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International Journal of Molecular Sciences logoLink to International Journal of Molecular Sciences
. 2020 May 26;21(11):3743. doi: 10.3390/ijms21113743

Urinary 8-OHdG as a Biomarker for Oxidative Stress: A Systematic Literature Review and Meta-Analysis

Melanie Graille 1, Pascal Wild 1,2, Jean-Jacques Sauvain 1, Maud Hemmendinger 1, Irina Guseva Canu 1,†, Nancy B Hopf 1,3,*,†
PMCID: PMC7313038  PMID: 32466448

Abstract

Oxidative stress reflects a disturbance in the balance between the production and accumulation of reactive oxygen species (ROS). ROS are scavenged by the antioxidant system, but when in excess concentration, they can oxidize proteins, lipids, and DNA. DNA damage is usually repaired, and the oxidized products are excreted in urine. 8-hydroxy-2-deoxyguanosine is considered a biomarker for oxidative damage of DNA. It is needed to define background ranges for 8-OHdG, to use it as a measure of oxidative stress overproduction. We established a standardized protocol for a systematic review and meta-analysis to assess background ranges for urinary 8-OHdG concentrations in healthy populations. We computed geometric mean (GM) and geometric standard deviations (GSD) as the basis for the meta-analysis. We retrieved an initial 1246 articles, included 84 articles, and identified 128 study subgroups. We stratified the subgroups by body mass index, gender, and smoking status reported. The pooled GM value for urinary 8-OHdG concentrations in healthy adults with a mean body mass index (BMI) ≤ 25 measured using chemical methods was 3.9 ng/mg creatinine (interquartile range (IQR): 3 to 5.5 ng/mg creatinine). A significant positive association was observed between smoking and urinary 8-OHdG concentrations when measured by chemical analysis. No gender effect was observed.

Keywords: oxidative stress, biomarker, 8-OHdG, systematic review, meta-analysis

1. Introduction

Oxidative stress reflects a disturbance in the balance between the production and accumulation of reactive oxygen species (ROS), and an overproduction of ROS has negative consequences for cell physiology [1]. When ROS concentration is in excess, oxidative damage to proteins, lipids, and DNA occurs, thus causing structural and functional cellular changes. DNA damage is usually repaired primarily via the base excision repair pathway, and oxidized products are excreted in urine [2]. 8-hydroxy-2-deoxyguanosine (8-OHdG) is one of the most widely studied oxidized metabolites and is considered as a biomarker for oxidative damage of DNA [3,4]. The formation of 8-OHdG by oxygen radicals was first reported in 1984 by Kasai and Nishimura [5].

The interaction of the hydroxyl radical, the most important oxygen-free radical, with the nucleobases of the DNA strand, such as guanine, leads to the formation of 8-OHdG [6] (Figure 1).

Figure 1.

Figure 1

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Structure of 8-OHdG.

Some diseases, such as cardiovascular or chronic obstructive pulmonary diseases (COPD), have been associated with excessive concentrations of 8-OHdG [7,8]. 8-OHdG levels also increase due to smoking, aging, or occupational exposure to physical, chemical, or biological substances [9,10].

A recent study suggested that 8-OHdG had high intraclass correlation coefficients (0.96), reproducible measurements, and low coefficients of variation and was the most suitable biomarker of oxidative stress in spot urine samples [11]. Concentrations of urinary oxidative stress biomarkers have been proposed as an effect biomarker to survey populations exposed to xenobiotics such as particulates, oxidizing agents, and lately, engineered nanomaterials [12,13].

Measuring urinary 8-OHdG has some advantages as it is very stable in urine [14], it is noninvasive, and its excretion is likely to reflect the oxidative DNA damage [15] and can be assessed by two main analytical techniques: mass-based methods (using either gas (GC) or liquid (LC) chromatography) and immunological methods. Another source of 8-OHdG in urine is DNA polymerase-dependent incorporation of 8-oxodGTP from the nucleotide pool [16]. Chromatographic methods are considered to be the gold standard; however, immunological techniques, which are less costly and time-consuming, are widely used because enzyme-linked immunosorbent assay (ELISA) kits have been developed for rapid detection and quantification of 8-OHdG [14,17].

A background range for 8-OHdG has been reported in different studies for healthy persons [11,18,19,20]. However, these studies reported a wider range of values, making the identification of background cut-off values challenging.

Therefore, the systematic review and meta-analyses of the reported values appears the most appropriate approach to bypass this issue. Our objective was to assess background ranges for urinary 8-OHdG concentrations in healthy adults.

2. Results

Chemical methods were used in 44 of the 128 study subgroups, and immunological techniques were used in 84 (Table 1). We decided to stratify the subgroups by body mass index (BMI), gender, and smoking status reported.

