U
rinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area with out obvious arsenic exposure
Chao-Yuan Huang, MD,1,2 Chien-Tien Su, MD,3 Chi-Jung Chung, PhD,4,5 Yeong-Shiau Pu, MD, PhD,2 Jan-Show Chu, MD,1,6 Hsiu-Yuan Yang, MSc,7 Chia-Chang Wu, MD,7,8 Yu-Mei Hsueh, PhD,9,7
1Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
2Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan
3 Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
4Department of Health Risk Management, College of Public Health; China Medical University and Hospital, Taichung, Taiwan.
5 Department of Medical Research, China Medical University Hospital, Taichung, Taiwan. 6 Department of Pathology, College of Medicine, Taipei Medical University, Taipei, Taiwan 7 School of Public Health, College of Public Health and Nutrition, Taipei Medical University,
Taipei, Taiwan
8 Department of Urology, Taipei Medical Universtiy-Shuang Ho Hospital
9 Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Address correspondence to Yu-Mei Hsueh, PhD,
Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, No. 250 Wu-Hsing Street, Taipei 110, Taiwan.
E-mail: ymhsueh@tmu.edu.tw. TEL: 886-2-27361661 ext. 6513 FAX: 886-2-27384831
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 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.
Introduction
Previous epidemiologic studies have strongly implicated arsenic exposure in the etiology of human cancers of the skin, lung, and bladder (IARC, 2004). Renal cell carcinoma (RCC) accounts for 0.9% of all cancers in Taiwan (Bureau of Health Promotion, 2006). Previous studies reported that arsenic in drinking water is associated with kidney cancer (Chen et al., 1992; Yuan et al., 2010). A study showed that reduction in kidney cancer mortality following installation of a tap water supply system in an arsenic-endemic area of Taiwan supporting the likelihood of a causal association between arsenic exposure and kidney cancer (Yang et al., 2004). Our recent study demonstrated that individuals with high urinary total arsenic levels and low estimated glomerular filtration rates had a higher odds ratio (OR) of RCC than those with low urinary total arsenic levels and high estimated glomerular filtration rates in an area with low arsenic exposure (Huang et al., 2011). The carcinogenic property of arsenic is still unclear, but arsenic-induced oxidative DNA damage has been studied (Chung et al., 2008; Wen et al., 2011). Reactive oxygen species (ROS) can be formed during arsenic methylation (Nishikawa et al., 2002) and by stimulating the NADP(H) oxidase p22phox subunit (Chou et al., 2004; Bedard and Krause, 2007), which causes oxidative DNA damage. The activation of oxidative-sensitive signaling pathways could result in cell damage (Lii et al., 2010), chromosome instability (Liu et al., 2003), cell proliferation (Chowdhury et al., 2010), and altered telomerase activity and apoptosis (Shen et al., 2008), which may be involved in tumor progression or tumorigenesis.
ROS can interact with DNA and cause damage, including DNA breaks, deletions, and
nucleoside modifications (Valko et al., 2006). 8-Hydroxydeoxyguanosine (8-OHdG), the oxidized form of the nucleoside 2'-deoxyguanosine present in DNA, is one of the most reliable and abundant markers of DNA damage (Hu et al., 2006a). Liquid chromatography tandem mass spectrometry (LC-MS/MS) is a relatively new and powerful technology that overcomes the issues of sensitivity and selectivity that can compromise analysis of DNA damage (for example, of 8-OHdG) (Hu et al., 2010). Many studies have demonstrated that urinary 8-OHdG levels are higher in smokers (Han et al., 2010), cancer patients (Rozalski et al., 2002), patients with chronic renal failure (Akagi et al., 2003), and semiconductor workers exposed to low arsenic level could induce oxidative stress by measuring the level of urinary 8-oxodGuo (Hu et al., 2006a).
No previous study has elucidated the relationship of urinary arsenic species and ROS in RCC patients. Our study aimed to investigate the effect of urinary arsenic profile and urinary 8-OHdG level determined by LC-MS/MS on the RCC in individuals from an area with no obvious sources of arsenic exposure.
