Essential Metals Zinc, Selenium, and Strontium Protect against

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The Essential Metals Zinc, Selenium, and Strontium Protect against Chromosome Damage Caused by Polycyclic Aromatic Hydrocarbons Exposure Yansen Bai, Wei Feng, Suhan Wang, Xiao Zhang, Wangzhen Zhang, Meian He, Xiaomin Zhang, Tangchun Wu, and Huan Guo Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.5b03945 • Publication Date (Web): 24 Dec 2015 Downloaded from http://pubs.acs.org on December 26, 2015

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Environmental Science & Technology

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The Essential Metals Zinc, Selenium, and Strontium Protect against

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Chromosome Damage Caused by Polycyclic Aromatic Hydrocarbons Exposure

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Yansen Bai, † Wei Feng, † Suhan Wang, † Xiao Zhang, † Wangzhen Zhang, ‡ Meian

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He,† Xiaomin Zhang, † Tangchun Wu,† Huan Guo *,†

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Authors’ affiliations:

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†

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Environmental Health (Incubating), School of Public Health, Tongji Medical College,

Department of Occupational and Environmental Health, State Key Laboratory of

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Huazhong University of Science and Technology, Wuhan, China;

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‡

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430070, China.

Institute of Industrial Health, Wuhan Iron & Steel (group) Corporation, Wuhan

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*Correspondence to: Huan Guo, MD, PhD, Associate Professor, Department of

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Occupational and Environmental Health, School of Public Health, Tongji Medical

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College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan

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430030, Hubei, China. Tel: 86-27-83657914; Fax: 86-27-83657765; E-mail:

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[email protected].

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Conflict of Interest Statement: No potential conflicts of interest exist or are

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disclosed.

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Running title: Zn, Se and Sr Protect against DNA Damage

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ACS Paragon Plus Environment


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Abbreviations:

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PAHs, polycyclic aromatic hydrocarbons; ΣOH-PAHs, total concentration of urinary

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monohydroxy PAHs; MN, micronucleus; BPDE-Alb, benzo[a]pyrene-r-7, t-8, t-9,

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c-10-tetrahydotetrol-albumin; Zn, zinc; Se, selenium; Sr, strontium; Fe, iron; Cu,

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copper; Co, cobalt; Mn, manganese; Mo, molybdenum; Rb, rubidium; Sn, stannum; V,

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vanadium; CBMN, cytokinesis-block micronucleus; LOD, limits of detection; LOQ,

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limits of quantity; BMI, body mass index; SD, standard deviation.

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Abstract

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Essential metals play important roles in maintaining cellular homeostasis, but the

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effects of their interaction with the environmental pollutants still not very well known

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in human subjects. The aim of this study was to evaluate the roles of essential metals

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and their interactions with polycyclic aromatic hydrocarbons (PAHs) on chromosome

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damage, an early carcinogenic event. A total of 1245 male workers were included in

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this study and the levels of 11 urinary essential metals, 12 urinary PAH metabolites,

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plasma concentrations of benzo[a]pyrene-r-7, t-8, t-9, c-10-tetrahydotetrol-albumin

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(BPDE-Alb) adducts, and lymphocyte micronucleus (MN) frequencies were

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monitored. We found that zinc (Zn), selenium (Se), and strontium (Sr) have

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significant inverse dose-response relationships with MN frequencies (all P1.23µg/mmol creatinine, Q4 subgroups), and Sr (>17.39 µg/mmol

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creatinine, Q4 subgroups), suggesting that the dose was a critical factor for

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determining the biological roles of these metals. Similar dose-depended effects of Zn

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and Se with risk of specific cancers have also been reported in other prospective and

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epidemiological studies. The Harvard Nurses' Health Study found that the beneficial

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effect of Zn against rectal cancer was mainly observed among those with highest

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quintile of dietary Zn intake when compared to those with lowest quintile of dietary

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Zn intake [RR(95%CI)=0.51(0.29-0.86)]. This effect was not seen for the other

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quintile subgroups.50 One recent large systematic review and meta-analysis, including

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approximately 400,000 participants, revealed that higher Zn intake was significantly

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associated with reduced colorectal cancer risk, comparing the highest with lowest

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categories, while this effect was not reflected in the middle subgroups.51 In a nested

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case-control study that, when compared with those subjects with lowest tertile of Se

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(60.6 µg/L) (RR = 0.41), but not seen among participants

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with middle tertile of Se (45.5-60.6 µg/L).52 However, some other studies proposed a

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correlation between over-accumulation of Zn and Se with an increased risk of cancer

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and Alzheimer's disease, respectively.53, 54 As a result, it should be kept in mind that

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the supplemental dose of essential element needs to be controlled carefully in order to

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establish the optimal levels of these metals in the human body.

