Depressive symptoms and oxidative DNA damage in Japanese municipal employees

Psychiatry Research 200 (2012) 318–322

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Depressive symptoms and oxidative DNA damage in Japanese municipal employees Siyan Yi a,b,n, Akiko Nanri a, Yumi Matsushita a, Hiroshi Kasai c, Kazuaki Kawai c, Tetsuya Mizoue a a

Department of Epidemiology and International Health, International Clinical Research Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan b The Walter H. Shorenstein Asia-Pacific Research Center, the Freeman Spogli Institute for International Studies, Stanford University, CA, USA c Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 April 2011 Received in revised form 24 May 2012 Accepted 29 May 2012

We sought to explore the relationship between depressive symptoms and urinary 8-hydroxydeoxyguanine (8-OHdG), a biomarker of systemic oxidative DNA damage and repair, among 301 men and 210 women aged 21–67 years working in two municipal offices. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale (CES-D). The geometric mean and its 95% confidence interval (CI) of urinary 8-OHdG concentrations were calculated according to the quartile of CES-D score. The prevalence of depressive symptoms, defined as having CES_D of Z 16, was 35.9% in men and 35.2% in women. There was no significant difference in geometric mean of urinary 8-OHdG concentrations according to the levels of depressive symptoms. In men, the multivariable-adjusted geometric mean of urinary 8-OHdG concentrations (95% CIs) in the first, second, third, and fourth category of depressive symptoms was 1.09 (1.02–1.16), 1.16 (1.08–1.24), 1.15 (1.07–1.24), and 1.10 (1.02–1.18), respectively (p for trend¼ 0.86). Similarly, no significant association was found in the analyses among women, nonsmoking men, and smoking men. The lack of association between depressive symptoms and urinary 8-OHdG concentrations may indicate the absence or more complex interactions between milder forms of depression and systemic oxidative DNA damage and repair in well-functioning population. & 2012 Elsevier Ireland Ltd. All rights reserved.

Keywords: Depressive symptoms Urinary 8-OHdG Oxidative DNA damage General population Japanese

1. Introduction A link between a history of depression and cancer incidence has been postulated in the past several decades. It has been proposed that depression may cause alterations in the immune system, predisposing a person to immune-related diseases including cancer (Blumberg et al., 1954; Kowal, 1955; Miller et al., 1993). However, empirical findings on the association between depression and cancer risk are controversial and inconclusive. While some prospective studies reported an increased risk of developing cancer among depressive individuals (Knekt et al., 1996; Gross et al., 2010; Chen and Lin, 2011), some others did not find such significant association (Hanh and Petitti, 1988; Kaplan and Reynolds, 1988; Zonderman et al., 1989). Two meta-analyses reported a small and marginally significant association between depression and subsequent overall cancer risk (McGee et al.,

n Corresponding author at: Department of Epidemiology and International Health, International Clinical Research Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. Tel.: þ81 3 3202 7181; fax: þ81 3 3202 7364. E-mail addresses: [email protected], [email protected] (S. Yi).

0165-1781/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2012.05.035

1994; Oerlemans et al., 2007); of these studies, one found a significantly increased risk of breast cancer emerging many years after a previous depression episode (Oerlemans et al., 2007). Oxidative DNA damage plays an important role in the etiology and progression of numerous cancers (Jackson and Loeb, 2001). Among biomarkers of oxidative DNA damage, 8-hydroxydeoxyguanine (8OHdG) has been of particular interest of research and examined in association with depression in different populations. In clinical settings, higher levels of serum 8-OHdG concentrations were observed in patients with clinical depression (Forlenza and Miller, 2006) and in depressive patients with gastric adenocarcinoma (Wei et al., 2009) and chronic heart failure (Kupper et al., 2009) compared to their non-depressive controls. Association between increased levels of urinary 8-OHdG and major depression was also detected in patients with myalgic encephalomyelitis and chronic fatigue syndrome (Maes et al., 2009). In nonclinical settings, higher levels of 8-OHdG concentrations in peripheral blood leukocytes were observed in Japanese office workers with various psychological problems including anxiety and psychological stress (Irie et al., 2001) and depressive state (Irie et al., 2003) relative to their comparison groups. To the best of our knowledge, no published studies have examined the relationships between depressive symptoms and

S. Yi et al. / Psychiatry Research 200 (2012) 318–322

oxidative DNA damage as measured by using urinary 8-OHdG in nonclinical general population. It remains unclear whether depressive symptoms modify urinary excretion of 8-OHdG in apparently healthy populations in which milder forms of depression is common. This study was conducted to investigate crosssectionally the association between depressive symptoms and levels of urinary 8-OHdG in a well-functioning population of Japanese municipal employees. We hypothesized that increased depressive symptoms would be significantly associated with increased levels of urinary 8-OHdG concentrations.

