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Abstract

Paraoxonase 1 (PON1) has been proposed as an antioxidant enzyme. Although lead-inhibited PON1 activity has been demonstrated mostly based on in vitro experiments, it is uncertain whether this phenomenon is relevant in pathogenesis of lead-induced oxidative stress in the lead exposure. We examined associations of blood lead levels (BLL) and PON1 activity along with oxidative stress parameters in lead exposure workers. We determined malondialdehyde (MDA), conjugated diene (CD), total peroxides (TP), total antioxidant status (TAS), the oxidative stress index (OSI), and PON1 activity in earthenware factory workers (n = 60) and control subjects (n = 65). The lead-exposed group significantly increased lipid peroxidation parameters and OSI compared to the control group (p < 0.001). The lead-exposed group had significantly decreased PON1 activity and TAS levels compared to the control group (p < 0.001). Multiple linear regression analysis revealed that BLL were significantly correlated with decreased TAS (r = −0.496) and PON1 activity (r = −0.434), but with increased CD (r = 0.694), TP (r = 0.614), MDA (r = 0.788), and OSI (r = 0.722). Interestingly, BLL at 10 µg/dL significantly decreased PON1 activity and increased oxidative stress parameters with insignificant changes in other biochemical and hematological parameters. Altogether, the reduction of PON1 activity may associate in an imbalance in pro-oxidants and antioxidants, leading to oxidative damage in lead-exposed workers even at low BLL.

Keywords

lead oxidative stress paraoxonase 1

Introduction

Although, the International Agency for Research on Cancer classified inorganic lead compounds as 2A chemicals,¹ lead has become widely dispersed in the environment due to its usefulness in many applications.² Lead-related disorders occur in many organs and systems, such as the kidney and liver as well as the central and peripheral nervous, hematopoietic, reproductive, and cardiovascular systems.^{3
–5} A recent epidemiology retrospective study on lead toxicity revealed that high blood lead levels (BLL) as well as low BLL are associated with cardiovascular mortality in several cohorts.^6,7 These may be due to an increase in oxidative stress as caused by lead-induced toxicity that leads to atherosclerosis and cardiovascular diseases.^4,6,8 Several lines of evidence have demonstrated the potential of lead in inducing oxidative stress by increased reactive oxygen species (ROS) formation⁹ and reduced antioxidant system via the inhibition of antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase^10,11 as well as decreasing glutathione: glutathione disulfide ratio.¹²

Paraoxonase 1 (PON1) is a high-density lipoprotein–associated antioxidant enzyme. Recent evidence using both in vivo and in vitro models have pointed to an anti-atherosclerotic mechanism of PON1 via its antioxidant property in reducing low-density lipoprotein (LDL) and high-density lipoprotein (HDL) oxidations.^13,14 Increasing evidence has demonstrated that other environmental factors, in addition to genetics, also influence PON1 activity. Other pollution-causing metal ions such as cadmium, mercury, and copper have been shown to inhibit PON1 activity in serum and liver tissues from rats and humans^{15
–17} and purified PON1.^17,18 In addition, lead chloride (PbCl₂) has been shown to inhibit the arylesterase activity of purified human PON1 in vitro.¹⁹ Recently, Li et al. found that lead exposure is associated with decreased serum PON1 activity towards paraoxon and phenyl acetate.²⁰ However, substantial evidence on the effect of lead on PON1 activity along with oxidative status in lead-exposed workers remains to be clarified. Our study presented here explored the association between lead exposure and oxidative stress status as well as PON1 activity in Thai earthenware factory workers. We also analyzed the association of different levels of BLL with PON1 activity, oxidative status, biochemical, and hematological parameters.

Materials and methods

Subjects and blood collections

Sixty earthenware factory workers were recruited for this study. Their duration of work varied from 7 to 420 months. Sixty-five sex- and age-matched controls with no history of occupational lead exposure were used for the purposes of comparison, and the validity of the selection was confined by basic screening questionnaires and interviews. Blood pressure and physical examinations were performed before collection of specimens, and subjects with diabetes mellitus, hyperthyroidism, malignancy, lipid reducing therapy, and pregnant or lactating women were excluded. The protocol was approved by the Ethics Committee of Mahidol University. All subjects provided informed consent.

Blood samples were collected into EDTA tubes for determination of complete blood counts (CBC) and blood lead levels (BLL). Blood collected in plain and heparinized tubes was separated for serum and plasma, respectively, and immediately aliquoted and stored at −80°C until assaying. Serum was used for determination of biochemical parameters and PON1 activities while heparinized plasma was used for determination of oxidative stress parameters.