Materials and methods Study participants
Between November 2006 and May 2009, 132 patients with pathologically proven RCC were diagnosed and recruited from the Department of Urology, National Taiwan University Hospital. Pathological verification of RCC was completed by image-guided biopsy or surgical resection of renal tumors. The tumor-nodes-metastasis (TNM) classification of the American Joint Committee on Cancer was used for pathological staging (American Joint Committee on Cancer, 2002). Tumor grading was based on the Fuhrman grading system (Fuhrman et al., 1982). Two hundred forty five age- and gender-matched control individuals with no evidence of RCC or any other malignancy were recruited from those receiving adult health examinations at Taipei Municipal Wan Fang Hospital and those receiving senior citizen health examinations at Taipei Medical University Hospital (Huang et al., 2011). The Research Ethics Committee of National Taiwan University Hospital approved the study, and all patients signed informed consent forms before sample and data collections.
Questionnaire interview and biological specimen collection.
Highly trained personnel carried out standardized personal interviews based on a structured questionnaire during subject recruitment. Information collected included demographic and
socioeconomic characteristics, lifestyle factors such as consumption of alcohol, tea and coffee, and cigarette smoking in quantified detail, as well as histories of hypertension and diabetes (Huang et al., 2011). Daytime midstream urine samples and serum samples were collected. Serum creatinine level was measured after diagnosis but before surgery or treatment. Urine samples were stored at -20°C until analysis for urinary arsenic species.
Urinary creatinine level is used to adjust urinary analyte concentrations for variation in
hydration status (Barr et al., 2005). Therefore, we adjusted urinary total arsenic concentration with reference to the urinary creatinine value (mg/dL). According to one report comparing the
concentration of arsenic in individual urine voids with arsenic in a 24-hour urine collection, the concentration of arsenic in urine is stable throughout the day (Calderon et al., 1999). Therefore, we considered that arsenic levels in spot-collected urine samples reliably reflected arsenic excretion levels over 24 hours.
Determination of urinary arsenic species
Frozen urine samples were thawed at room temperature, dispersed by ultrasonic waves, filtered through a Sep-Pak C18 column (Mallinckrodt Baker Inc., NJ, USA). Arsenic species in a 200-L aliquot were determined using high performance liquid chromatography (HPLC; Waters 501, Waters Associates, Milford, MA, USA) with columns obtained from Phenomenex (Nucleosil, Torrance, CA, USA). The concentrations of arsenite (As3+), arsenate (As5+), monomethylarsonic acid (MMA5+) and dimethylarsinic acid (DMA5+) were quantified by hydride generator atomic
absorption spectrometry (Hsueh et al., 1997). This method for arsenic speciation is not influenced by the ingestion of shellfish, fish or other seafood (Hsueh et al., 2002). Recovery rates of the four arsenic species were calculated by [(sample spiked standard solution concentration) - sample concentration]/standard solution concentration × 100. Recovery rates for As3+, As5+, MMA5+, and DMA5+ ranged from 93.8% to 102.2%, with detection limits of 0.02, 0.06, 0.07, and 0.10 g/L, respectively. The standard reference material, SRM 2670, contained 480 ± 100 g/L inorganic arsenic and was obtained from the National Institute of Standards and Technology (NIST;
Gaithersburg, MD, USA) and was analyzed, as a quality standard, with the urine samples. The mean concentration ± standard deviation (SD) of SRM 2670 was determined as 507 ± 17 g/L (n=4).
Urinary 8-OHdG analysis using isotope-dilution LC-MS/MS
Urinary 8-OHdG concentrations were determined using the isotope-dilution LC-MS/MS method described by Hu et al. (Hu et al., 2006b). Briefly, a 250-μL sample of urine was first diluted with 500 μL water, to which was added 20 μl 15N
5-8-OHdG solution (42.6 ng/mL) as internal standard.
