Annals of Occupational and Environmental Medicine

Review

Gene mutation discovery research of non-smoking lung cancer patients due to indoor radon exposure: Jung Ran Choi, Seong Yong Park, O Kyu Noh, Young Wha Koh, Dae Ryong Kang; Ann Occup Environ Med 2016;28:13. Published online March 16, 2016; DOI: https://doi.org/10.1186/s40557-016-0095-2

Although the incidence and mortality for most cancers such as lung and colon are decreasing in several countries, they are increasing in several developed countries because of an unhealthy western lifestyles including smoking, physical inactivity and consumption of calorie-dense food. The incidences for lung and colon cancers in a few of these countries have already exceeded those in the United States and other western countries. Among them, lung cancer is the main cause of cancer death in worldwide. The cumulative survival rate at five years differs between 13 and 21 % in several countries. Although the most important risk factors are smoking for lung cancer, however, the increased incidence of lung cancer in never smokers(LCINS) is necessary to improve knowledge concerning other risk factors. Environmental factors and genetic susceptibility are also thought to contribute to lung cancer risk. Patients with lung adenocarcinoma who have never smoking frequently contain mutation within tyrosine kinase domain of the epidermal growth factor receptor(EGFR) gene. Also, K-ras mutations are more common in individuals with a history of smoking use and are related with resistance to EFGR-tyrosine kinase inhibitors. Recently, radon(Rn), natural and noble gas, has been recognized as second common reason of lung cancer. In this review, we aim to know whether residential radon is associated with an increased risk for developing lung cancer and regulated by several genetic polymorphisms.

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Analysis of human papillomaviruses and human polyomaviruses in lung cancer from Swedish never-smokers
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Gene polymorphism of DNA repair gene X‐ray repair cross complementing group 1 and xeroderma pigmentosum group D and environment interaction in non‐small‐cell lung cancer for Chinese nonsmoking female patients
Lei Wang, Le‐Le Wang, Di Shang, Sheng‐Jie Yin, Li‐Li Sun, Xiao‐Ying Wang, Hong‐Bo Ji
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Qiaowei Liu, Hao Li, Lukuan You, Tao Li, Lingling Li, Pingkun Zhou, Xiaochen Bo, Hebing Chen, Xiaohua Chen, Yi Hu, Christophe Antoniewski
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Non-Smoking-Associated Lung Cancer: A distinct Entity in Terms of Tumor Biology, Patient Characteristics and Impact of Hereditary Cancer Predisposition
Elisabeth Smolle, Martin Pichler
Cancers.2019; 11(2): 204. CrossRef
Indoor radon exposure increases tumor mutation burden in never-smoker patients with lung adenocarcinoma
Sun Min Lim, Jae Woo Choi, Min Hee Hong, Dongmin Jung, Chang Young Lee, Seong Yong Park, Hyo Sup Shim, Seungsoo Sheen, Kyeong Im Kwak, Dae Ryong Kang, Byoung Chul Cho, Hye Ryun Kim
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Radon and Lung Cancer: Disease Burden and High-risk Populations in Korea
Young Woo Jin, Songwon Seo
Journal of Korean Medical Science.2018;[Epub] CrossRef
Radon Exposure-induced Genetic Variations in Lung Cancers among Never Smokers
Jung Ran Choi, Sang Baek Koh, Hye Ryun Kim, Hyojin Lee, Dae Ryong Kang
Journal of Korean Medical Science.2018;[Epub] CrossRef
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Original Article

The Association among Exposure of Bisphenol A, Genetic Polymorphism of Metabolic Enzyme and Urinary Metabolite: Sang Baek Koh, Jun Ho Park, Su Song Yun, Sung Su Oh, Sei Jin Chang, Sun Haeng Choi, Bong Suk Cha; Korean Journal of Occupational and Environmental Medicine 2008;20(2):112-118. Published online June 30, 2008; DOI: https://doi.org/10.35371/kjoem.2008.20.2.112