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No significant associations between urinary Fe, Cu, Co, Mn and chromosome

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damage were found in this study. However, in a study on a rat model, Fe, Mn and

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their compounds have been shown to increase MN frequency due to oxidative stress

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induction.55 Faccioni et al. in a clinical study reported that Co (0.57 µg/l) induced

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DNA damage in oral mucosa cells.56 The discrepancy between our findings and others

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is perhaps due to the different exposure levels, as the concentration of urinary Co in

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our investigation was significantly lower than in the above-mentioned study (0.19 vs.

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0.57 µg/l). Indeed, while some essential metals play protective anti-carcinogenic roles

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at low concentration, they may exert the toxic actions when in higher

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concentrations.57 In addition, difference in genetic background and variability in DNA

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repair mechanisms may play important roles on DNA repair capacity and DNA

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damage,58, 59 and thus affecting the connection.

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In this study, we also found that plasma BPDE-Alb adducts can significantly

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modify the associations of urinary metals (Zn, Se, and Sr) with MN frequencies:

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elevated levels of urinary metals Zn, Se, and Sr are related to reduced MN frequencies

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among subjects with the highest levels of plasma BPDE-Alb adducts. One explanation,

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in our study subjects, was that among individuals with higher plasma BPDE-Alb

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adducts, they had also higher levels of Zn, Se, and Sr, which may have improved the

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cellular DNA repair capacity. It was also reported that Se can help to protect the body

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from the poisonous effects of heavy metals and other harmful substances.60 Se exerts

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its biological roles through selenoproteins, and the experiments carried out by

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Touat-Hamici Z et al. indicated that oxidative stress could cause a selective

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up-regulation of several selenoproteins involved in antioxidant defense.61 In the

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process of chemical carcinogenesis, PAHs are thought to produce ROS that increase

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the burden of oxidative stress.62 It is plausible that increased levels of Zn, Se, and Sr

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can counteract ROS actions, and reduced the oxidative stress caused by PAHs

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exposure. However, the underlying mechanisms of how PAHs interact with these

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essential metals warrant further investigation.

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There are several strengths in our study. First, we used a large sample-sized

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cross-sectional study to explore the dose-effect relationships between essential metals

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and chromosome damage levels, which may provide a sufficient statistical power.

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Second, the internal exposure biomarkers (urinary metals, OH-PAHs, and plasma

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BPDE-Alb adducts) provided more accurate individuals’ exposure levels than the

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environmental monitoring. Third, our study investigated a wide range of essential

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metals rather than well-known carcinogenic heavy metals and this may provide a new

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research focus and field in cancer prevention for occupational and environmental

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exposed populations. However, some limitations should not be neglected. Firstly, the

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cross-sectional design of this study is limited to establish the casual relationships

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between essential metals and chromosome damage and carcinogenesis. In addition,

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spot morning rather than 24-h urine samples testing was used to assess the exposure

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levels of PAHs and metals, which may introduce measurement error due to biorhythm

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throughout the day. Lastly, the coke-oven workers investigated in the present study

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were a typical population exposed to higher levels of PAHs than the general

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populations, so the extrapolations of the protective effects of Zn, Se, and Sr to the

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general population need further validations.

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Our study showed for the first time that elevated concentrations of Zn, Se and Sr

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were negatively associated with MN frequencies among coke-oven workers, and the

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protective qualities of Zn, Se and Sr were most evident when PAH exposure were

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particularly high, leading to elevated adduct levels. More importantly, plasma

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BPDE-Alb adducts can significantly modify the effects of Zn, Se and Sr on MN

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frequencies. The results of this study provided evidence on the dose-related effects of

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essential metals and their protective effects against the chromosome damage caused

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by PAHs exposure. These findings may add potential epidemiological evidence for the

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preventive effects of Zn, Se, and Sr against carcinogenesis in human subjects. Further

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prospective studies should be taken in consideration to verify our findings and clarify

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the underlying mechanisms.

