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Title: Urinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic exposure

Abstract

8-Hydroxydeoxyguanosine (8-OHdG) is one of the most reliable and abundant markers of DNA damage. The study was designed to explore the relationship between urinary 8-OHdG and renal cell carcinoma (RCC) and to investigate whether individuals with a high level of 8-OHdG would have a modified odds ratio (OR) of arsenic-related RCC. This case–control study was conducted with 132 RCC patients and 245 age- and sex-matched controls from a hospital-based pool between November 2006 and May 2009. Pathological verification of RCC was completed by image-guided biopsy or surgical resection of renal tumors. Urinary 8-OHdG levels were determined using liquid chromatography with tandem mass spectrometry (LC–MS/MS). Concentrations of urinary arsenic species, including inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Level of urinary 8-OHdG was significantly associated with the OR of RCC in a dose–response relationship after multivariate adjustment. Urinary 8-OHdG was significantly related to urinary total arsenic. The greatest OR (3.50) was seen in the individuals with high urinary 8-OHdG and high urinary total arsenic. A trend test indicated that the OR of RCC was increased with one of these factors and was further increased withmore » both (p = 0.002). In conclusion, higher urinary 8-OHdG was a strong predictor of the RCC. High levels of 8-OHdG combined with urinary total arsenic might be indicative of arsenic-induced RCC. -- Highlights: ► Urinary 8-OHdG was significantly related to urinary total arsenic. ► Higher urinary 8-OHdG was a strong predictor of RCC risk. ► Urinary 8-OHdG may modify arsenic related RCC risk.« less

Authors:
 [1];  [2];  [3];  [4];  [2];  [5];  [1];  [2];  [6];  [6];  [2];  [7];  [2]
  1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)
  2. (China)
  3. Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan (China)
  4. Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan (China)
  5. Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan (China)
  6. School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan (China)
  7. Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)
Publication Date:
OSTI Identifier:
22215872
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 262; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ABSORPTION SPECTROSCOPY; ARSENIC; BIOPSY; CARCINOMAS; CONCENTRATION RATIO; HEALTH HAZARDS; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; HOSPITALS; IMAGES; KIDNEYS; MASS SPECTROSCOPY; MULTIVARIATE ANALYSIS; PATIENTS