Abstract PDF

OBJECTIVES
To examine bisphenol A (BPA) exposure with subjects in the manufacturing industry and to determine its correlation with metabolites according to genetic polymorphism of metabolic enzymes.
METHODS
The study subjects comprised 104 workers in the manufacturing industry, 64 and 40 in the exposed and control groups, respectively. The questionnaire variablesincluded age, use of protective equipment, smoking habit and alcohol intake. Their urine samples were collected in the afternoon and urinary BPA concentration was measured by revising with the urinary creatinine concentration. The genetic polymorphism of the metabolic enzymes was examined by using restriction fragment length polymorphism (RFLP) after extracting DNA from leucocytes.
RESULTS
The minimum and maximum BPA level of the exposed group during working time was 34.22 and 221.20 ng/mg, respectively. The urinary BPA concentration was significantly higher in the exposed groups than in the control group. There was no significant difference in the urinary BPA level according to genetic polymorphism of CYP1A1 and CYP2E1, but UGT1A6 showed a significant difference. In multiple regression analysis on the urinary and airborne BPA levels, UGT1A6, use of protective equipments and workplaces were significant variables.
CONCLUSIONS
The urinary BPA concentration was affected by the levels to which workers were exposed during their working time and was considered to be metabolized by UGT1A6.

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Filling gaps between exposure modeling and the analysis of urinary biomarkers using personal air monitoring: An intervention study of permethrin used in home insecticide spray
Seon‐Kyung Park, Heon‐Jun Lee, Eugene Song, Yerin Jung, Hyun Jung Yoo, Jeong‐Eun Oh, Hyeong‐Moo Shin, Jung‐Hwan Kwon
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Study Design, Rationale and Procedures for Human Biomonitoring of Hazardous Chemicals from Foods and Cooking in Korea
Seokwon Lee, Ryoung Me Ahn, Jae Hyoun Kim, Yoon-Deok Han, Jin Heon Lee, Bu-Soon Son, Kyoungho Lee
International Journal of Environmental Research and Public Health.2019; 16(14): 2583. CrossRef

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Original Article

Effect of Genetic Polymorphisms of CYP2E1 and ALDH2 on the Relationship between the Levels of Urinary 8-Hydroxydeoxyguanosine and t,t-Muconic Acid: Yong Dae Kim, Jong Won Kang, Sang Yong Eom, Yan Wei Zhang, Sung Hoon Kim, Eun Young Kim, Chul Ho Lee, Jai Dong Moon, Heon Kim; Korean Journal of Occupational and Environmental Medicine 2007;19(2):164-170. Published online June 30, 2007; DOI: https://doi.org/10.35371/kjoem.2007.19.2.164

Abstract PDF: OBJECTIVES
This study was performed to investigate the effect of genetic polymorphisms on the oxidative genetic damage caused by benzene exposure in workers.
METHODS
We measured urinary t,t-muconic acid levels as a biomarker for benzene exposure and measured the level of urinary 8-OHdG to assess oxidative DNA damage in benzene-exposed healthy male workers. Genetic polymorphisms of ALDH2 and CYP2E1 were determined by TaqMan assay. We estimated Pearson correlation coefficients between urinary t,t-muconic acid and 8-OHdG according to the genetic polymorphisms of CYP2E1 and ALDH2.
RESULTS
There was a significant relationship between urinary t,t-muconic acid and 8-OHdG concentrations in overall subjects (R=0.532, p<0.001). Smokers showed a higher correlation coefficient between the markers than nonsmokers did (R=0.520 vs. 0.010). Individuals with CYP2E1 c1/c1 genotype also showed a higher correlation coefficient between them than those with CYP2E1 c1/c2 or c2/c2 genotypes (R=0.670 vs. -0.145). In multiple linear regression analysis including smoking status, sorbic acid intake, age and genetic polymorphisms of CYP2E1 and ALDH2 as the independent variables, urinary t,t-muconic acid showed a significant association with urinary 8-OHdG.
CONCLUSIONS
There was a significant correlation between urinary 8-OHdG and urinary t,t-muconic acid in benzene-exposed workers. This relationship was affected by genetic polymorphisms of CYP2E1and ALDH2.