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Acknowledgements:

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This study was supported by the National Key Basic Research and Development

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Program (973 project, 2015CB553403, 2011CB503806), the funds from the Natural

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National Scientific Foundation of China (grant no. 81102102, 81272589), Program

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for New Century Excellent Talents in University of Ministry of Education of China,

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2012 (grant no. NCET-12-0209), and Foundation for the Author of National Excellent

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Doctoral Dissertation of PR China (grant no. 201484).

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Supporting Information Available

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Table S1-S2. This information is available free of charge via the Internet at

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http://pubs.acs.org.

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smoking, and pancreatic adenocarcinoma risk. Cancer Res. 2008, 68 (12), 4928-4935.

675

(59) Coelho, P.; Garcia-Leston, J.; Costa, S.; Costa, C.; Silva, S.; Dall'Armi, V.;

676

Zoffoli, R.; Bonassi, S.; de Lima, J. P.; Gaspar, J. F.; Pasaro, E.; Laffon, B.; Teixeira, J.

32


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677

P. Genotoxic effect of exposure to metal(loid)s. A molecular epidemiology survey of

678

populations living and working in Panasqueira mine area, Portugal. Environ. Int. 2013,

679

60, 163-170.

680

(60) Gupta, S.; Jaworska-Bieniek, K.; Lubinski, J.; Jakubowska, A. Can selenium be a

681

modifier of cancer risk in CHEK2 mutation carriers? Mutagenesis. 2013, 28 (6),

682

625-629.

683

(61) Touat-Hamici, Z.; Legrain, Y.; Bulteau, A. L.; Chavatte, L. Selective

684

up-regulation of human selenoproteins in response to oxidative stress. J. Biol. Chem.

685

2014, 289 (21), 14750-14761.

686

(62) Valavanidis, A.; Fiotakis, K.; Bakeas, E.; Vlahogianni, T. Electron paramagnetic

687

resonance study of the generation of reactive oxygen species catalysed by transition

688

metals and quinoid redox cycling by inhalable ambient particulate matter. Redox Rep.

689

2005, 10 (1), 37-51.

690

33



691

Figure Legend

692

Figure 1. Interactions of urinary essential metals and BPDE-Alb adducts on MN

693

frequencies among coke-oven workers. Each interaction model included one

694

metal-risk factor interaction term and covariates, adjusted for work years, smoking,

695

alcohol drinking, BMI, and ΣOH-PAHs. The values of the y-axis represent MN

696

frequencies (Mean ± SD). Cut-off points were determined according to the medians of

697

each metal (Zn: 32.02, Se: 0.82, and Sr: 11.32 µg/mmol creatinine) and the 66.7th

698

percentile of BPDE-Alb adducts (4.70 ng/mg albumin).

34


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Table 1 General characteristics of study participants (n=1245) Characteristics

Values

Age (years, mean ± SD)

42.5 ± 8.5

Working years (mean ± SD)

21.5 ± 9.7

2

Body mass index (kg/m , mean ± SD)

24.1 ± 3.0

Smoking, n (%) yes

873 (70.1)

no

372 (29.9)

Alcohol drinking, n (%) yes

507 (40.7)

no

738 (59.3)

Education levels, n (%) middle school and below

257 (21.5)

high school

485 (40.4)

college and above

456 (38.1)

MN frequencies (‰, mean ± SD)

3.61 ± 2.67

35



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Table 2 Distributions of urinary essential metals, ΣOH-PAHs, and plasma BPDE-Alb adducts in the study subjects Biomarkers

No.