Table 1.

Summary of geometric mean urinary 8-OHdG concentrations (ng/mg creatinine) in subgroups of healthy adult (18+ years) participants.

BMI ≤ 25 BMI > 25
Analytical Techniques All Participants Smoking Status All Participants Smoking Status
Chemical 3.9 *
(3–5.5)
(n ** = 31)		 Nonsmokers 4.3 2.8
(2.4–3.5)
(n = 9)		 Nonsmokers 2.5
(n = 14) (2.9–5.5) (n = 3) (1.9–2.8)
Smokers 22.2 Smokers 4.0
(n = 2) (3–41.4) (n = 2) (3.5–4.5)
Immunological 9.0
(5.9–19.8)
(n = 47)		 Nonsmokers 11.5 7.7
(5.8 – 10.9)
(n = 26)		 Nonsmokers 9.3
(n = 24) (5.9–21.6) (n = 13) (7.8–14.7)
Smokers NA Smokers 6.0
(n = 0) (n = 6) (5.4–7)
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* Median (IQR: 25%–75%); ** Number of included study subgroups; NA: Not Available.

2.1. Descriptive Results

We retrieved 1246 articles, included 84 articles, and considered 129 study subgroups (Figure 2, Table 2, Table 3, Table 4 and Table 5) in the quantitative synthesis, which we stratified by main quantification techniques: immunological and chemical methods. For subgroups evaluated with the chemical methods, 31 studies had participants with a mean BMI between 18 and 25 (14 study subgroups of nonsmokers and 2 study subgroups of smokers) (Figure 3, Table 2). Nine studies had participants with a mean BMI > 25 (three study subgroups of nonsmokers and two study subgroups of smokers) (Figure 4, Table 3). The mean BMI was unknown for four study subgroups.

Figure 2.

Figure 2

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Flow chart of study selection.

Table 2.

References for urinary 8-OHdG concentrations and computed GM (ng/mg creatinine) measured with chemical techniques in healthy (mean BMI ≤ 25 and no known disease), adult (18+ years) participants.