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Original Article

The Association between Pneumoconiosis and Genetic Polymorphism of GSTM1, GSTT1, GSTP1, NAT2, CYP2E1 and CYP1A1: Cha Jae Oh, Moon Young Hwang, Kang Jin Lee, Hoo Rak Lee, Byung Mann Cho; Korean Journal of Occupational and Environmental Medicine 2005;17(2):85-94. Published online June 30, 2005; DOI: https://doi.org/10.35371/kjoem.2005.17.2.85

Abstract PDF: OBJECTIVES
To investigate effects of genetic polymorphism of glutathione S-transferase M1 (GSTM1), glutathione S-transferase T1 (GSTT1), glutathione S-transferase P1 (GSTP1), N-acetyltransferase (NAT2), cytochrome P450 2E1 (CYP2E1) and cytochrome P450 1A1 (CYP1A1) on pneumoconiosis.
METHODS
Eighty-five pneumoconiosis patients and 122 age and sex matched healthy controls were enrolled. Direct interview and standard questionnaire were conducted and the genotypes of GSTM1, GSTT1, GSTP1, NAT2, CYP2E1 and CYP1A1 were investigated using multiplex PCR or PCR-RFLP methods with DNA extracted from venous blood. The relationship was investigated between the severity of pneumoconiosis and the polymorphism of GSTM1, GSTT1, GSTP1, NAT2, CYP2E1 and CYP1A1, and also with various environmental factors including smoking.
RESULTS
We observed a significantly higher rate of genetic polymorphism in pneumoconiosis patients than in normal subjects. The odds ratio (95% CI) of NAT2 was 2.09 (1.19-3.68). In addition, smoking was related significantly with pneumoconiosis (OR 2.89, 95% CI 1.40-5.95). In multiple logistic regression analyses, NAT2 and smoking were significant risk factors for the development of pneumoconiosis (OR 1.84, 95% CI 1.00-3.37; OR 2.98, 95% CI 1.40-6.35, respectively). The age of onset of the disease and smoking were significantly related with moderate or severe pneumoconiosis (OR 0.91, 95% CI 0.83-0.99; OR 6.94, 95% CI 1.54-31.30, respectively). However there was no significant difference between the rate of genetic polymorphism of GSTM1, GSTT1, GSTP1, CYP2E1 and CYP1A1 in the two groups.
CONCLUSION
NAT2 genetic polymorphism was higher in pneumoconiosis patients than in normal subjects. The age of onset of the disease and smoking were significantly related with pneumoconiosis. However, the genetic polymorphism of GSTM1, GSTT1, GSTP1, CYP2E1 and CYP1A1 was not related with development or severity of pneumoconiosis.

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Original Article

CYP2E1 Genetic Polymorphism relating to Styrene Metabolism of Korean Workers: Chang Hee Lee, Jin Ho Chun, Jun Han Park, Dong Mug Kang, Dae Hwan Kim, Deog Hwan Moon, Chae Un Lee; Korean Journal of Occupational and Environmental Medicine 1999;11(2):161-173. Published online June 30, 1999; DOI: https://doi.org/10.35371/kjoem.1999.11.2.161

Abstract PDF: The goal of this study is to observe the associations between the metabolic phenotype by personal exposure and urinary metabolites and genetic polymorphism of CYP2E1 which is known to be related with styrene metabolism. To complete this study, the author executed a battery of tests on 46 workers who were working at laminating department of fiberglass- reinforced plastics (FRP) industry located in Pusan and Kyungnam area during April to June 1998. Those were - (1) personal exposure assessment with organic vapour monitor and gas chromatography. (2) measurement of urinary metabolites - mandelic acid (MA) and phenylglyoxylic acid (PGA) - with high performance liquid chromatography (HIPLC), (3) CYP2E1 genotying with PCR and restriction fragment length polymorphism (RFLP) using Dra I and Rsa I, and (4) questionnaire survey for some individual characteristics. Study subjects were composed of 32 men and 14 women, and whose average age was 39.4 years, average tenure was 7.7 years. Each concentration expressed by geometric mean(range) was as follows; air styrene 15.6(3.1-81.0) ppm, urinary MA 187.8(36.8-1007.2) mg/g creatinine, PGA 232.8(46.8-1075.7) mg/g creatinine. Correlation coefficients between air styrene were MA 0.54, PGA 0.37, MA+PGA 0.54 (p < 0.05). The relative frequency of CYP2E1 mutant allele was 45.7%(Dra I 43.5%, lIsa 1 37.0%), and homozygous mutant type (M/M) was not observed. The value of (geometric mean of (air styrene/urinary metabolites)) x 1000 according to genotype was significantly higher in mutant type than wild type (p<0.05), as in case of MA, mutant type 106.4 and wild type 84.4, and in case of MA+PGA, mutant type 84.4 and wild type 55.6. The value of air styeneTLV-TWA/urinary metabolitesBEI was used as a cut-off value of classifying phenotype. That is, the value of air styeneTLV-TWA/urinary MABEI >or= 0.063 and air styreneTLV-TWA/urinary MA+PGABEI >or= 0.048 was classified as poor metabolizer, and, the value of air styreneTLV-TWA/urinary MABEI~ < 0.063 and air styreneThV~A/urinary MA+PGABEI < 0.048 was classified as extensive metabolizer. As the result, the frequency of poor metabolizer was higher in mutant type than wild type with no statistical significance (p > 0.05), as in case of MA, mutant type 66.7% and wild type 48.0%, and in case of MA+PGA, mutant type 81.0% and wild type 56.0%. These results suggests that CYP2E1 mutant allele has a tendency toward the poor metabolizer. This study has several limitations as small sample size, and no considerations on work intensity, alcohol habit, obesity, etc which can affect styrene metabolism. However, this study is of value because this is first study to propose the fundamental data about associations between exposure level, biological monitoring, and CYP2E1 genetic polymorphism in Korean workers dealing with pure styrene. To improve accuracy of the study, that means, to applicate the result of this study on the personal risk assessment of styrene workers, larger sample size and consideration for confounders are needed.