2. Methods 2.1. Study subjects and procedures This study was conducted in July (study site A) and November (study site B) 2006 in northeastern Kyushu, Japan. The procedure of the study has been described in more detail elsewhere (Murakami et al., 2008; Hori et al., 2010). All employees (n ¼601) working for two municipal offices were invited to participate in this study, except for those who were on long sick or maternity leave. Out of those who were invited, 547 employees volunteered to participate in the study, yielding a response rate of 91%. We excluded 15 (2%) participants who did not complete information regarding depressive symptoms, 8-OHdG, and current smoking status. We further excluded 22 participants with a history of any cancer, cardiovascular disease, current hepatitis, current nephritis, and pregnancy that may alter levels of urinary 8-OHdG concentrations. In total, 511 subjects remained in the analyses. Participants were requested to fill in the survey questionnaires well before the day of health checkup. The questionnaires were then checked by research staff for completeness, and where necessary, clarifications were made by asking the participants on the day of examination. Participants were instructed to receive the screening after an overnight fasting and refrain from smoking prior to the examination. Of the study participants, 96% received checkup on fasting condition. We measured demographic characteristics, lifestyle, anthropometric, and biochemical markers according to the same survey protocol at both study sites. Written informed consent was obtained from each participant after the nature and possible consequences of the study had been fully explained. The study protocol was approved by the Ethics Committee of the National Center for Global Health and Medicine, Tokyo, Japan. 2.2. Variables and measurements 2.2.1. Urinary 8-OHdG Spot urine samples (1 mL  2 tubes) were collected during the checkup in the morning, conveyed in a cooler box to a laboratory, and frozen at  20 1C until the analyses were performed. The measurement of 8-OHdG was done within 6 months of urine sampling. The samples were analyzed for 8-OHdG using an automated high-performance liquid chromatography system (HPLC) composed of anion-exchange (HPLC-1) and reverse-phase (HPLC-2) columns and an electrochemical detector (Kasai et al., 2005, 2008). Each urine sample was mixed with the same volume of a dilution solution containing the ribonucleoside marker 8-hydroxyguanosine. A 20-mL aliquot of the diluted urine sample was injected into HPLC-1 (MCI GEL CA08F, 7 mm, 1.5  120 mm; elution, 2% acetonitrile in 0.3 mM sulfuric acid, 50 mL/min, 65 1C), via the guard column (1.5  40 mm), and the chromatograms were recorded by a Gilson UV detector (UV/VIS-155 with 0.2 mm light path cell). Creatinine was detected at 245 nm. The 8-OHdG fraction was collected, depending on the relative elution position from the peak of the added marker, 8-hydroxyguanosine, and was automatically injected into the HPLC-2 column. The 8-OHdG fraction was fractionated by the HPLC-2 column (Capcell Pak C18, Shiseido, Tokyo, Japan; 5 mm, 4.6  250 mm; elution, 10 nM sodium phosphate buffer [pH 6.7] containing 5% methanol and an antiseptic reagent MB [100 mL/L], 1 mL/min, 40 1C). The 8-OHdG was detected by using a Coulochem II EC detector (ESA, Chelmsford, MA, USA) with a guard cell (5020) and an analytical cell (5011) (applied voltage: guard cell, 350 mV; E1, 170 mV; E2, 300 mV). The accuracy of the measurement, estimated from the recovery of an added 8-OHdG standard, was 90–98%. When the same urine sample was analyzed three times, the variation of the data was within 7%. Levels of 8-OHdG concentrations were adjusted for urinary creatinine levels before statistical analyses. 2.2.2. Depressive symptoms Depressive symptoms were assessed using a Japanese version (Shima et al., 1985) of the Center for Epidemiologic Studies Depression scale (CES-D) (Radloff, 1977). This scale consists of 20 questions addressing six symptoms of depression including depressed mood, guilt or worthlessness, helplessness or hopelessness,

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psychomotor retardation, loss of appetite, and sleep disturbance experienced during the preceding week. Each question is scored on a scale of 0–3 according to the frequency of the symptoms, and the total CES-D score ranges from 0 to 60. The criterion validity of the CES-D scale has been well established in Japanese (Shima et al., 1985) and Western (Radloff, 1977) populations.