Reference Study Group Analytic Method Sample Country Sample Size Mean Age Female Male Smoking Status Mean BMI AM GM IQR Range Median CI Units
(8-OHdG/Creatinine)		 Computed GM (ng/mg Creatinine) GSD
[21] Control group HPLC spot urine China 497 42.48 113 384 50% 23.72 4.47 ± 1.26 * nmol/mmol 11 1
[22] Control group HPLC-MS/MS spot urine China 106 31.62 0 106 52.8% 23.79 3 ± 1.08 * μg/g 3 1
[23] Selenium group baseline value HPLC with EC detection spot urine USA 17 30.7 0 17 0% 24.2 3.16 ± 1.28 * ng/mg 3 1
[24] Baseline value UPLC-MS-MS in positive EI mode spot urine Belgium 48 40 3 45 31.2% 24.2 10.76 ± 2.83 * 7.05–20.92 μg/g 10 1
[25] Men baseline HPLC spot urine Japan 2370 60.7 0 2370 24.9% 23.6 3.7 ± 1.6 * ng/mg 4 2
[25] Women baseline HPLC spot urine Japan 4052 60.2 4052 0 4.7% 22.2 4.1 ± 1.7 * ng/mg 4 2
[26] Baseline value LC-MS/MS spot urine Taiwan 58 23.84 0 58 51.7% 24.55 2.63–11.54 4.42 µg/g 16 2
[27] Service staff group HPLC spot urine China 67 24.8 0 67 0% 23.2 1.4 0.9–1.8 μmol/mol 2 3
[28] All population HPLC spot urine Japan 503 42.4 209 294 27.4% 22.5 2.37–4.03 0.8–10.0 3.01 μg/g 3 1
[29] Baseline value HPLC spot urine Korea 102 55 102 0 0% 24.1 6.5 ± 3.9 * μg/g 6 2
[30] Control group HPLC spot urine Japan 805 40.3 0 805 46.7% 23.7 3.79 ± 1.44 * ng/mg 4 1
[31] Baseline value GC-MS spot urine Singapore 24 22.8 NA NA 0% 21.6 2.02 ± 1.12 * µmol/mol 5 2
[32] Non smoker group baseline HPLC with EC detection 24 h urine China 30 21.5 0 30 0% 22.8 6.3 ± 0.5 ** µmol/mol 14 2
[32] Smoker group baseline HPLC with EC detection 24 h urine China 60 21.8 0 60 100% 22.6 18 ± 1 ** µmol/mol 41 2
[33] Participants without stroke LC–MS/MS spot urine Taiwan 131 64.9 57 74 50% 22.9 8.3–22.8 13 μg/g 13 2
[34] Male baseline HPLC-EC spot urine Japan 79 47.9 0 79 0% 22.3 2.81 ± 1.07 * μg/g 3 2
[34] Female baseline HPLC-EC spot urine Japan 16 46.7 16 0 0% 20.6 3.04 ± 1.42 * μg/g 3 1
[35] Women baseline HPLC spot urine Japan 37 28–57 37 0 5.4% 21.5 3.2–5.2 3.9 μg/g 4 1
[35] Non smoking men group baseline HPLC spot urine Japan 87 28–57 0 87 0% 24.2 2.9–4.7 3.6 μg/g 4 1
[36] Baseline value HPLC with an EC detector spot urine Japan 23 46.8 11 12 100% 23.6 3.02 2.24–4.07 ng/mg 5 1
[37] Control group LC–MS/MS spot urine Taiwan 125 34.1 0 125 0% 22.8 4.1 ± 2.1 * μg/g 4 2
[38] Control group HPLC-MS/MS spot urine China 185 40.4 124 61 0% 24.4 5.5 ± 2.2 * µg/g 6 2
[39] Control group LC EC spot urine India 135 41.31 0 135 0% 22.38 3.57 ± 0.63 * μmol/mol 9 1
[40] All population HPLC spot urine Japan 6517 60.3 4064 2453 12.6% 22.7 3.9 ± 1.6 * ng/mg 4 2
[41] Placebo group end of study LC-MS/MS spot urine USA 12 69 6 6 0% 25 2 ± 0.2 ** µmol/mol 5 1
[41] Tart cherryjuice group end of study LC-MS/MS spot urine USA 12 69 6 6 0% 25 1.8 ± 0.1 ** µmol/mol 4 1
[42] Male group LC-MS/MS spot urine China 69 37.83 0 69 43.5% 24.1 4.55 ± 4.44 * μg/g 3 2
[42] Female group LC-MS/MS spot urine China 23 38.55 23 0 0% 22.1 4.34 ± 3.85 * μg/g 3 2
[43] Control group LC–MS/MS spot urine Taiwan 129 51.7 39 90 27.9% 24.6 4.3 ± 0.5 ** ng/mg 3 3
[44] Men group HPLC spot urine Japan 196 44.4 0 196 43.9% 23.8 3.3 ± 1.1 * µg/g 3 1
[44] Women group HPLC spot urine Japan 136 40.4 136 0 2.9% 21 3.3 ± 1.1 * µg/g 3 1
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* SD, ** SEM.

Table 3.

References for urinary 8-OHdG concentrations measured and computed GM (ng/mg creatinine) with chemical techniques in healthy (mean BMI > 25 and no known disease), adult (18+ years) participants.

Reference Study Group Analytic Method Sample Country Sample Size Mean Age Female Male Smoking Status Mean BMI AM IQR Median Units
(8-OHdG/Creatinine)		 Computed GM
(ng/mg Creatinine)		 GSD
[45] Elderly low expose group LC–MS/MS spot urine Taiwan 71 66.36 36 35 9.9% 26.36 3.16 ± 4.07 * μg/g 3 2
[23] Placebo group HPLC with EC detection spot urine USA 19 31.1 0 19 0% 25.2 4.18 ± 4.78 * ng/mg 3 2
[46] Control group LC/MS/MS spot urine Taiwan 168 43.2 NA NA 34% 26.4 10.61 ± 7.77 * µmol/mol 21 2
[47] Control group HPLC spot urine China 31 38.7 0 31 19.4% ≤24 38.7%
>24 61.3%		 1.0–4.0 1.3 µmol/mol 3 3
[48] Control non smoker group HPLC–ECD spot urine Turkey 19 54.8 3 16 0% 29.1 2.1 ± 1 * μg/g 2 1
[48] Control ex-smoker group HPLC–ECD spot urine Turkey 21 57.5 3 18 0% 27.2 2.6 ± 0.8 * μg/g 2 2
[48] Control smoker group HPLC– ECD spot urine Turkey 24 51.1 4 20 100% 26.5 4.2 ± 2.8 * μg/g 3 2
[35] Smoking men group baseline HPLC spot urine Japan 40 28–57 0 40 100% 25.1 3.6–5.6 4.5 μg/g 4 1
[49] Control group baseline HPLC spot urine USA 20 39 20 0 50% 29 2.8 ± 1.7 * µg/g 2 2
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* SD.

Table 4.

References for urinary 8-OHdG concentrations measured and computed GM (ng/mg creatinine) with immunological techniques in healthy (mean BMI ≤ 25 and no known disease), adult (18+ years) participants.