Blood lead level measurement

BLL were determined in whole blood containing EDTA with an atomic absorption spectrophotometer with a graphite furnace atomic absorption (GFAAS) SpectraAA600 (Variance) at Faculty of Medical Technology, Mahidol University, which routinely participates in lead proficiency testing.

Routine blood parameters

A complete blood count (CBC) was analyzed using a Hematology Analyzer Coulter JT (Coulter). Serum biochemical parameters were determined using an auto analyzer Hitachi 917 Automate (Boehringer Mannheim).

Oxidative stress parameters

Lipid peroxidation parameters: Conjugated diene (CD) was determined by absorbance at 233 nm as previously described by Buege and Aust,²¹ total peroxides were determined by using the FOX2 method as described by Kosecik,²² and malondialdehyde (MDA) was determined using thiobabituric acid.²³ Total antioxidant status (TAS) were determined using ABTS as previously described by Kosecik.²² Each assay has intra- and inter-assay for quality control. The oxidative stress index (OSI) was calculated from a percent ratio of total peroxide level to the TAS level.²²

PON1 activities determination

PON1 activities were determined by using paraoxon and phenyl acetate as substrates.²⁴ PON1 activity was measured using paraoxon as a substrate and the rate of hydrolysis of paraoxon was continuously monitored at 405 nm and 37°C. PON1 activity towards paraoxon was expressed as nanomoles of hydrolysis products formed per minute per milliliter. PON1 arylesterase activity was measured using phenyl acetate as previously described.²⁴ The rate of hydrolysis of phenyl acetate was continuously monitored at 270 nm and 37°C. PON1 activity towards phenyl acetate was expressed as micromoles of hydrolysis products formed per minute per milliliter.

Statistical analysis

SPSS for Windows, version 17.0, was used for all statistical analysis. The parameters with normal distribution were performed by independent sample t-tests for comparison. The Mann-Whitney U test was used to compare the differences of non-normally distributed parameters. Pearson and Spearman correlation tests were used to test the strength of correlations of parameters with normal distributions and non-normal distributions, respectively. Statistical significance was defined as p < 0.05.

Results

Demographic data and clinical parameters of the control and lead-exposed groups

The demographic characteristics of the control and lead-exposed groups are presented in Table 1 . There were no significant differences between these two groups in terms of age, sex, body mass index (BMI), systolic blood pressure (SBP), or diastolic blood pressure (DBP). The BLL were found to be significantly higher in the lead-exposed group compared to the control group (31.4 ± 2.5 μg/dL vs 3.9 ± 0.2 μg/dL, p < 0.001). All clinical biochemical parameters were insignificantly different between the lead-exposed group and the control group, whereas the analysis of complete blood counts revealed significant decreases in hemoglobin and hematocrits in the lead-exposed group (p < 0.05).

Table 1.

Demographic characteristics and screening tests for study subjects^a

Characteristic	Control group (n = 65)	Lead-exposed group (n = 60)
Blood lead levels (µg/dL)	3.9 ± 0.2	31.4 ± 2.5^b
Age (year)	38.2 ± 1.3	41.0 ± 1.1
Male %	29.2 % (19/65)	25.0 % (15/60)
Female %	70.8 % (46/65)	75.0 % (45/60)
BMI (Kg/m²)	23.3 ± 0.5	22.2 ± 0.4
SBP (mm Hg)	116.1 ± 19.0	120.0 ± 1.9
DBP (mm Hg)	78.9 ± 1.3	80.6 ± 1.6
FBS (mmol/L)	4.97 ± 0.08	4.94 ± 0.07
BUN (mg/dL)	11.2 ± 0.4	12.4 ± 0.6
Creatinine (mg/dL)	0.83 ± 0.03	0.83 ± 0.03
Total cholesterol (mmol/L)	5.41 ± 0.13	5.18 ± 0.13
Triglycerides (mmol/L)	1.23 ± 0.09	1.24 ± 0.09
HDL-C (mmol/L)	1.54 ± 0.04	1.68 ± 0.5
LDL-C (mmol/L)	3.12 ± 0.11	3.04 ± 0.12
AST (U/L)	20.1 ± 0.5	19.9 ± 0.9
ALT (U/L)	19.5 ± 1.2	19.1 ± 1.3
ALP (U/L)	69.4 ± 3.7	66.8 ± 3.5
Hemoglobin (g/dL)	13.7 ± 0.2	12.7 ± 0.2^c
Hematocrit (%)	41.6 ± 0.6	38.6 ± 0.5^c

Abbreviations: ALP: alkaline phosphatase, ALT: alanine aminotranferease, AST: aspartate aminotransferase, BMI: body mass index, BUN: blood urea nitrogen, DSP: diastoloc blood pressure, FBS: fasting blood sugar, HDL-C: high-density lipoprotein, LDL-C: low-density lipoprotein, SBP: systolic blood pressure.