Citation Formats

Huang, Chao-Yuan, Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan, Su, Chien-Tien, Chung, Chi-Jung, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Pu, Yeong-Shiau, Chu, Jan-Show, Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan, Yang, Hsiu-Yuan, Wu, Chia-Chang, Department of Urology, Taipei Medical Universtiy-Shuang Ho Hospital, Taipei, Taiwan, Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw, and School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan. Urinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic exposure. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.05.013.
Huang, Chao-Yuan, Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan, Su, Chien-Tien, Chung, Chi-Jung, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Pu, Yeong-Shiau, Chu, Jan-Show, Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan, Yang, Hsiu-Yuan, Wu, Chia-Chang, Department of Urology, Taipei Medical Universtiy-Shuang Ho Hospital, Taipei, Taiwan, Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw, & School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan. Urinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic exposure. United States. doi:10.1016/J.TAAP.2012.05.013.
Huang, Chao-Yuan, Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan, Su, Chien-Tien, Chung, Chi-Jung, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, Pu, Yeong-Shiau, Chu, Jan-Show, Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan, Yang, Hsiu-Yuan, Wu, Chia-Chang, Department of Urology, Taipei Medical Universtiy-Shuang Ho Hospital, Taipei, Taiwan, Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw, and School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan. 2012. "Urinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic exposure". United States. doi:10.1016/J.TAAP.2012.05.013.
@article{osti_22215872,
title = {Urinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic exposure},
author = {Huang, Chao-Yuan and Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan and Su, Chien-Tien and Chung, Chi-Jung and Department of Medical Research, China Medical University Hospital, Taichung, Taiwan and Pu, Yeong-Shiau and Chu, Jan-Show and Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan and Yang, Hsiu-Yuan and Wu, Chia-Chang and Department of Urology, Taipei Medical Universtiy-Shuang Ho Hospital, Taipei, Taiwan and Hsueh, Yu-Mei, E-mail: ymhsueh@tmu.edu.tw and School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan},
abstractNote = {8-Hydroxydeoxyguanosine (8-OHdG) is one of the most reliable and abundant markers of DNA damage. The study was designed to explore the relationship between urinary 8-OHdG and renal cell carcinoma (RCC) and to investigate whether individuals with a high level of 8-OHdG would have a modified odds ratio (OR) of arsenic-related RCC. This case–control study was conducted with 132 RCC patients and 245 age- and sex-matched controls from a hospital-based pool between November 2006 and May 2009. Pathological verification of RCC was completed by image-guided biopsy or surgical resection of renal tumors. Urinary 8-OHdG levels were determined using liquid chromatography with tandem mass spectrometry (LC–MS/MS). Concentrations of urinary arsenic species, including inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Level of urinary 8-OHdG was significantly associated with the OR of RCC in a dose–response relationship after multivariate adjustment. Urinary 8-OHdG was significantly related to urinary total arsenic. The greatest OR (3.50) was seen in the individuals with high urinary 8-OHdG and high urinary total arsenic. A trend test indicated that the OR of RCC was increased with one of these factors and was further increased with both (p = 0.002). In conclusion, higher urinary 8-OHdG was a strong predictor of the RCC. High levels of 8-OHdG combined with urinary total arsenic might be indicative of arsenic-induced RCC. -- Highlights: ► Urinary 8-OHdG was significantly related to urinary total arsenic. ► Higher urinary 8-OHdG was a strong predictor of RCC risk. ► Urinary 8-OHdG may modify arsenic related RCC risk.},
doi = {10.1016/J.TAAP.2012.05.013},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 262,
place = {United States},
year = 2012,
month = 8
}
  • Arsenic is a well-documented human carcinogen and is known to cause oxidative stress in cultured cells and animals. A hospital-based case-control study was conducted to evaluate the relationship among the levels of urinary 8-hydroxydeoxyguanosine (8-OHdG), the arsenic profile, and urothelial carcinoma (UC). Urinary 8-OHdG was measured by using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. The urinary species of inorganic arsenic and their metabolites were analyzed by high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). This study showed that the mean urinary concentration of total arsenics was significantly higher, at 37.67 {+-} 2.98 {mu}g/g creatinine, for UC patients thanmore » for healthy controls of 21.10 {+-} 0.79 {mu}g/g creatinine (p < 0.01). Urinary 8-OHdG levels correlated with urinary total arsenic concentrations (r = 0.19, p < 0.01). There were significantly higher 8-OHdG levels, of 7.48 {+-} 0.97 ng/mg creatinine in UC patients, compared to healthy controls of 5.95 {+-} 0.21 ng/mg creatinine. Furthermore, female UC patients had higher 8-OHdG levels of 9.22 {+-} 0.75 than those of males at 5.76 {+-} 0.25 ng/mg creatinine (p < 0.01). Multiple linear regression analyses revealed that high urinary 8-OHdG levels were associated with increased total arsenic concentrations, inorganic arsenite, monomethylarsonic acid (MMA), and dimethylarsenate (DMA) as well as the primary methylation index (PMI) even after adjusting for age, gender, and UC status. The results suggest that oxidative DNA damage was associated with arsenic exposure, even at low urinary level of arsenic.« less