Reference Study Group Sample Country Sample Size Mean Age Female Male Smoking Status Mean BMI AM GM IQR Range Median CI Units (8-OHdG/Creatinine) Computed GM (ng/mg Creatinine) GSD
[50] Healthy control group 24 h urine Thailand 30 41.43 19 11 NA 22.56 4.32 ± 4.93 * μg/g 3 2
[51] Healthy control group 24 h urine Thailand 30 41.43 19 11 NA 22.56 5.27 ± 2.77 * μg/g 5 2
[52] Control group spot urine China 35 60 15 20 0% 22.9 11.9 ± 4.9 * ng/mg 11 1
[53] Control group spot urine Korea 416 64.4 92 324 28.1% 23.7 5.06 4.55–5.62 μg/g 5 2
[54] Control group spot urine Korea 140 68.8 32 108 65.5% 22.46 4.88 4.43–5.38 μg/g 5 1
[55] Healthy young group 24 h urine Canada 12 22.8 0 12 0% 25 5333 ± 1191 * ng/g 5 1
[56] Apple group final value spot urine China 13 62.8 3 10 0% 24.2 824.41 ± 343.66 * ng/mmol 7 1
[56] Pomegranate group final value spot urine China 13 64.1 3 10 0% 23 651.57 ± 332.44 * ng/mmol 5 2
[57] placebo group baseline value spot urine China 150 51.58 92 58 41.3% 23.8 60.89 ± 1.62* 58.19 ng/mg 61 2
[57] Baseline line value Low FA group spot urine China 145 48.9 87 58 33.8% 24.5 55.48 ± 1.74 * 53.51 ng/mg 55 2
[57] Baseline value high FA group spot urine China 143 48.66 94 49 30.1% 24.6 55.81 ± 1.72 * 54.73 ng/mg 56 2
[58] Control group 24 h urine Japan 15 40 6 9 0% 23.2 9.7 ± 4.6 * ng/mg 9 2
[59] Control group I spot urine China 20 25.55 17 3 0% 19.74 10.68 ± 1.07 ** ng/mg 10 2
[59] Control group II spot urine China 20 24.5 15 5 0% 20.09 11.96 ± 0.73 ** ng/mg 12 1
[60] Male group spot urine Japan 195 41.7 0 195 49.7% 23.6 9.35 ± 3.66 * ng/mg 9 1
[60] Female group spot urine Japan 194 41.7 194 0 29.9% 22.1 10.97 ± 5 * ng/mg 10 2
[61] Non MS group spot urine Japan 638 40.8 385 253 27.3% 22.3 9.28 ± 4.15 * ng/mg 8 2
[62] Male control spot urine Pakistan 34 39.7 0 34 0% 19.85 24.5 ± 6.6 * 11.08–33.85 25.72 ng/mg 26 1
[62] Female control spot urine Pakistan 32 39.52 32 0 0% 20.83 24.5 ± 6.33 * 11.1–33.85 24.47 ng/mg 24 1
[63] Control group spot urine Pakistan 34 39.7 0 34 0% 20.9 24 ± 4 * 9–30 25 ng/mg 25 1
[64] Control group spot urine Pakistan 34 37 0 34 0% 20.8 25.8 ± 7 * 9.1–33.9 27.9 ng/mg 28 1
[65] Pregnant women spot urine Korea 261 29.6 261 0 0% 21 20.8 ± 14.2 * µg/g 17 2
[66] Control group baseline spot urine UK 32 31.7 15 17 0% 22.4 21.6 ± 12.6 * ng/mg 19 2
[66] Test group baseline spot urine UK 32 31.7 15 17 0% 22.4 24 ± 13.3 * ng/mg 21 2
[67] Control group spot urine Turkey 20 40.7 10 10 NA 22.52 7.84 ± 7.04 * ng/mg 6 2
[68] Control group spot urine Japan 108 23 0 108 NA 22.5 10.4 ± 3.2 * ng/mg 10 1
[69] Non exposed group spot urine Iran 43 35.58 0 43 21% 19–24 54.16 ± 26.98 * ng/mg 48 2
[70] Control group spot urine Japan 52 62.4 27 25 0% 24 8.8 ± 0.5 ** ng/mg 8 1
[71] Male group spot urine Japan 276 42.1 0 276 NA 23.8 8.8 ± 0.2 ** ng/mg 8 1
[71] Female group spot urine Japan 445 42.7 445 0 NA 21.9 9.8 ± 0.2 ** ng/mg 9 2
[72] Male healthy population spot urine Japan 142 43.6 0 142 31% 22.4 11.5 ± 5.2 * ng/mg 10 2
[72] Female healthy population spot urine Japan 136 43.4 136 0 52.2% 23.8 9.4 ± 3.4 * ng/mg 9 1
[73] Control group spot urine USA 43 32.6 43 0 0% 23.2 6.31 ± 2.49 * ng/mg 6 1
[74] Male group spot urine Japan 323 42 0 323 42.7% 23.7 8.85 ± 3.29 ng/mg 8 1
[74] Female group spot urine Japan 443 42.7 443 0 13.5% 21.9 9.89 ± 4.54 * ng/mg 9 2
[75] Green tea catechin-no exercise group baseline value spot urine Japan 8 22.4 0 8 0% >18 <25 15.9 ± 3.6 * ng/mg 16 1
[75] Green tea catechin-exercise group baseline value spot urine Japan 8 21.1 0 8 0% >18 <25 22.9 ± 7.9 * ng/mg 22 1
[75] Placebo group spot urine Japan 8 21.1 0 8 0% >18 <25 18 ± 6.2 * ng/mg 17 1
[76] Men group spot urine Japan 272 43.5 0 272 60.7% 23.7 8.86 ± 3.36 * 2.13–21.87 μg/g 8 1
[76] Women group spot urine Japan 295 40.3 295 0 15.6% 21.7 9.25 ± 4.03 * 0.05–25.56 μg/g 8 2
[77] Baseline value 50km group spot urine Italy 6 41.83 NA NA 0% 21.08 4.38 ± 1.16 * ng/mg 4 1
[78] Summer Non heating season spot urine China 34 47.9 34 0 0% 23.2 12.7 ± 4.7 * 2.60, 25.8 13.6 ng/mg 9 2
[79] Healthy volunteers Young group spot urine Turkey 30 41.6 22 8 0% 22.1 3.24 ± 1.54 * ng/mg 3 2
[79] Healthy volunteers Elderly group spot urine Turkey 30 69.1 20 10 0% 23.6 5.74 ± 2.68 * ng/mg 5 2
[80] Baseline value spot urine China 25 20.9 12 13 0% 20.67 3765.63 ± 958.14 * ng/mmol 32 1
[15] Women group spot urine Italy 33 30 33 0 29% 20.7 3.68–7.20 5.21 ng/mg 4 2
[81] Non exposed group spot urine China 143 27.89 100 43 8% 21.03 17.36 ± 13.5 * ng/mg 14 2
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* SD; ** SEM.