^a Values shown as mean ± SEM.

^b p < 0.001 lead-exposed group vs control group.

^c p < 0.05 lead-exposed group vs control group.

Oxidative status and PON1 activities

The given major postulates that lead generates reactive oxygen species and inhibits antioxidant enzymes activities, stimulates lipid peroxidation, and consequently can contribute to lead-related diseases. We determined the lipid peroxidation parameters and total antioxidant status by using OSI to indicate the proof of the existence of oxidative stress in these study groups. Conjugated diene, TP, MDA, and OSI levels were significantly elevated in the lead-exposed group compared to the control group (p < 0.001; Table 2). In contrast, the level of TAS in the lead-exposed group (0.462 ± 0.02 mmol Trolox Equiv/L) was significantly decreased compared to the control group (0.761 ± 0.02 mmol Trolox Equiv/L; p < 0.001; Table 2).

Table 2.

Effects of lead on oxidative stress parameters and PON1 activities^a

Oxidative stress parameters	Control group (n = 65)	Lead-exposed group (n = 60)	% Change
CD (OD. 233 nm)	0.169 ± 0.004	0.247 ± 0.009^b	+46.4
TP (μmol H₂O₂/L)	9.8 ± 0.19	11.8 ± 0.35^b	+20.3
MDA (µmol/L)	11.1 ± 0.3	14.6 ± 0.4^b	+31.6
TAS (mmol Trolox Equiv/L)	0.761 ± 0.02	0.462 ± 0.02^b	−40.5
OSI	1.34 ± 0.04	2.75 ± 0.07^b	+105.7
PON1
Paraoxonase activity (nmol/min/mL)	172.1 ± 10.3	171.1 ± 9.5	−0.5
Arylesterase activity (µmol/min/mL)	155.0 ± 4.2	117.9 ± 3.9^b	−23.9

Abbreviations: CD: conjugated diene, MDA: malondialdehyde, OSI: oxidative stress index, PON1: paraoxonase 1, TAS: total antioxidant status, TP: total peroxides.

^a Values shown as mean ± SEM. % Change is the percentage difference of mean between lead-exposed group and the control group.

^b p < 0.001 lead-exposed group vs control group.

Table 2 shows that PON1 activity towards phenyl acetate in the lead-exposed group was significantly decreased (117.9 ± 3.9 µmol/min/mL) when compared to the control group (155.0 ± 4.2 µmol/min/mL). However, PON1 activity towards paraoxon was not significantly different between the control group and lead-exposed group.

Relationship between blood lead, oxidative biomarkers, and PON1 activity

The strength of the correlation between blood lead levels, oxidative stress parameters, and PON1 activity are shown in Figure 1 . A strong negative correlation was found between BLL and TAS (r = −0.496, p < 0.001), but strong positive correlations were found between BLL and CD (r = 0.694, p < 0.001) and TP (r = 0.614, p < 0.001). Interestingly, a very strong positive correlation was found between BLL and OSI (r = 0.722, p < 0.001) and MDA (r = 0.788, p < 0.001). In addition, a negative correlation was observed between BLL and PON1 activity toward phenyl acetate (r = −0.434, p < 0.001).

Figure 1.

Linear regression analysis between blood lead levels and CD (A), MDA (B), TP (C), TAS (D), OSI (E), and PON1 activity toward phenyl acetate (F) in study group.

For comparison of the various levels of blood lead and oxidative biomarkers, we grouped the BLL into four categories: control (BLL < 10 μg/dL), low (BLL ≥ 10 μg/dL), medium (BLL ≥ 20 μg/dL), and high (BLL ≥ 30 μg/dL). The results show that all oxidative stress parameters were also significantly increased even at low BLL (p < 0.05). Significant decreases in TAS and PON1 activity at low BLL (p < 0.001) were also noted (Table 3). The hematological parameters were significantly different at medium BLL compared to controls, and the degree of difference was stronger in high BLL. In contrast, insignificant differences in biochemical parameters were observed for all ranges of BLL (Table 4).

Table 3.