After adding 150 μl of 1 mol/L ammonium acetate buffer (pH 5.25), and vigorous vortexing, the sample was loaded onto a Sep-Pak C18 cartridge (100 mg/1 mL, Waters Associates) preconditioned with 1 mL methanol and 1 mL distilled water. The column was then washed with 1 mL water. The fraction containing 8-OHdG was eluted with 1 mL 40% methanol, collected, dried under vacuum for 2 hours, and dissolved in 250 μl of 80% acetonitrile containing 0.1% formic acid. Sample solution, 20 L, was injected onto an HPLC-MS/MS system comprising a PE 200 autosampler and two PE 200 micropumps (Perkin-Elmer, Boston, MA, USA), and a polyamine-II endcapped HPLC column (150 × 2.0 mm; 5 μm; YMC Co., Yawata, Kyoto, Japan) with an identical guard column (10 × 2 mm; YMC). The mobile phase was 80% acetonitrile with 0.1% formic acid and delivered at a flow rate of 300 μL/min. The sample was delivered by the HPLC system to a triple quadrupole mass spectrometer (API 3000; Applied Biosystems, Foster City, CA, USA) equipped with a TurboionSpray source.
Statistical analysis
Total arsenic concentration (μg/g creatinine) was the sum of urinary inorganic arsenic (As3+ and As5+; InAs) and its metabolites, such as MMA5+ and DMA5+. Arsenic methylation capability indices, including InAs%, MMA%, and DMA% were calculated by dividing the concentration of each arsenic species by the total arsenic concentration. Student's t-test was used to compare the
differences of 8-OHdG levels between RCC cases and healthy controls. ANOVA and the Duncan test were used to evaluate the differences in urinary 8-OHdG levels between more than two strata of baseline characteristics. Pearson’s correlation was used to assess the relationship between urinary 8-OHdG levels and the concentrations of various arsenic species. Subsequently, we developed
confidence interval (CI). Cutoff points for continuous variables were the respective tertiles of the controls. Significance tests for linear trend among ORs across exposure strata were calculated by categorizing exposure variables and treating scored variables as continuous. For the joint effect analysis, the cutoff points for the urinary total arsenic species and 8-OHdG were the respective medians of the controls. The joint effects were evaluated by estimating the synergy index (Hosmer and Lemeshow, 1992). All data were analyzed using the SAS statistical package (SAS, version 8.0, Cary, NC, USA). A p value <0.05 (two-sided) was considered significant.
Results
A total of 377 individuals, including 132 RCC patients and 245 healthy controls, were enrolled in this study. The mean age was 57.19 1.13 and 60.15 0.81 years, respectively. In both groups, those aged 60 years or older had significantly higher levels of total arsenic than those aged below 60 years. In addition, women in both groups had significantly lower concentrations of MMA% than men (data not shown).
Urinary 8-OHdG levels
Participants with RCC had a significantly higher urinary 8-OHdG level than non-cancer controls (Table 1). Urinary 8-OHdG levels significantly differed between men and women in all participants and in the RCC patients. Aged 60 years or older had significantly higher levels of 8-OHdG than those aged below 60 years in all participants and in the non cancer controls. Notably, urinary 8-OHdG levels did not differ with differences in total arsenic strata, cigarette smoking or alcohol drinking strata. The 8-OHdG levels associated with different stages or grades of RCC were similar (4.66 0.39, 4.48 0.49, 5.99 1.14 ng/mg creatinine in stage 1 to 3; 4.66 0.73, 4.45 0.30, 5.65
1.09 ng/mg creatinine in grade 1-3) (data not shown).
Dose-response of urinary 8-OHdG and total arsenic levels on RCC risk
Table 2 shows that urinary 8-OHdG level was significantly associated with risk of RCC in a dose-response relationship after multivariate adjustment. In addition, urinary total arsenic level was significantly associated with risk of RCC in a dose-response relationship after multivariate adjustment. However,
arsenic methylation capability indices (i.e., InAs%, MMA%, and DMA%) were not corr e lated with RCC well .
Correlation between urinary 8-OHdG and urinary total arsenic
After adjusting for age, sex, and RCC status, urinary 8-OHdG levels were found to be
significantly associated with the concentrations of total arsenic after adjusting for the confounding effects of alcohol, tea, and coffee drinking as shown in Figure 1.