Table 5.

References for urinary 8-OHdG concentrations measured and computed GM (ng/mg creatinine) with immunological techniques in healthy (mean BMI > 25 and no known disease), adult (18+ years) participants.

Reference Study Group Sample Country Sample Size Mean Age Female Male Smoking Status MeanBMI AM IQR Range Median Units (8-OHdG/Creatinine) Computed GM (ng/mg Creatinine) GSD
[82] Cocorit communities spot urine Mexico 10 45.9 5 5 30% 27 8.2 ± 4.3 * μg/g 7 2
[82] Pueblo Yaqui communities spot urine Mexico 15 35.3 9 6 7% 26.7 5.7 ± 2.9 * μg/g 5 2
[82] Campo 47 spot urine Mexico 15 39.5 10 5 40% 29.8 5.7 ± 3.3 * μg/g 5 2
[83] Control group spot urine UK 61 28.4 61 0 9% 26 39.83 ± 2.92 ** ng/mg 35 2
[55] Healthy older group 24 h urine Canada 12 71.8 0 12 0% 28.8 7714 ± 1402 * ng/g 8 1
[84] Water group baseline value spot urine USA 42 18–79 32 10 100% 25.9 8.7 ± 1.3 ** ng/mg 5 3
[84] Green tea group baseline value spot urine USA 35 18–79 27 8 100% 26.5 10.8 ± 1.3 ** ng/mg 9 2
[84] Black tea baseline value spot urine USA 43 18–79 31 12 100% 26.7 9.5 ± 2.1 ** ng/mg 6 2
[85] Water group baseline value spot urine USA 45 49.8 32 13 100% 26.9 9.5 ± 1.3 ** ng/mg 6 3
[85] Black tea baseline value spot urine USA 46 52.1 34 12 100% 27.2 10.8 ± 2.5 ** ng/mg 7 2
[85] Green tea group baseline value spot urine USA 42 51.6 32 10 100% 27.2 8.7 ± 1.8 ** ng/mg 5 3
[86] Placebo group baseline value 24 h urine USA 47 58.1 23 24 0% 28.9 17.6 ± 10.4 * ng/mg 15 2
[86] Vit C group baseline value 24 h urine USA 46 61.2 26 20 0% 28.7 19.3 ± 9.3 * ng/mg 17 2
[86] Vit E group baseline value 24 h urine USA 45 55.5 29 16 0% 28.6 16.5 ± 8.4 * ng/mg 15 2
[86] Vit C + Vit E baseline value 24 h urine USA 46 57.7 24 22 0% 28.9 17.7 ± 9.5 * ng/mg 16 2
[87] Control group 24 h urine Finland 100 65 46 54 18% 27.7 24.3 ± 15.2 * ng/mg 21 2
[88] Control group spot urine Taiwan 27 49 0 27 55.6% 25.8 5 ± 4.92 * µg/g 4 2
[89] All population spot urine Japan 90 52 60 30 0% 25.2 5.8–23.2 0.90–48.0 9.3 ng/mg 9 3
[90] Baseline value spot urine Canada 28 68.5 NA NA 0% 27.1 10783 ± 5856 * ng/g 9 2
[91] control group baseline spot urine Spain 23 30.42 23 0 0% 25.32 9.29 ± 0.69 ** ng/mg 9 1
[91] DHA group baseline spot urine Spain 23 29.97 23 0 0% 25.62 9.81 ± 0.79 ** ng/mg 9 1
[92] Placebo group men 24 h urine Canada 8 74.8 0 8 0% 25.9 8329 ± 3032 * ng/g 8 1
[92] Placebo group women 24 h urine Canada 10 68.3 10 0 0% 25.2 11622 ± 4379 * ng/g 7 1
[92] Intervention group men baseline 24 h urine Canada 11 71.8 0 11 0% 27.8 7245 ± 2703 * ng/g 11 1
[92] Intervention group women baseline 24 h urine Canada 10 69.5 10 0 0% 25.5 7942 ± 3071 * ng/g 7 1
[15] Men group early morning spot urine Italy 22 34 0 22 38.1% 25.3 2.76–5.25 3.76 ng/mg 5 2
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* SD; ** SEM.