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Original Article

ALDH2 Genetic Polymorphism and Urinary Hippuric Acid Concentration in Toluene Exposed Workers: Oh Choon Kwon, Ree Joo, Jung Jeung Lee, Chang Yoon Kim, Jong Hak Chung, Seong Yong Kim; Korean Journal of Occupational and Environmental Medicine 1997;9(2):332-340. Published online June 30, 1997; DOI: https://doi.org/10.35371/kjoem.1997.9.2.332

Abstract PDF: In this study we evaluated the effects of the genetic polymorphism of aldehyde dehydrogenase2 (ALDH2) on toluene metabolism and determined biological exposure indices (BEIs) for toluene by the genotypes of ALDH2. The study subject were 77 men workers who are handling toluene in a video tape manufacturing factory and a textile company. Through the face-to-face interview, the information about smoking and drinking behavior wag obtained. For determination of ALDH2 poly morphism, 5 ml of venous blood sample was obtained from each subject after informed consent. DNA was extracted from the buffy coat and ALDH2 genotyping were performed using a polymerase chain reaction (PCR) method. The genotype of ALDH2 was classified into the homozygous genotype of normal ALDH2 (NN), and the heterozygous genotype of normal and inactive ALDH2 (ND), and homozygous genotype of an inactive ALDH2(DD). The concentration of hippuric acid (HA), the main metabolite of toluene, was determined in urine specimens collected at the end of shift, corrected with creatinine (HA/C), and compared with BEI for toluene, which is 2.5 g/g creatinine. The personal exposure level of toluene were monitored, using personal air sampler and analyzed by gas chromatography. The frequencies of the three genotypes in this study subjects were, NN : 45 (58.4%), ND : 26 (33.8%) and DD : 6 (7.8%), and frequencies of the genotypes in the middle or heavy toluene exposure workers were not significantly different from those in the mild toluene exposure workers. The frequencies of the DD type of ALDH2 was lower among alcohol drinkers than among non-drinkers. The urinary HA concentration of DD group was significantly lower than that of the NN or ND group, which suggests that the HA formation from toluene decreased in DD group. Regression lines were used to estimate the BEIs of the NN, ND, and DD groups. NN : y = 0.0085x + 0.23, r = 0.90 ND : y = 0.0074x + 0.21, r = 0.85 DD : y = 0.0041x + 0.82, r = 0.83 The three regression lines revealed that the estimated urinary HA concentration of NN, ND, and DD groups at 377 mg/m3 toluene(TLV-TWA) exposure were 3.43, 3.00, and 2.37 g/g creatinine, respectively. The HA concentration of the NN, and ND group were higher than that of the ACGIH BEI (2.5 g/g creatinine) ; however, the HA level of DD group was lower than the BEI. These results suggests that the ACGIH BEI is not adequate to estimate the toluene exposure of the NN, ND and DD groups at the same time. Based upon those results, a new BEI for ALDH2 deficient workers may be necessary.

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