Both 8-OHdG and total arsenic levels affected the OR of RCC, and we found that the estimated glomerular filtration rate (eGFR) and hypertension were related to RCC in a previous study (Huang et al., 2011). We further analyzed multivariate adjusted OR of urinary total arsenic level and 8-OHdG on the RCC after adjusted for age, sex, eGFR, hypertension, cigarette smoking, and alcohol, tea and coffee consumption (Figure 2). With urinary total arsenic ≤ 15.85 (μg/g creatinine) and 8-OHdG ≤ 3.34 (ng/mg creatinine) as the reference group, the ORs (95% CI) for urinary total arsenic ≤ 15.85 (μg/g creatinine) and 8-OHdG > 3.34 (ng/mg creatinine), urinary total arsenic > 15.85 (μg/g creatinine) and 8-OHdG ≤ 3.34 (ng/mg creatinine), and urinary total arsenic > 15.85 (μg/g
creatinine) and 8-OHdG > 3.34 (ng/mg creatinine) were 2.30 (1.04-5.06), 2.47 (1.09-5.62), and 3.50 (1.64-7.46), respectively. The combined effect was noted for total arsenic level plus 8-OHdG, with a significant dose-response relationship for RCC ( P trend = 0.002 ) , but the interaction was statistically
insignificant.
Discussion
In this study we evaluated the oxidative stress in RCC patients and non-cancer controls by measuring urinary 8-OHdG levels using LC-MS/MS, and found that urinary 8-OHdG level was significantly associated with RCC. In addition, urinary 8-OHdG level was found to correlate with the level of individual urinary total arsenic level after adjusting for the confounding effects of alcohol, tea, and coffee drinking. Therefore, we consider urinary arsenic species to be one of the main factors affecting 8-OHdG levels. Our results showed that even with low urinary total arsenic concentrations, a clear association was observed between urinary total arsenic concentration and 8-OHdG level. Trend analysis revealed the OR of RCC to increase progressively with the acquisition of these two factors, being lowest levels of urinary total arsenic
concentration and 8-OHdG, increasing with an increase in one variable only, and increasing further with increases in both.
Urinary 8-OHdG has been widely studied and used as a biomarker of oxidative stress because it reflects extremely low levels of oxidative damage, is remarkably stable in this matrix, and multiple methods exist for its measurement (Pan et al., 2008). LC-MS/MS is considered to have high sensitivity and selectivity in the analysis of 8-OHdG to detect DNA damage (Hu et al., 2010). The detection of 8-OHdG is considered important because of its abundance and mutagenic potential through G to T transversion mutations on replication of DNA (Cheng et al., 1992). 8-OHdG is one of the main DNA modifications produced by ROS (Marczynski et al., 1997). Indicators of oxidative DNA damage, such as 8-OHdG, can be used as biomarkers of early biological effects (de Zwart et al., 1999).
Our study demonstrates that individuals with RCC had a significantly higher urinary 8-OHdG level than healthy controls. Furthermore, urinary 8-OHdG was significantly associated with
the OR of RCC in a dose-response relationship after multivariate adjustment. Previous studies demonstrated that 8-OHdG level was related to risk of cancer. Miyake et al. reported that the mean value of 8-OHdG in RCC tissue was significantly greater than that in the adjacent normal tissue and found that the 8-OHdG ratio could be a useful prognostic indicator for patients with RCC (Miyake et al., 2004). Akcay et al. demonstrated that the 8-OHdG levels in DNA from leukocytes of bladder cancer patients were significantly higher than those from controls and recommended reduction of oxidative stress as a very important measure for the primary prevention of bladder cancer (Akcay et al., 2003). The study of Ichiba et al. suggested that oxidative DNA damage is increased in association with necroinflammation in chronic liver disease and that determination of 8-OHdG would be useful in assessing high-grade malignancy in hepatocellular carcinoma (HCC) (Ichiba et al., 2003); another study showed 8-OHdG to be a risk factor for the development of HCC in patients with chronic hepatitis C virus infection (Chuma et al., 2008). Shen et al. investigated 8-OHdG as a potential biomarker of survival in patients with non small-cell lung cancer, reporting that patients with low levels of 8-OHdG had significantly longer survival times compared with those with high levels of OHdG (Shen et al., 2007). Furthermore, the urinary 8-OHdG level decreased in the order of metastatic lung cancer, primary lung cancer and benign disease (Yano et al., 2009).
