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Abstract

The aim of the study was to determine the effect of occupational exposure to lead on the blood levels of pro-inflammatory cytokines and selected factors that influence angiogenesis. The study population was divided into two groups. The first group consisted of 56 male workers chronically exposed to lead. The second group (control) was comprised of 24 male administrative workers. The serum levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were significantly higher in the group of workers chronically exposed to lead compared to control values by 38%, 68%, and 57%, respectively. Similarly, the values of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and fibroblast growth factor-basic (FGF-basic) were higher by 19% and 63%, respectively. In the group of workers chronically exposed to lead, there were positive correlations between the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and angiogenic factors (VEGF, FGF-basic, sVEGFR-1, and soluble angiopoietin receptor). In the control group, there were no correlations between the levels of the abovementioned parameters. Results of the present study indicate that chronic occupational lead exposure promotes inflammatory processes via induction of pro-inflammatory cytokines, modulates angiogenesis, and elicits interdependencies between the immune response and angiogenic factors.

Keywords

Lead inflammation cytokines angiogenesis

Introduction

Lead is a toxic heavy metal ubiquitously distributed around the world, especially in industrial areas. Occupational and environmental exposures to lead have detrimental effects on human health. Lead affects function of many systems of the human body, including the nervous, hematopoietic, renal, cardiovascular, and immune systems.¹

Molecular mechanisms of lead toxicity are still not clearly understood. Lead targets proteins that naturally bind calcium or zinc, especially catalytic zinc-binding sites with two or more cysteine residue.² Furthermore, studies suggest that lead is able to induce oxidative stress.^3,4 Imbalance between production and utilization of reactive oxygen species (ROS) leads to damage of many cell structures, especially phospholipids of cellular membranes. Oxidative damage to lipids, called lipid peroxidation, triggers, in turn, signaling cascades of the inflammatory processes.⁵ Lead is also able to induce inflammatory processes by modulation and activation of intracellular signaling pathways. It has been shown that lead activates cell-surface receptor tyrosine kinases, including epidermal growth factor receptor (EGFR)⁶ which is not only responsible for modulation of cell proliferation, survival, migration, and differentiation⁷ but also induces inflammatory response via increasing expression of cyclooxygenase-2.^8
–10 Moreover, increased levels of some pro-inflammatory cytokines were reported in occupationally lead-exposed humans.¹¹

Angiogenesis is the process of forming new blood vessels from preexisting capillaries controlled by angiopoietins (Ang-1 and Ang-2) acting via soluble angiopoietin receptor (sTie2) and vascular endothelial growth factor (VEGF). Angiogenesis plays an important role in various physiological and pathological states.^12,13 Studies concerning neoplasia revealed the relationship between the levels of pro-inflammatory cytokines and angiogenic factors, such as VEGF.^14,15 It has been shown that lead may interfere with angiogenesis via local production of interleukin 8 (IL-8).^9,16 However, there are no studies on the relations between other parameters of the immune response and angiogenic factors under conditions of lead exposure. In light of this, the present study was undertaken to determine the effect of occupational exposure to lead on the blood levels of pro-inflammatory cytokines and selected factors that influence angiogenesis.

Material and methods

Study population

Each study subject provided written consent to participate in the study. Questionnaire data on age, weight, height, body mass index (BMI), work period, and smoking were obtained. The levels of lead and zinc protoporphyrin (ZPP) in the blood served as biomarkers of lead exposure.

The study population was divided into two groups. The first group consisted of 56 male workers chronically exposed to lead for a maximum of 38 years, aged from 23 to 55 years (mean age was 40 ± 9 years). Workers in that group worked in lead-zinc works as smelters, fitters, and production masters. Blood lead levels (BLLs) in this group ranged 15.1–55.6 µg/dl (mean BLL was 37.0 ± 8.93 µg/dl).

The second group (control) was comprised of 24 male administrative workers aged 26–59 years (mean age was 43 ± 9 years). BLL in this group ranged 1.0–6.9 µg/dl (mean BLL was 2.15 ± 1.40 µg/dl). None of the individuals in the control group was occupationally exposed to lead.

Exclusion criteria included a history of any chronic diseases (such as immune disorders, diabetes, arterial hypertension, coronary artery disease, and malignant neoplasm) and abnormal physical examination findings, especially symptoms and signs of any infectious diseases. All of the lead-exposed subjects were employed in the same lead-zinc works in the southern region of Poland. Subjects in all examined groups inhabited the same region.

The experimental setup was approved by the bioethics committee of the Medical University of Silesia in Katowice (no. KNW/0022/KB1/108/14).

