 persons, male, 10; female, 10 for the each group). Urinary 1-OHP and ${\varepsilon}dA$ were analyzed with HPLC-FD and IP-HPLC-FD, respectively. As results, the distance from the incinerator was not associated with urinary 1-OHP nor ${\varepsilon}dA$ levels (p=0.43 and 0.82, respectively). On the other hand, urinary ${\varepsilon}dA$ levels were significantly higher in the hyperlipidemia group (N=10) than normal group (N=30). In conclusion, urinary 1-OHP nor ${\varepsilon}dA$ levels can not be suggested as an incinerator-related exposure nor effective biomarker. However, not only distance from the incinerator bot also systemic approaches including wind and soil contamination are required to assume exposure levels of incinerator-related EDC.

• Journal of Ginseng Research
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• 제13권1호
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• pp.42-48
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• 1989

PAH 계 화합물들의 Bay region diol epoxide 들의 target tissue에 대한 결합은 암유발과 관련 되어 있다. 본 논문에서는 ICR mice의 간에서의 BP-DNA-adduct 생성에 미치는 poly acetylene 화합물인 panaxynol 과 panaxydol 의 효과를 조사하였 다. Panaxynol 과 panaxydol 을 전처리한 ICR mice 의 간 마이크로좀을 포함하는 incubation system 은 calf thymus DNA 에 대한 BP binding을 뚜렷이 감소시켰다. [$^3H$]-BP($300\mu$Ci/21nmoles/0.1ml DMSO. i. v. ) 즐 mice 에 주사 후 24시간 후에 간 DNA 에서의 방사능을 측정하였다. HPLC 에 의해 cochromatography 한 두개의 standard marker (acetophenone. bytyrophenone)을 사이에 나타나는 DNA adduct 들을 잠정적으로 확인한 결과 (-) BP-7.8-diol로부터 생성되는 major adduct 인 (+) BP-diol epoxide I: dGuo adduct (peak II)는 대조군보다 약 22% 감소된 반면에 minor adduct 인 (-) BP-diol epoxide I: dGuo adduct (peak III)는 대조군의 69%로 감소되었다. 그리고 (+) BP-7, 8-diol로부 터 생성되는 minor adduct 인 BP-diol epoxide I II : Guo adduct (peak IV)는 대조군의 58%로 감소되었다. 이러한 결과는 panaxydol이 ($\pm$) B BP-7,8-diol로부터 일반적으로 생성되는 adduct들 중 major보다는 minor adduct들의 생성에 더 많이 관석했음을 보여준다.

• Toxicological Research
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• 제25권2호
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• pp.85-92
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• 2009

4,4'-Methylenedianiline (MDA) is an aromatic amine that is widely used in the industrial synthetic process. Genotoxic MDA forms DNA adducts in the liver and is known to induce liver damage in human and rats. To elucidate the molecular mechanisms associated with MDA-induced hepatotoxicity, we have identified genes differentially expressed by microarray approach. BALB/c male mice were treated once daily with MDA (20 mg/kg) up to 7 days via intraperitoneal injection (i.p.) and hepatic damages were revealed by histopathological observation and elevation of serum marker enzymes such as AST, ALT, ALP, cholesterol, DBIL, and TBIL. Microarray analysis showed that 952 genes were differentially expressed in the liver of MDA-treated mice and their biological functions and canonical pathways were further analyzed using Ingenuity Pathways Analysis (IPA). Toxicological functional analysis showed that genes related to hepatotoxicity such hyperplasia/hyperproliferation (Timp1), necrosis/cell death (Cd14, Mt1f, Timp1, and Pmaip1), hemorrhaging (Mt1f), cholestasis (Akr1c3, Hpx, and Slc10a2), and inflammation (Cd14 and Hpx) were differentially expressed in MDA-treated group. This gene expression profiling should be useful for elucidating the genetic events associated with aromatic amine-induced hepatotoxicity and for discovering the potential biomarkers for hepatotoxicity.

• Toxicological Research
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• 제21권2호
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• pp.99-105
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• 2005

Photo-mutagenic compounds have been known to alter skin cancer rates by acting as initiators or by affecting subsequent steps in carcinogenesis. The objectives of this study are to investigate the utility of photo-chromosomal aberration (photo-CA) assay for detecting photo-clastogens, and to evaluate its ability to predict rodent photocarcinogenicity. Photo-CA assay was performed with five test substances that demonstrated positive results in photo-carcinogenicity tests: 8-Methoxypsoralen (photoactive substance that forms DNA adducts in the presence of ultraviolet A irradiation), chlorpromazine (an aliphatic phenothiazine an alpha-adrenergic blocking agent), lomefloxacin (an antibiotic in a class of drugs called fluoroquinolones), anthracene (a tricyclic aromatic hydrocarbon a basic substance for production of anthraquinone, dyes, pigments, insecticides, wood preservatives and coating materials) and Retinoic acid (a retinoid compound closely related to vitamin A). For the best discrimination between the test substance-mediated genotoxicity and the undesirable genotoxicity caused by direct DNA absorption, a UV dose-response of the cells in the absence of the test substances was firstly analyzed. All 5 test substances showed a positive outcome in photo-CA assay, indicating that the photo-CA test is very sensitive to the photo-genotoxic effect of UV irradiation. With this limited data-set, an investigation into the predictive value of this photo-CA test for determining the photo-carcinogenicity showed that photo-CA assay has the high ability of a test to predict carcinogenicity. Therefore, the photo-CA test using mammalian cells seems to be a sensitive method to evaluate the photo-carcinogenic potential of new compounds.

• 한국환경성돌연변이발암원학회지
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• 제25권1호
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• pp.6-12
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• 2005

Many compounds might become activated after absorption of UV light energy. In some cases, the resulting molecule may undergo further biological reaction of toxicological relevance related especially to the photo-carcinogenicity resulting from photo-genotoxicity. However, no regulatory requirements have been issued with the exception of guideline issued by the Scientific Committee of Cosmetology, Commission of the European Communities (SCC/EEC) on the testing of sunscreens for their photo-genotoxicity. Thus, the objectives of this study are to investigate the utility of photo-Ames assay for detecting photo-mutagens, and to evaluate its ability to predict rodent photo-carcinogenicity. Photo-Ames assay was performed on five test substances that demonstrated positive results in photo-carcinogenicity tests: 8-methoxypsoralen (photoactive substance that forms DNA adducts in the presence of ultraviolet A irradiation), chlorpromazine (an aliphatic phenothiazine an a-adr-energic blocking agent), lomefloxacin (an antibiotic in a class of drugs called fluoroquinolones), anthracene (a tricyclic aromatic hydrocarbon a basic substance for production of anthraquinone, dyes, pigments, insecticides, wood preservatives and coating materials) and retinoic acid (a retinoid compound closely related to vitamin A). Out of 5 test substances, 3 showed a positive outcome in photo-Ames assay. With this limited data set, an investigation into the predictive value of this photo-Ames test for determining the photo-carcinogenicity showed that photo-Ames assay has relatively low sensitivity (the ability of a test to predict carcinogenicity). Thus, to determine the use of in vitro genotoxicity tests for prediction of carcinogenicity,' several standard photo-genotoxicity assays should be compared for their suitability in detecting photo-genotoxic compounds.