Effect of lead levels on oxidative stress parameters and PON1 activities^a

Parameters	Blood lead levels (μg/dL)
Parameters	Control (n = 65; <10 μg/dL)	Low (n = 19; ≥10 μg/dL)	Medium (n = 15; ≥20 μg/dL)	High (n = 26; ≥30 μg/dL)
CD (OD. 233 nm)	0.169 ± 0.004	0.240 ± 0.014^b	0.256 ± 0.013^b	0.271 ± 0.017^b
TP (μmol H₂O₂/L)	9.8 ± 0.19	10.9 ± 0.4^c	11.7 ± 0.6^c	12.7 ± 0.6^b
MDA (μmol/L)	11.1 ± 0.3	13.2 ± 0.4^d	14.0 ± 0.6^d	16.6 ± 0.7^b
TAS (mmol Trolox Equi/L)	0.761 ± 0.02	0.467 ± 0.02^b	0.461 ± 0.04^b	0.435 ± 0.03^b
OSI	1.34 ± 0.04	2.46 ± 0.05^b	2.57 ± 0.04^b	2.68 ± 0.08^b
PON1, arylesterase activity (mmol/min/mL)	155.0 ± 4.2	127.4 ± 8.0^d	113.0 ± 8.1^d	111.5 ± 5.7^d

Abbreviations: CD: conjugated diene, MDA: malondialdehyde, OSI: oxidative stress index, PON1: paraoxonase 1, TAS: total antioxidant status, TP: total peroxides.

^a Values are shown as the mean ± SEM.

^b p < 0.001 lead-exposed group vs control group.

^c p < 0.05 lead-exposed group vs control group.

^d p < 0.01 lead-exposed group vs control group.

Table 4.

Effect of lead levels on biochemical and hematological parameters^a

Parameters	Blood lead levels (μg/dL)
Parameters	Control (n = 65; <10 μg/dL)	Low (n = 19; ≥10 μg/dL)	Medium(n = 15; ≥20 μg/dL)	High (n = 26; ≥30 μg/dL)
Blood lead levels (μg/dL)	3.9 ± 0.2	16.2 ± 0.6^b	26.8 ± 0.9^b	50.5 ± 3.8^b
BUN (mg/dL)	11.2 ± 0.4	11.9 ± 0.8	12.3 ± 1.4	14.0 ± 1.0^c
Creatinine (mg/dL)	0.83 ± 0.03	0.81 ± 0.04	0.80 ± 0.07	0.84 ± 0.06
LDL-C (mmol/L)	3.13 ± 0.11	3.08 ± 0.22	2.91 ± 0.17	2.97 ± 0.17
AST (U/L)	20.1 ± 0.5	20.4 ± 1.6	19.7 ± 2.7	19.9 ± 1.4
ALT (U/L)	19.5 ± 1.2	20.5 ± 3.4	19.6 ± 1.9	18.8 ± 1.0
ALP (U/L)	69.4 ± 3.7	66.9 ± 3.4	66.6 ± 3.0	66.4 ± 3.7
Hemoglobin (g/dL)	13.6 ± 0.2	13.1 ± 0.4	12.7 ± 0.3^c	12.7 ± 0.3^d
Hematocrit (%)	41.4 ± 0.5	39.7 ± 1.1	38.0 ± 1.0^c	38.5 ± 0.8^d

Abbreviations: ALP: alkaline phosphatase, ALT: alanine aminotranferease, AST: aspartate aminotransferase, BUN: blood urea nitrogen, LDL-C: low-density lipoprotein.

^a Values are shown as the mean ± SEM.

^b p < 0.001 lead-exposed group vs control group.

^c p < 0.05 lead-exposed group vs control group.

^d p < 0.01 lead-exposed group vs control group.

Discussion

Several lines of evidence have demonstrated that lead induces oxidative damage and alters biological functions of macromolecules and subsequently causes hematological disorders and circulatory, liver, and kidney dysfunction.²⁵ In this study, hemoglobin and hematocrit levels were lowered, while no significant changes were observed in blood pressure or clinical biochemical parameters for kidney and liver function. Lead-induced hematological disorders have been known to interfere with the heme synthetic pathway by inhibiting 50% of delta-aminolevulinic acid dehydratase (ALAD) activity when BLL exceed 20 µg/dL,²⁵ while classical renal insufficiency is usually found in acute lead toxicity (BLL exceed 80 μg/dL).²⁶ A tendency in increasing of blood pressure found in this study is agreed with the previous finding by meta-analysis that reported a 0.6 mm Hg increased for each doubling of BLL.^27,28 Over time, such a slight increase in blood pressure can increase the risk of cardiovascular disease (CVD), and thereby result in an increased incidence of CVD following lead exposure.^29,30 Such evidence was found in animal studies indicating that hypertension in lead poisoning is, at least in part, the result of lead-induced oxidative stress.^31,32