Although arsenic is a human carcinogen, the mechanism underlying arsenic-induced carcinogenesis is still unknown. Arsenic can directly or indirectly alter cellular redox levels or affect signal transduction pathways to cause oxidative DNA damage (Lynn et al., 2000; Wijeweera et al., 2001). It has been shown that inorganic arsenic induced concentration-dependent and time-dependent superoxide generation in a human keratinocyte cell line (Shi et al., 2004). Treatment of mesencephalic cells with low concentrations of sodium arsenate resulted in the activation of early transcription factors such as nuclear factor-B (NF-B) and activator protein-1 (AP-1), which regulate the expression of a variety of downstream target genes, such as proinflammatory genes known to be involved in carcinogenesis (Felix et al., 2005). A report has suggested that chronic arsenic exposure through burning coal rich in arsenic is associated with oxidative DNA damage, and that secondary methylation capacity [DMA/(DMA + MMA)] is potentially related to the susceptibility of individuals to oxidative DNA damage (8-OHdG) (Li et al., 2008). Another study showed early elevation of 8-OHdG and cell proliferation via generation of oxidative stress by trimethylarsine oxide (TMAOV) and DMAV contributes to carcinogenesis in the rat liver and bladder (Kinoshita et al., 2007). Oxidative damage to DNA has been considered an important mechanism in arsenic-induced carcinogenesis (De Vizcaya-Ruiz et al., 2009; Flora, 2011). Wu et al. found a positive association between blood arsenic concentration and level of reactive oxidants and an inverse relationship between blood arsenic concentration and level of plasma antioxidant
increment. Huang et al. confirmed the association between low levels of arsenic exposure and urinary 8-OHdG increment and found that 8-OHdG levels were positively correlated with tubular damage in the kidney (Huang et al., 2009). All the individuals recruited in our study had consumed drinking water containing arsenic < 10 g/L as standard for many years. Similar to the findings of Huang et al., our results also showed OR of RCC to be significantly related to high levels of urinary total arsenic or 8-OHdG.
Our study has some issues that need to be considered when interpreting our results. Use of a different method of 8-OHdG determination (Chiou et al., 2003) may mean that measured levels of urinary 8-OHdG were lower compared with those in other studies. Additionally, RCC prevalence cases were recruited in this study. We cannot exclude the possibility that the association between urinary 8-OHdG levels and RCC in the present study might have resulted from and not be the cause of RCC. Future studies should evaluate the mechanisms of arsenic metabolism and oxidative stress in arsenic-induced carcinogenesis in more detail.
Conclusion
To our knowledge, this is the first study showing that urinary 8-OHdG levels are correlated with individual total arsenic level in a human population with low exposure to arsenic. Our data provide evidence that chronic exposure to low levels of arsenic in drinking water in humans may be related to the induction of oxidative stress as indicated by the increase in urinary 8-OHdG level. Moreover, high levels of 8-OHdG combined with urinary total arsenic might be indicative of arsenic-induced RCC.
Conflict of Interest Statement
The authors disclosed all financial and interpersonal relationships that present a potential conflict of interest.
Acknowledgment
The study was supported by grants from the National Science Council of the ROC (NSC 86-2314-B-038-038, NSC 87-2314-B-038-029, NSC-88-2314-B-038-112, N2314-B038-049, SC-89-2320-B038-013, NSC-90-2320-B-038-021, NSC-91-3112-B-038-0019, NSC-92-3112-B-038-001, NSC-93-3112-B-038-001, NSC-94-2314-B-038-023, NSC-95-2314-B-038-007, NSC-96-2314-B038-003, 2314-B-038-015-MY3 (1-3), 2314-B-038-015-MY3 (2-3), NSC-97-2314-B-038-015-MY3 (3-3)), and from the Department of Health, Executive Yuan of the ROC (DOH99-TD-C-111-001, DOH100-TD-C-111-001).
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