2.2.3. Other variables A self-reported lifestyle questionnaire was used to collect information regarding marital status, job title, and status of current smoking and alcohol drinking. Occupational physical activity was divided into sedentary or active work according to job title; clerical jobs were classified as sedentary work, whereas other types of work including childcare work, school lunch cooking, and technical jobs were classified as active work. Total amount of non-job physical activity was computed as average metabolic equivalent-hours per week (Ainsworth et al., 1993) on the basis of self-reported usual frequency and duration of six different activities (walking, low–moderate–and high-intensity activities, gardening, and commuting to work). Body height was measured to the nearest 0.1 cm with the subject standing without shoes. Body weight in light indoor clothes was measured to the nearest 0.1 kg. Body mass index (BMI) was calculated as body weight (kg) divided by the square of body height (meters). We assessed dietary intake during the preceding month by using a validated brief self-administered diet history questionnaire (BDHQ) (Sasaki, 2004), which contains queries about the consumption frequency of 56 foods and beverages commonly consumed in general Japanese populations. Dietary intake for energy and selected nutrients were estimated using an ad hoc computer algorithm for the BDHQ, with reference to the Standard Tables of Food Composition in Japan (Science and Technology Agency, 2005).

2.3. Statistical analyses To address gender differences, all statistical analyses were conducted separately in men and women. Characteristics of the study participants were assessed using w2 test or Fisher’s exact test for categorical variables and independent student t-test for continuous variables. Urinary 8-OHdG concentrations were logtransformed for the following parametric analyses. The geometric mean and its 95% confidence interval (CI) of urinary 8-OHdG concentrations were calculated according to the quartile of CES-D score (0–8, 9–12, 13–18, or Z 19). To control for the effects of potential confounding variables, two models were constructed. In Model 1, we adjusted for age (continuous) and study site (A or B). In Model 2, we additionally adjusted for job type (sedentary or physically active), overtime work (o10 h/month or Z 10 h/month), BMI (continuous), total amount of non-occupational physical activity (o 5 MET-h or Z5 MET-h/week), current smoking status (nonsmokers or smokers), current alcohol drinking status (nondrinkers or drinkers), dietary intakes of vitamin C and vitamin E (continuous), serum folate (continuous), and serum ferritin (log-transformed, continuous). Trend of the association was assessed using multiple linear regression analyses with ordinal number 1–4 assigned to the lowest to highest categories of depressive symptoms. Because smoking is a known, consistent determinant of 8-OHdG concentrations (Loft et al., 1992), additional analyses were conducted in men stratified by current smoking status. Further analyses were conducted to compare levels of urinary 8-OHdG concentrations in subjects with and without depressive symptoms defined by using different cutoffs: a CES-D score of Z16, which has been universally recommended; Z19, which has been recommended for use among Japanese workers (Wada et al., 2007); and Z 23, which may indicate severe depressive status. We also repeated the analyses separately among participants in study sites A and B. Two-sided p-values of less than 0.05 were regarded as statistically significant. Data analyses were performed with STATA version 11.0 (Lakeway Drive College Station, TX, USA).

3. Results Of total, 301 (58.9%) subjects were men, and 371 (69.6%) were married. The age of the participants ranges between 21 years and 67 years. Of total, 141 (27.6%) were current smokers and 218 (42.7%) were current alcohol drinkers. The prevalence of depressive symptoms, defined as having CES_D of Z16, was 35.9% in men and 35.2% in women. Compared to women, men had significantly older mean age (44.1 710.8 vs. 40.8710.4, p¼0.001). Men were more likely to be current smokers (45.5% vs. 1.9%, p o0.001) and current alcohol drinkers (54.5% vs. 25.7%, po0.001). Men were also significantly more likely to do non-job physical activity of Z5 MET-h/week (38.2% vs. 18.1%, p o0.001) and to have higher mean BMI (23.673.3 vs. 21.073.1, p o0.001) compared to women. Dietary intake of vitamins was significantly