Figure 3.

Figure 3

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Forest plot of urinary 8-OHdG concentrations (ng/mg creatinine) measured with chemical techniques in healthy (mean BMI ≤ 25 and no known disease), adult (18+ years) participants.

Figure 4.

Figure 4

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Forest plot of urinary 8-OHdG levels (ng/mg creatinine) measured with chemical techniques in healthy (mean BMI > 25 and no known disease), adult (18+ years) participants

For subgroups analyzed with immunological techniques, 47 studies had participants with a mean BMI between 18 and 25 (24 study subgroups of nonsmokers, no study subgroups of smokers and 6 study subgroups with unknown smoking status) (Figure 5, Table 4). Twenty-six studies had participants with a mean BMI > 25 (13 study subgroups of nonsmokers and 6 study subgroups of smokers) (Figure 6, Table 5). The mean BMI was unknown for 11 study subgroups. Supplementary material provides detailed information on the criteria used for the quality assessment (S1) and on the quality level of each included study subgroup (S2). Overall, two study subgroups (1.8%) were classified as low quality, 66 (58.4%) as moderate quality, and 45 study subgroups (39.8%) were of high quality.

Figure 5.

Figure 5

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Forest plot of urinary 8-OHdG concentrations (ng/mg creatinine) measured with immunological techniques in healthy (mean BMI ≤ 25 and no known disease), adult (18+ years) participants.

Figure 6.

Figure 6

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Forest plot of urinary 8-OHdG concentrations (ng/mg creatinine) measured with immunological techniques in healthy (mean BMI > 25 and no known disease), adult (18+ years) participants.

2.2. Meta-Analysis Results

As between-study heterogeneity was much larger than the between-subject heterogeneity, we decided to use a mixed model with study ID as a random effect. The IQR of subgroup-specific GM in subgroups with a mean BMI ≤ 25 with 8-OHdG measured using chemical methods was 3 to 5.5 ng/mg creatinine (Table 1). IQR of subgroup-specific GM in subgroups with a mean BMI > 25 measured using immunological methods was 5.9 to 19.8 ng/mg creatinine (Table 1).

We compared urinary 8-OHdG concentrations by smoking status within the study subgroups analyzed with chemical techniques and found that for study subgroups with mean BMI ≤ 25, smokers were 2.84 ([2.56, 3.16], p < 0.0001) times greater compared to nonsmoker study subgroups.

For study subgroups with mean BMI > 25, smokers were 1.61 ([1.17, 2.23], p = 0.004) times greater compared to the nonsmoker study.

No consistent effects of BMI and gender were observed in our mixed model either for chemical or immunological methods. Gender and BMI seem to not influence urinary 8-OHdG concentrations.