  • Our recent study demonstrated the increased risk of renal cell carcinoma (RCC) associated with high urinary total arsenic levels among people living in a low arsenic exposure area. Genomic instability is important in arsenic carcinogenesis. This study evaluated the relationship between the polymorphisms of p53, p21, and MDM2, which plays a role in gene stability, and the arsenic-related RCC risk. Here, we found that p53 Pro/Pro genotype and MDM2 SNP309 GG genotype significantly increased RCC risk compared to the p53 Arg/Arg genotype and MDM2 SNP309 TT genotype. RCC patients with the p53Arg/Arg genotype had a signicantly low percentage of inorganicmore » arsenic, a low percentage of monomethylarsonic acid (MMA), and a high percentage of dimethylarsinic acid (DMA), which indicates efcient arsenic methylation capacity. Subjects with the p53 Arg/Pro + Pro/Pro genotype or MDM2 SNP309 TG + GG genotype, in conjunction with high urinary total arsenic ({>=} 14.02 {mu}g/L), had a signicantly higher RCC risk than those with the p53 Arg/Arg or MDM2 SNP309 TT genotypes and low urinary total arsenic. Taken together, this is the first study to show that a variant genotype of p53 Arg{sup 72}Pro or MDM2 SNP309 may modify the arsenic-related RCC risk even in a non-obvious arsenic exposure area. -- Highlights: Black-Right-Pointing-Pointer Subjects with p53 Pro/Pro or MDM2 GG genotype significantly increased RCC risk. Black-Right-Pointing-Pointer A significant multiplicative joint effect of p53 and p21 on RCC risk. Black-Right-Pointing-Pointer RCC patients with p53 Arg/Arg genotype had efficient arsenic methylation capacity. Black-Right-Pointing-Pointer Joint effect of p53 or MDM2 genotype and high urinary total arsenic on RCC risk.« less
  • Arsenic exposure is associated with an increased risk of urothelial carcinoma (UC). To explore the association between individual risk and urinary arsenic profile in subjects without evident exposure, 177 UC cases and 313 age-matched controls were recruited between September 2002 and May 2004 for a case-control study. Urinary arsenic species including the following three categories, inorganic arsenic (As{sup III} + As{sup V}), monomethylarsonic acid (MMA{sup V}) and dimethylarsinic acid (DMA{sup V}), were determined with high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Arsenic methylation profile was assessed by percentages of various arsenic species in the sum of the threemore » categories measured. The primary methylation index (PMI) was defined as the ratio between MMA{sup V} and inorganic arsenic. Secondary methylation index (SMI) was determined as the ratio between DMA{sup V} and MMA{sup V}. Smoking is associated with a significant risk of UC in a dose-dependent manner. After multivariate adjustment, UC cases had a significantly higher sum of all the urinary species measured, higher percent MMA{sup V}, lower percent DMA{sup V}, higher PMI and lower SMI values compared with controls. Smoking interacts with the urinary arsenic profile in modifying the UC risk. Differential carcinogenic effects of the urinary arsenic profile, however, were seen more prominently in non-smokers than in smokers, suggesting that smoking is not the only major environmental source of arsenic contamination since the UC risk differs in non-smokers. Subjects who have an unfavorable urinary arsenic profile have an increased UC risk even at low exposure levels.« less
  • To compare the differences in DNA aberrations between arsenic-exposed and non-arsenic-exposed transitional cell carcinoma (TCC), we analyzed 19 arsenic-exposed and 29 non-arsenic-exposed urinary TCCs from Chi-Mei Hospital using comparative genomic hybridization. DNA aberrations were detected in 42 TCCs including 19 arsenic-exposed and 23 non-arsenic-exposed TCCs. Arsenic-exposed TCCs had more changes than unexposed TCCs (mean {+-} SD, 6.6 {+-} 2.9 vs. 2.9 {+-} 2.2). Arsenic exposure was significantly associated with the number of DNA aberrations after adjustment for tumor stage, tumor grade and cigarette smoking in multiple regression analysis. The most frequent DNA gains, which were strikingly different between arsenic-exposed andmore » non-arsenic-exposed TCCs, included those at 1p, 4p, 4q and 8q. A much higher frequency of DNA losses in arsenic-exposed TCCs compared with non-arsenic-exposed TCCs was observed in 10q, 11p and 17p. Chromosomal loss in 17p13 was associated not only with arsenic exposure, but also with tumor stage and grade. The p53 immunohistochemistry staining showed that chromosome 17p13 loss was associated with either p53 no expression (25%) or p53 overexpression (75%). The findings suggest that long-term arsenic exposure may increase the chromosome abnormality in TCC, and 17p loss plays an important role in arsenic-induced urinary carcinogenesis.« less
  • Introduction: Polymorphisms in p53, p21 and CCND1 could regulate the progression of the cell cycle and might increase the susceptibility to inorganic arsenic-related cancer risk. The goal of our study was to evaluate the roles of cell cycle regulatory gene polymorphisms in the carcinogenesis of arsenic-related urothelial carcinoma (UC). Methods: A hospital-based case-controlled study was conducted to explore the relationships among the urinary arsenic profile, 8-hydroxydeoxyguanosine (8-OHdG) levels, p53 codon 72, p21 codon 31 and CCND1 G870A polymorphisms and UC risk. The urinary arsenic profile was determined using high-performance liquid chromatography (HPLC) and hydride generator-atomic absorption spectrometry (HG-AAS). 8-OHdG levelsmore » were measured by high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymerase (PCR-RFLP). Results: Subjects carrying the p21 Arg/Arg genotype had an increased UC risk (age and gender adjusted OR = 1.53; 95% CI, 1.02-2.29). However, there was no association of p53 or CCND1 polymorphisms with UC risk. Significant effects were observed in terms of a combination of the three gene polymorphisms and a cumulative exposure of cigarette smoking, along with the urinary arsenic profile on the UC risk. The higher total arsenic concentration, monomethylarsonic acid percentage (MMA%) and lower dimethylarsinic acid percentage (DMA%), possessed greater gene variant numbers, had a higher UC risk and revealed significant dose-response relationships. However, effects of urinary 8-OHdG levels combined with three gene polymorphisms did not seem to be important for UC risk. Conclusions: The results showed that the variant genotype of p21 might be a predictor of inorganic arsenic-related UC risk.« less