There are many studies reporting that lead has the potential to induce oxidative stress, and evidence continues to accumulate supporting the notion that such oxidative stress would eventually lead to the development of CVD.³³ Lead can promote ROS both in vitro and in vitro³⁴ and this ROS, highly reactive, can attack macromolecules including lipids.³⁵ We investigated the oxidative status in the lead-exposed group by measuring lipid peroxidation parameters and TAS. Our results show a highly significant increase in all lipid peroxidation parameters and OSI with strong correlation to BLL. Lead exposure also showed significantly decreased TAS levels with a strong correlation to BLL. These data indicate that the lead-exposed groups are prone to face oxidative stress as has been seen in several cohort studies.^12,36

On the other hand, lead-induced oxidative stress may be a consequence of the reduction in antioxidant enzyme activity. PON1 has been proposed as anti-atherosclerosis because of its antioxidant property.^13,14 We investigated the effect of lead on PON1 activity towards dual substrates. We observed a significant decrease in PON1 activity towards phenyl acetate as previously demonstrated in workers from a lead battery manufacturer and lead recycling plant²⁰ and in vitro with purified human PON1.¹⁹ Moreover, our multiple linear regression revealed a strong correlation between BLL and decreased PON1 arylesterase activity. We speculate that a decrease in PON1 activity under oxidative stress may be partly attributable to changes in the redox status leading to an increase in lipid peroxidation and a decrease in TAS, as seen in this study. However, we did not observe the reduction of PON1 activity towards paraoxon as much as that demonstrated in workers from a lead battery manufacturer and lead recycling plant.²⁰ This discrepancy may be due to differences in the presence of sodium chloride as stimulating agent of PON1 activity towards paraoxon. The greater inhibition of lead on arylesterase activity than paraoxonase activity in present study may be probably from affinity binding differences between lead to the substrates, resulting to a new orientation of the substrates, such that the hydrolytic reaction is impaired, leading to a decreased overall affinity of the substrates.¹⁷

Lead exposure has declined substantially since the phasing out of leaded gasoline and applicable industries and the US Occupational Safety and Health Administration³⁷ allows a BLL of 10 µg/dL for children and women of child-bearing ages and of 30 µg/dL for industrial workers in general. However, in more recent studies, it has been found that there is an association of low BLL with cardiovascular mortality in several cohorts.^6,7 Some reports have also observed an oxidative stress at low BLL.^38,39 Our data show that there are differences found for the range of BLL as follows: control (<10 µg/dL), low (≥10 µg/dL), medium (≥20 µg/dL), and high (≥30 µg/dL). We found highly significant increases in lipid peroxidation parameters, OSI, and PON1 arylesterase activity, but insignificant changes in levels of clinical biochemical and hematological parameters at 10 µg/dL of BLL. This implies that exposure to low lead levels can cause lead-induced oxidative stress and may contribute to initiating lead-related disorders without any abnormal levels of routine clinical laboratory metabolites detected. These results may, in part, explain the high incidence of cardiovascular mortality found in recent studies.

In conclusion, in this study, we found evidence of oxidative stress and reduction of PON1 activity at low BLL without any statistical change in biochemical and hematological parameters. The reduction of PON1 activity may be a cause of lead-induced oxidative stress and may partly contribute to an increased incidence of CVD following low lead exposure.

Footnotes

Acknowledgements

We acknowledge the participants for their cooperation. We also thank Mr. Lerson Suwannathon (Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Thailand) for his assistance with the blood lead assays.

This study was partially supported by the Thailand Research fund and Faculty of Medical Technology, Huachiew Chalermprakiet University, Thailand.

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Decreased paraoxonase 1 activity and increased oxidative stress in low lead−exposed workers

Abstract

Keywords

Introduction

Materials and methods

Subjects and blood collections

Blood lead level measurement

Routine blood parameters

Oxidative stress parameters

PON1 activities determination

Statistical analysis

Results

Demographic data and clinical parameters of the control and lead-exposed groups

Oxidative status and PON1 activities

Relationship between blood lead, oxidative biomarkers, and PON1 activity

Discussion

Footnotes

Acknowledgements

References