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lower in men for both vitamin C (5.4 72.4 vs. 7.672.5, p o0.001) and vitamin E (5.472.4 vs. 7.672.5, p o0.001) than in women. Table 1 shows the characteristics of participants with and without depressive symptoms stratified by gender. Men without depressive symptoms were significantly more likely to do non-job physical activity of Z5 MET-h/week compared to those with depressive symptoms (p¼0.04). Men and women with depressive symptoms were more likely to have worked overtime of Z10 h/month than those without depressive symptoms (p¼0.04 for men and p¼0.006 for women). Dietary intake of vitamin C was significantly lower among participants with depressive symptoms compared to those without depressive symptoms in both men (p¼0.03) and women (p¼ 0.03). Bivariate correlation analyses showed that urinary 8-OHdG concentrations were not significantly associated with CES-D score in both men (p¼0.72) and women (p¼0.41). As shown in Table 2, no significant difference was detected in the comparisons of geometric mean of urinary 8-OHdG concentrations according to levels of depressive symptoms. In men, in Model 1 adjusted for age and study site, the geometric mean of urinary 8-OHdG concentrations (95% CIs) in the first, second, third, and fourth category of depressive symptoms was 1.11 (1.04–1.17), 1.11 (1.03–1.18), 1.15 (1.07–1.23), and 1.07 (1.00–1.14), respectively (p for trend¼ 0.68). After further adjustment for potential confounders in Model 2, the geometric mean of urinary 8-OHdG concentrations (95% CIs) in the first, second, third, and fourth category of depressive symptoms in men was 1.09 (1.02–1.16), 1.16 (1.08–1.24), 1.15 (1.07–1.24), and 1.10 (1.02–1.18), respectively (p for trend¼0.86). Similarly, no significant association was found in the same analyses among women (p for trend¼0.56), nonsmoking men (p for trend¼0.79), and smoking men (p for trend¼0.97). Additional analyses comparing levels of urinary 8-OHdG concentrations in subjects with and without depressive symptoms defined by using different cutoffs (CES-D score Z16, Z19, and Z23) also could not detect any significant difference in any subgroup of men, women, nonsmoking men, or smoking men (data not shown). Similarly, no significant association was found in the separate analyses among participants in study sites A and B (data not shown).

4. Discussion In this cross-sectional study of a Japanese working population, there was no association between depressive symptoms and urinary 8-OHdG concentrations, a biomarker of oxidative DNA damage and repair, in both men and women. In men, no significant association was found in further analyses in subgroups of current smokers and nonsmokers. This study represents a few attempts to assess the association between depressive symptoms and oxidative DNA damage using levels of urinary 8-OHdG concentrations in an apparently healthy population. Our findings of the null association between depressive symptoms and oxidative DNA damage as measured by urinary 8-OHdG concentrations do not support findings from previous studies conducted among clinical samples which have found increased levels of serum 8-OHdG in patients with clinical depression (Forlenza and Miller, 2006; Wei et al., 2009; Kupper et al., 2009; Maes et al., 2009). The present findings are also not consistent with those obtained from a series of studies conducted among Japanese office workers which reported increased levels of 8-OHdG concentrations in peripheral blood leukocytes in people with various psychological problems (Irie et al., 2001, 2003). However, our findings are in line with results obtained from a study conducted in a sample of college students in Japan, in which depressive symptoms were not significantly associated with oxidative stress, as measured by serum reactive oxygen metabolites (ROMs) and the biological antioxidant potential (BAP), after controlling for potential confounding factors (Matsushita et al., 2010). The inconsistency of the findings in the current study relative to those obtained from most of previous published work might be caused in part by the differences in characteristics of the study samples, ability to control for potential confounding factors, and the methods used to measure oxidative DNA damage. A limited number of observational studies have examined the association between depression and oxidative DNA damage in well functioning populations. In those studies, 8-OHdG has been most commonly measured

Table 1 Characteristics of study subjects with and without depressive symptoms. Characteristics

Number of subjects Age (years) Study site Ab Job type (physically active)c Overtime work (Z 10 hours/month) Current cigarette smoking Current alcohol drinking Non-job physical activity ( Z5 MET-h/ week) Body mass index (kg/m2) Vitamin C dietary intake (mg/ 1000 kcal) Vitamin E dietary intake (mg/ 1000 kcal) Serum folate (ng/mL) Serum ferritin (mg/L) Urinary 8-OHdG (mg/g creatinine)

Men (n¼ 301)

Women (n¼ 210)

Without depressive symptoms

With depressive symptomsa

pvaluey

Without depressive symptoms

With depressive symptomsa

pvaluey

196 (65.1) 44.4 711.1 69 (35.2) 21 (10.7) 63 (32.1) 86 (43.9) 114 (58.2) 83 (42.3)

105 (34.9) 43.4 7 10.3 29 (27.6) 10 (9.5) 46 (43.8) 51 (48.6) 50 (47.6) 32 (30.5)