3. Discussion

3.1. Interpretation of Findings

We found that urinary 8-OHdG concentrations in smokers were greater than in nonsmokers when analysis was conducted with chemical techniques. However, in the population with mean BMI between 18 and 25, this finding was mainly due to one study [32] and needs to be confirmed. The absence of BMI effect on 8-OHdG in urine is in line with data from Lee et al. 2010 [93].

The IQR range for 8-OHdG in urine given in this meta-analysis is in line with two other studies trying to define reference values for the Italian population (female: 3.25–6.85 ng/mg creatinine; male: 2.9–5.5 ng/mg creatinine) [94]. The absence of gender effect observed for 8-OHdG in this study is in line with data from the Italian population [94] but in contradiction with two others [93,95].

The analysis of the data was difficult due to the diversity in study design, analytical methods (chemical or immunoassay techniques), statistical analysis, and data presentation in studies included.

3.2. Quantification of 8-OHdG

The heterogeneity in techniques used to quantify urinary 8-OHdG makes it more difficult to compare data between laboratories.

Chemical techniques are superior to immunological techniques due to their sensitivity and specificity [14,96]. Chemical techniques require expensive instruments and trained users, but we recommend using chemical quantification methods as standard methods for future studies of biomonitoring.

3.3. Lack of Homogeneity in Data Collection and Reporting

Most studies used spot urine samples for 8-OHdG rather than 12- or 24-h collection. However, 8-OHdG levels showed fluctuation during the day under oxidative states [97], but good correlations have been observed between levels of 8-OHdG in spot morning urine and levels of 8-OHdG in the 24-h urinary collection [14]. Therefore, we included studies reporting spot morning urine, 12- or 24-h urinary samples. The first morning urine void is particularly valuable because it provides a time average for biomarker concentrations that may occur during the hours of sleep (approximately 8 h) and is also relatively free of dietary, physical, and environmental exposures [15]. A significant increase in time in the urinary 8-OHdG during the first part of the day was recently reported among smokers [15]. To make it easier to compare results between studies, we recommend collecting spot morning urine.

3.4. Limitations

We confirm that smokers have a significantly greater concentration of urinary 8-OHdG, as has been previously reported in the literature. The concentration differences need to be quantified, but with only a few studies in smokers available, this cannot be done at the present time.

We emphasize here that the values we report are for a healthy population. We were not able to analyze parameters previously reported to influence 8-OHdG concentrations such as occupation, pregnancy, special diet, vitamin, and physical activity due to the limited number of studies with such data.

3.5. Recommendations

The fluctuation in urine flow rate could in fact affect the assessment of urinary 8-OHdG. The urinary 8-OHdG concentrations need to be normalized by urinary creatinine concentrations for healthy adults. Different studies indicated a correlation between excretion of creatinine and 8-OHdG [94,95]. In addition, normalization with creatinine for spot urine can be considered as a surrogate for the 24-h excretion of 8-OHdG [94,98].

To reach consensual background of urinary 8-OHdG values, harmonization of the unit (ng/mg creatinine) is needed. Harmonization of the statistical reporting of the results is also recommended (geometric means (GM) and geometric standard deviations (GSD)). We suggest reporting the median and the 1st and 3rd quartile as GSDs are not easy to interpret.

4. Materials and Methods

We established a standardized protocol for systematic review and meta-analysis for a set of biomarkers of oxidative stress. This protocol was registered in the International Prospective Register of Systematic Reviews (registration number CRD 42020146623) [99] and described in detail by Hemmendinger et al. [100]. The protocol was then adapted for each biomarker depending on the biological matrix focused, here the urinary 8-OHdG. The methods and results of this study are reported following recommendations from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations [101,102].

4.1. Literature Search

The search strategy was done with a medical librarian. The MeSH (Medical Subject Headings) terms from the PubMed database and free text words were combined. The complete search string was: (“Smoking/urine”[Mesh] OR “Urine”[Mesh] OR Urine*[tiab] OR Urinary[tiab] OR Urinal*[tiab]) AND (“8-oxo-7-hydrodeoxyguanosine”[Supplementary Concept] OR 8-OHdg[tw] OR 8ohdg[tw] OR 8-oh-dg[tw] OR 8-ohg[tw] OR 8-OH-2dG[tw] OR 8-hydroxydeoxyguanosine[tw] OR 8-hydroxyguanine[tw] OR 8-hydroxy-g[tw] OR 8-hydroxy-dg[tw] OR 8-hydroxy-guanine[tw] OR 8-hydroxy-2-deoxyguanosine[tw]) NOT ((“Child”[Mesh] OR “Infant”[Mesh] OR “Adolescent”[MeSH]) NOT “adult”[MeSH]) NOT (animals[mh] NOT humans[mh]).