Geometric Mean

Median

Selected percentiles 5%

25%

75%

90%

95%

Urinary metals (µg/mmol creatinine) Zinc (Zn)

1245

33.17

32.02

10.47

20.90

51.64

81.69

113.79

Selenium (Se)

1245

0.81

0.82

0.27

0.55

1.23

1.83

2.39

Strontium (Sr)

1245

11.27

11.32

3.27

6.98

17.39

28.23

40.39

Iron (Fe)

1245

8.30

7.37

1.85

4.14

14.79

32.97

55.18

Copper (Cu)

1245

0.76

0.72

0.27

0.48

1.11

1.75

2.53

Cobalt (Co)

1245

0.016

0.015

0.006

0.010

0.024

0.043

0.059

Manganese (Mn)

1245

0.25

0.24

0.05

0.13

0.45

0.96

1.54

Molybdenum (Mo)

1245

3.94

3.98

1.08

2.49

6.47

9.74

13.02

Rubidium (Rb)

1245

182.74

180.32

63.63

120.51

281.86

425.61

573.94

Stannum (Sn)

1245

15.75

15.78

6.61

11.50

21.76

29.39

37.79

Vanadium (V)

1245

0.021

0.035

0.001

0.016

0.060

0.104

0.149

ΣOH-PAHs (µg/mmol creatinine)

1245

12.38

11.78

4.10

7.79

18.63

30.88

42.50

BPDE-Alb adducts (ng/mg albumin)

1225

4.31

4.25

1.75

3.60

5.05

6.23

7.75

36


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Table 3 Regression analyses on lymphocytic MN frequencies Variables

MN frequencies FR (95%CIs)

P

1.010 (1.007, 1.013) 0.909 (0.850, 0.971) 1.073 (1.009, 1.141) 0.987 (0.977, 0.996) 1.336 (1.266, 1.412)

17.39 0.894 (0.814, 0.982) >14.79 0.919 (0.839, 1.009) >1.11 0.992 (0.900, 1.093) >0.024 1.016 (0.922, 1.119) >0.49 0.917 (0.839, 1.002) >6.47 0.996 (0.910, 1.091) >281.86 0.929 (0.846, 1.019) >21.76 1.041 (0.955, 1.134) >0.060 0.976 (0.893, 1.068)

P for trend

Abbreviations: FR (95%CIs), frequency ratios and their 95% confidence intervals. Note: Poisson regression models with adjustment for working years, smoking, alcohol drinking, BMI, BPDE-Alb adducts and ΣOH-PAHs, and the ln-transformed urinary essential metals were used as continuous variables in the models. 38


0.002 0.011 0.020 0.024 0.779 0.753 0.048 0.908 0.552 0.350 0.325

Page 39 of 41


Table 5 The levels of Zn, Se, Sr, and their associations with MN frequencies in subgroups stratified by the plasma BPDE-Alb adducts levels. T1 (BPDE-Alb adducts 4.70)

Median (25%-75%), µg/mmol creatinine

27.42 (18.55,45.42)

33.48 (22.85,51.9)

35.39 (22.62,58.47)

FR (95%CIs)

0.926 (0.845, 1.016)

0.941 (0.857, 1.034)

0.894 (0.829, 0.965)

0.104

0.203

0.004

0.73 (0.51,1.16)

0.85 (0.57,1.21)

0.85 (0.58,1.34)

1.038 (0.948, 1.137)

0.895 (0.814, 0.984)

0.890 (0.823, 0.965)

0.420

0.022

0.004

9.77 (6.44,15.94)

11.74 (6.97,18.32)

12.28 (8.23,18.47)

0.947 (0.868, 1.034)

0.935 (0.864, 1.011)

0.905 (0.841, 0.974)

0.222

0.092

0.008

Urinary metals Zn

P

a

Se Median (25%-75%), µg/mmol creatinine FR (95%CIs) P

a

Sr Median (25%-75%), µg/mmol creatinine FR (95%CIs) P

a

Note: FR(95%CIs), frequency ratios and their 95% confidence intervals. Median (25%-75%): the median, 25th and 75th percentiles of the concentrations of metals in different subgroups. Subjects were stratified by tertiles (33.3th and 66.7th percentiles) of BPDE-Alb adducts (ng/mg albumin). a Poisson regression models with adjustment for working years, smoking, alcohol drinking, BMI, and ΣOH-PAHs.

39



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Table of contents 47x26mm (300 x 300 DPI)


Essential Metals Zinc, Selenium, and Strontium Protect against

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