0.43 0.18 0.75 0.04 0.44 0.08 0.04

136 (64.8) 40.47 10.7 44 (42.4) 51 (37.5) 31 (23.5) 4 (2.9) 39 (28.7) 24 (17.6)

74 (35.2) 41.5 7 10.0 16 (21.6) 18 (24.3) 31 (41.9) 0 (0.0) 15 (20.3) 14 (18.9)

0.49 0.10 0.05 0.006 0.30 0.18 0.82

23.8 73.2 5.67 2.3

23.1 7 3.5 4.5 7 2.4

0.11 0.03

21.07 3.1 5.67 2.3

21.1 7 3.2 4.8 7 2.4

0.82 0.03

3.97 1.0

3.6 7 1.0

0.07

3.97 1.0

3.6 7 1.0

0.07

3.97 1.7 164.1 7 115.9 3.37 1.1

3.5 7 1.9 166.9 7 184.5 3.3 7 1.2

0.07 0.87 0.98

5.27 3.0 49.2 760.1 3.37 1.1

5.2 7 2.6 47.3 7 53.3 3.2 7 1.2

0.96 0.82 0.81

Abbreviations: 8-OHdG, 8-hydroxydeoxyguanosine; MET-h, metabolic equivalent-hour. Values are numbers of subjects (%) for categorical variables and means7 SD for continuous variables. a

Subjects with a Center for Epidemiology Studies Depression Scale (CES-D) score of Z 16. Study site A: survey conducted in July 2006; Study site B: survey conducted in November 2006. c Job type was divided into sedentary or active work according to job title; clerical jobs were classified as sedentary work, whereas other types of work including childcare work, school lunch cooking, and technical jobs were classified as active work. y p-values were based on the w2 test or Fisher’s exact test for categorical variables and independent student t-test for continuous variables. b

S. Yi et al. / Psychiatry Research 200 (2012) 318–322

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Table 2 Urinary 8-OHdG concentrations according to levels of depressive symptoms. Geometric mean (95% CI) of 8-OHdG concentrations (mg/g creatinine) CES-D score

n

Unadjusted

Men (n¼ 301) 0–8 9–12 13–18 Z19

92 77 66 75

1.11 1.10 1.15 1.08

(1.04–1.18) (1.03–1.18) (1.07–1.22) (0.99–1.15)

Women (n¼ 210) 0–8 9–12 13–18 Z19

68 40 50 52

1.14 1.03 1.11 1.02

(1.00–1.27) (0.88–1.19) (0.99–1.24) (0.89–1.16)

Men—nonsmokers (n ¼164) 0–8 9–12 13–18 Z19

56 29 39 40

1.05 1.00 1.15 1.04

(0.94–1.16) (0.90–1.09) (1.01–1.29) (0.90–1.19)

Men—smokers (n ¼137) 0–8 9–12 13–12 Z19

35 34 33 35

1.14 1.30 1.20 1.17

(1.06–1.23) (1.18–1.42) (0.09–1.31) (1.06–1.28)

p for trend

a

Model 1b

0.67

p for trend

a

Model 2

c

0.68 1.11 1.11 1.15 1.07

(1.04–1.17) (1.03–1.18) (1.07–1.23) (1.00–1.14)

1.14 1.03 0.11 1.02

(1.02–1.26) (0.88–1.19) (0.97–1.25) (0.88–1.16)

1.04 1.01 1.14 1.05

(0.94–1.15) (0.89–1.13) (1.00–1.29) (0.93–1.17)

1.15 1.31 1.19 1.17

(1.05–1.26) (1.20–1.41) (0.08–1.30) (1.06–1.27)

0.33

(1.02–1.16) (1.08–1.24) (1.07–1.24) (1.02–1.18)

1.06 1.14 1.10 1.01

(0.96–1.16) (1.00–1.27) (0.98–1.22) (0.90–1.13)

1.04 1.04 1.13 1.04

(0.95–1.14) (0.93–1.16) (0.99–1.26) (0.93–1.15)

1.14 1.30 1.19 1.17

(1.03–1.25) (1.20–1.41) (1.08–1.31) (1.06–1.27)