4.2. Study Selection

The search was performed on 7 May 2019. Rayyan [103], a systematic review web application, was used for title and abstract screening. We selected the studies in a stepwise process as depicted in Figure 6. To be included in the analysis, a study had to be in English and to provide urinary 8-OHdG concentrations in healthy adults (ages 18—no upper age limit) populations. We excluded non-human studies, in vitro studies, reviews, letters, expert opinions, and editorials. We read the eligible articles in depth, and only studies with original data from healthy (no known disease) adult populations were included in the statistical analysis. All techniques used for the quantification of 8-OHdG were included and classified accordingly. We excluded studies with coefficient variation <10% or >200%. We also excluded data suspected to have unit or reported value mistakes (more than three orders of magnitude higher than the median levels).

4.3. Data Extraction

We extracted the following information: first author name, publication year, study type, country, analytic method, sample time, sample size, gender, mean age, mean BMI, smoking status, season, occupation, pregnancy, diet, vitamin, exercise, outcome (8-OHdG concentration), references, and article DOI. We extracted all subgroup-specific data when data on several subgroups were available in a given paper. Then, we excluded all subgroups selected based on disease status (e.g., cardiovascular disease) and all subgroups selected based on an exposure status (e.g., bus drivers). If data on the same subgroup were reported for different times (e.g., different seasons), only the data at the time of participant inclusion were included. In a third round, we excluded duplicate data (e.g., control population reported in more than one study) and retained the most complete and the most recent study.

4.4. Statistical Analysis

First, we analyzed the values of urinary 8-OHdG measured in original studies in view of establishing the background ranges using meta-analysis. Measured values were generally log-normally distributed. We therefore computed geometric means (GM) and geometric standard deviations (GSD) as the basis for the meta-analysis or equivalently muL=ln(GM) and sdL=ln(GSD). Further details on the data treatment and analyses are available elsewhere [104].

We could not compute standard errors on the geometric (or arithmetic) scale when neither standard deviation (SD), GSD, IQR, nor confidence interval (CI) were reported. As a consequence, we excluded these studies from the meta-analysis. We converted all the concentration values to the same units (ng/mg creatinine) before computing GM and GSD. We used 113.12 g/mol for the molecular weight for creatinine and 283.24 g/mol for 8-OHdG. We regrouped the data according to analytical techniques used; immunological techniques and chemical techniques. The data were analyzed separately.

We followed standard practice in meta-analysis [105] and represent the data as forest plots including the I-squared. This is an estimate of the between-study heterogeneity in percentage. If the between-study heterogeneity is much larger than the between-subject heterogeneity, then I2 is large. In this case, any attempt of obtaining a background value for individual participants will not be valid. In our case, a mixed model with study ID as a random effect is a more relevant analysis model. This yields results on the study subgroup level rather than at the individual level. Data management and statistical analyses were performed in STATA version 16 software.

5. Conclusions

We report pooled GM values for urinary 8-OHdG in healthy adults, separately for chemical and immunological methods. We observed a significant positive association between smoking status and urinary 8-OHdG concentrations when measured by chemical analysis. No gender effect was shown. Urinary 8-OHdG can potentially be used to quantify excess oxidative stress due to external exposures when background values have been established in different populations. We recommend adjusting urine samples with creatinine, quantifying 8-OHdG with chemical methods, and reporting results as median and quartiles. Comparing values across studies will then be feasible.

Abbreviations

8-OHdG 8-hydroxy-2-deoxyguanosine
ROS Reactive oxygen species
GM Geometric mean
GSD Geometric standard deviation
BMI Body mass index
SD Standard deviation
SEM Standard error of the mean
CV Coefficient of variation
IQR Interquartile range
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Supplementary Materials

Supplementary Materials can be found at https://www.mdpi.com/1422-0067/21/11/3743/s1.

Click here for additional data file. (20KB, xlsx)

Author Contributions

I.G.C. and N.B.H. conceived the project, developed the necessary tools, and managed funding acquisition; M.H. and M.G. wrote the study protocol and implemented the literature search; M.G. and N.B.H. performed the screening for study selection, the systematic review, and data extraction; J.-J.S. performed data conversion and validation; P.W. realized statistical analysis; M.G. wrote the manuscript, which was further amended by all authors. All authors have read and agreed to the published version of the manuscript.

Funding

This study was conducted within the framework of EU Life Project “NanoExplore” (Grant N° LIFE17 ENV/GR/000285) and Franco-Swiss project “ROBoCoP” (Swiss National Science Foundation Grant N° IZCOZ0_177067).

Conflicts of Interest

The authors declare no conflict of interest.

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