Laboratory procedures

Blood samples from each subject were collected from the cubital vein using tubes (Vacuette; Greiner Bio-One, Frickenhausen, Germany) coated with K₃EDTA to obtain whole blood or plain tubes to obtain serum. Assessments of the BLL were performed using graphite furnace atomic absorption spectrometry in an ICE 3400 system (Thermo Fisher Scientific, Waltham, MA, USA). The results were expressed as micrograms per deciliter. The blood concentration of ZPP was measured directly using Aviv Biomedical hematofluorometer model 206 (Lakewood, New Jersey, USA), using an excitation wavelength of 415 nm and an emission wavelength of 596 nm. The results were expressed as μg ZPP per g of hemoglobin (μg/g Hb). Levels of pro-inflammatory cytokines (interleukin 1β (IL-1β), IL-6, macrophage inflammatory protein 1α (MIP-1α), and tumor necrosis factor α (TNF-α)) in serum were evaluated using a Bio-Plex 200 System (Bio-Rad, Hercules, California, USA). Levels of angiogenic factors (VEGF, soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), sTie-2, and fibroblast growth factor-basic (FGF-basic)) were detected in serum using a Bio-Plex 200 System (Bio-Rad Laboratories Inc., Berkeley, California, USA) according to the manufacturer’s instruction. The results were expressed as picograms per milliliter.

Statistical analysis

All statistical analysis was performed using a Statistica version 9.1 PL. A Shapiro–Wilk’s test was used to verify normality, and a Levene’s test was used to verify homogeneity of variances. Statistical comparisons were made using a t-test, a t-test with separate variance estimates, a Mann–Whitney U-test, or a χ² test. The Spearman nonparametric correlation was calculated. A p value <0.05 was considered statistically significant.

Results

Epidemiologic data and lead exposure indices

There were no significant differences in age, work period, height, weight, BMI, and smoking habits between the chronically lead-exposed and control groups (Table 1). BLL and ZPP were approximately 17- and 2-fold higher in the chronically exposed workers than in the controls (Table 1).

Table 1.

Epidemiologic data and lead exposure markers in control group and workers chronically exposed to lead.^a

	Control group		Chronic lead-exposed group		p
	n = 24		n = 56
	Mean	SD	Mean	SD
Age (years)	43	9	40	9	0.147
Work period (years)	18	9	13	10	0.074
Height (cm)	179	7.80	177	5.53	0.124
Weight (kg)	90.2	12.7	84.9	14.2	0.107
BMI (kg/m²)	28.1	3.90	27.2	4.03	0.363
Smokers (%)	33		36		0.837
BLL (µg/dl)	2.15	1.4	37.0	8.93	<0.001
ZPP (μg/g Hb)	2.30	0.6	4.38	1.82	<0.001

BMI: body mass index; BLL: blood lead level; ZPP: zinc protoporphyrin.

^a p value: t-test.

The study parameter concentrations

The serum levels of IL-1β, IL-6, and TNF-α were significantly higher in the group of workers chronically exposed to lead compared to control values by 38%, 68%, and 57%, respectively. However, the levels of MIP-1α did not differ between studied groups (Table 2). The values of sVEGFR-1 and FGF-basic were higher in the chronically lead-exposed group compared to control by 19% and 63%, respectively. Levels of other angiogenic factors (sTie-2 and VEGF) did not differ between studied groups (Table 3).

Table 2.

Pro-inflammatory cytokine levels in the workers chronically exposed to lead and in controls.^a

	Control group		Chronic lead-exposed group		Relative change (%)	p
	Median	IQR	Median	IQR	Relative change (%)	p
IL-1β (pg/ml)	0.27	0.06	0.37	0.12	38	<0.001
IL-6 (pg/ml)	1.58	0.99	2.64	1.22	68	<0.001
TNF-α (pg/ml)	5.26	2.32	8.25	4.98	57	0.000
MIP-1α (pg/ml)	0.84	0.77	0.95	0.62	13	0.578

IQR: interquartile range; IL-1β: interleukin 1β; IL-6: interleukin 6; TNF-α: tumor necrosis factor α; MIP-1α: macrophage inflammatory protein 1α.

^a p value: Mann–Whitney U-test.

Table 3.

Levels of angiogenic factors in the workers chronically exposed to lead and in controls.^a

	Control group		Chronic lead-exposed group		Relative change (%)
	Median	IQR	Median	IQR	Relative change (%)	p
sTie-2 (pg/ml)	18583	9462	21143	11198	14	0.090
VEGF (pg/ml)	52.36	52.66	74.12	73.40	42	0.179
sVEGFR-1 (pg/ml)	688	284	817	372	19	0.020
FGF-basic (pg/ml)	0.71	1.04	1.16	0.61	63	0.008

IQR: interquartile range; sTie-2: soluble angiopoietin receptor; VEGF: vascular endothelial growth factor; sVEGFR-1: soluble vascular endothelial growth factor receptor-1; FGF-basic: fibroblast growth factor basic.

^a p value: Mann–Whitney U-test.

In the control group, there were no correlations between the levels of pro-inflammatory cytokines and angiogenic factors and BLL (data not shown). In the group of workers chronically exposed to lead, the analysis of correlations showed positive correlations between the levels of IL-1β and VEGF (R = 0.53), FGF-basic (R = 0.27), sTie-2 (R = 0.31), sVEGFR-1 (R = 0.36), and BLL (R = 0.45). A positive correlation was also found between the levels of IL-6 and VEGF (R = 0.38), FGF-basic (R = 0.31), sVEGFR-1 (R = 0.32), and BLL (R = 0.44) as well as between the levels of TNF-α and VEGF (R = 0.36), sVEGFR-1 (R = 0.29), FGF-basic (R = 0.27), and BLL (R = 0.41). In addition, positive correlation was also between BLL and FGF-basic (R = 0.23) and sVEGFR-1 (R = 0.25; Table 4).