0.56

0.67

0.93

a

0.86 1.09 1.16 1.15 1.10

0.30

0.73

p for trend

0.79

0.77

0.97

Abbreviations: 8-OHdG, 8-hydroxydeoxyguanosine; CES-D, Center for Epidemiology Studies Depression Scale; CI, confidence interval. a

p for trend values were based on linear regression analyses with ordinal numbers 1–4 assigned to quartile categories of depressive symptoms. Adjusted for age (continuous) and study site (A or B) Adjusted for age (continuous), study site (A or B), job type (sedentary or physically active), overtime work ( o 10 h/month or Z 10 h/month), total amount of non-job physical activity (o 5 MET-h or Z5 MET-h/week), body mass index (continuous), current smoking status (nonsmokers or smokers), current alcohol drinking status (nondrinkers or drinkers), dietary intakes of vitamin C and vitamin E (continuous), serum folate (continuous), and serum ferritin (log-transformed, continuous). b c

in serum, tissue, or leukocyte for quantifying levels of oxidative DNA damage (Irie et al., 2003; Forlenza and Miller, 2006; Kupper et al., 2009). It has been suggested that it is desirable to measure not only the amount of 8-OHdG produced but also its repair activity to assess health effects caused by oxidative DNA damage (Cooke et al., 2000). Urinary 8-OHdG is considered to reflect generalized repair activity against the formation of 8-OHdG in cellular DNA in a stable manner (Cooke et al., 2000; Wu et al., 2004). Moreover, increased urinary excretion of 8-OHdG has been reported in patients with various cancers (Yamamoto et al., 1996; Erhola et al., 1997; Honda et al., 2000; Chiou et al., 2003). Urinary 8-OHdG is thus a possible marker for assessing cancer risk. Findings from the present study are strengthened by the ability to adjust for the effects of several potential confounding factors in the analyses, the high participation rate (91.0%), and the use of a reliable method for the measurement of depressive symptoms (CES-D) and urinary 8-OHdG (HPLC). Moreover, there are some advantages of using urine sample over blood sample for 8-OHdG measurement. Urine excretion of 8-OHdG is independent of changes in DNA repair and plasma clearance, and higher concentrations of 8-OHdG in urine than in plasma make urinary 8-OHdG analysis easier and more accessible (Hu et al., 2010). Several limitations of the present study are, however, worth mentioning. First, our study samples were restricted to a relatively healthy subset of workers, in which milder forms of depressive symptoms are common relative to other subgroups in general population. Second, we used CES-D scale to measure depressive symptoms and did not include a psychiatric depression assessment. It is likely that the link between depression and 8-OHdG is stronger in psychiatric patients who suffer from more severe and chronic depressive symptoms. Thus, the present finding obtained at non-clinical setting using CES-D scale may not be applied to populations including patients with a clinical diagnosis of depression. Third, we did not confirm smoking and exercise on the morning of the checkup, which might have

influenced the results. Fourth, although adjustment for a variety of potential confounding factors was conducted, residual confounding could not be ruled out. Finally, the cross-sectional nature of the study does not permit the assessment of causality owing to the uncertain temporality of the association. Despite these limitations, we concluded that depressive symptoms were not associated with levels of urinary 8-OHdG concentrations in an apparently healthy Japanese population working in municipal offices. The lack of the association in this populationbased study indicates an absence or a more complex nature of interrelations between milder forms of depressive symptoms and urinary 8-OHdG in general population. Further research is needed to address this shortcoming.

Acknowledgments The authors thank all study participants for their cooperation. We are grateful to Tamami Hatano, Yasumi Kimura, Akihiko Tanaka, and Yuko Ejima (Kyushu University); Mio Ozawa (Fukuoka Women’s University); and Akiko Hayashi and Kie Nagao (National Center for Global Health and Medicine) for their support in data collection. References Ainsworth, B.E., Haskell, W.L., Leon, A.S., Jacobs, D.R, Montoye Jr., H.J., Sallis, J.F., Paffenbarger Jr., R.S., 1993. Compendium of physical activities: classification of energy costs of human physical activities. Medicine Science in Sports and Exercise 25, 71–80. Blumberg, E.M., West, P.M., Ellis, F.W., 1954. A possible relationship between psychological factors and human cancer. Psychosomatic Medicine 16, 277–286. Chen, Y-H., Lin, H-C., 2011. Increased risk of cancer subsequent to severe depression-A nationwide population-based study. Journal of Affective Disorders 131, 200–206. Chiou, C.C., Chang, P.Y., Chan, E.C., Wu, T.L., Tsao, K.C., Wu, J.T., 2003. Urinary 8-oxy-2-deoxyguanosine and its analogs as DNA marker of oxidative stress:

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