Table 4.

Correlations between levels of pro-inflammatory cytokines and angiogenic factors and BLL in the group of workers chronically exposed to lead.^a

Angiogenic factors →	VEGF	FGF-basic	sTie-2	sVEGFR-1	BLL↓
Pro-inflammatory cytokines ↓	VEGF	FGF-basic	sTie-2	sVEGFR-1	BLL↓
IL-1β	0.53	0.27	0.31	0.36	0.45
IL-6	0.38	0.31	NS	0.32	0.44
TNF-α	0.36	0.27	NS	0.29	0.41
MIP-1α	NS	NS	NS	NS	NS
BLL →	NS	0.23	NS	0.25

BLL: blood lead level; VEGF: vascular endothelial growth factor; FGF-basic: fibroblast growth factor basic; sTie-2: soluble angiopoietin receptor; sVEGFR-1: soluble vascular endothelial growth factor receptor-1; IL-1β: interleukin 1β; IL-6: interleukin 6; TNF-α: tumor necrosis factor α; MIP-1α: macrophage inflammatory protein 1α; NS: nonsignificant.

^a R values: Spearman’s rank correlation. p < 0.05.

Discussion

The pro-inflammatory effect of lead may be associated with its ability to cause oxidative stress due to the increased generation or decreased utilization of ROS. It has been established that ROS are responsible for activation of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B which are involved in the production of pro-inflammatory molecules.^17
–19 Results of the present study confirm the ability of lead to increase the levels of potent pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Consistently, in vitro and animal studies have shown that lead induces the expression and levels of TNF-α.^18,20
–22 Positive correlations between BLL and TNF-α concentrations were observed by Valentino et al.¹¹ and Di Lorenzo et al.²³ in lead-exposed workers (BLL = 9.1–46.0 µg/dl and BLL = 30.7 µg/dl, respectively), while lack of association between these parameters was shown by Yücesoy et al.²⁴ in battery plant workers (BLL = 59.35 µg/dl). Yucesoy et al.²⁴ reported also decreased serum IL-1β level due to the studied lead exposure. Besides, in vitro investigation on human peripheral blood mononuclear cells (PBMCs) showed that expression of IL-1β was decreased by low lead doses.²⁵ However, animal studies on this topic support our study. IL-1β expression has been shown to be increased by lead exposure in mouse cerebral cortex²⁶ and mouse hippocampi.²⁷ In other animal studies, both expression and levels of IL-1β were elevated due to lead toxic action.^18,28 Similarly, the increase of the IL-6 level as a result of lead exposure was reported in previous in vitro studies^20,21 and in a study based on epidemiological data on nonoccupationally exposed adults.²⁰ By contrast, Valentino et al.¹¹ did not report differences between the levels of IL-6 in a group of workers with very low BLL (3.2–18.0 µg/dl) and low BLL (9.1–46.0 µg/dl).

MIP-1α is a small protein, belonging to the family of MIP-1 (MIP-1α, β, γ, and δ). In acute and chronic inflammatory host responses, MIP-1α recruits pro-inflammatory cells, such as lymphocytes and monocytes.²⁹ Gillis et al.²¹ demonstrated that lead exposure resulted in a dose-dependent increase of MIP-1α production by PBMCs. In our previous study, the influence of lead on the other member of the MIP-1 family (MIP-1β) was not observed in chronically lead-exposed workers.³⁰ Similarly, the present study did not show significant difference between MIP-1α levels in the examined groups.

Khurana et al.³¹ postulate that inflammatory cells and cytokines are key players in the mechanisms mediating both atherogenesis and collateral vessel formation. Furthermore, several studies indicate that inflammatory reactions promote cancer progression via stimulating angiogenesis.³² IL-6 has been shown to influence angiogenic activity by upregulation of VEGF via (IL)-6/STAT3 signaling pathway in a variety of human tumors.^14,33 Carmi et al.³⁴ demonstrated that IL-1β is the primary mediator of tumor angiogenesis, invasiveness, and metastasis. Similarly, TNF-α has been shown to promote cell survival and angiogenesis.³⁵ Corroborating these findings, results of the present study revealed that the levels of IL-1β, IL-6, and TNF-α correlated positively with the levels of FGF-basic, VEGF, and sVEGFR-1 in the lead-exposed population. The level of IL-1β also correlated with the level of sTie-2. Analogical correlations between measured levels of pro-inflammatory cytokines and angiogenic factors were not observed in the control group. This observation suggests that the associations between inflammatory processes and angiogenesis become significant under pathological conditions of lead exposure. These associations may be also due to the influence of lead on the level of IL-8 which has been shown to have pro-inflammatory and angiogenic activity equipotent to that of VEGF and FGF-basic.³¹ Lead may induce expression of IL-8 gene through a MAPK pathway.⁹ Consistently, Dobrakowski et al.³⁶ showed that the level of IL-8 was significantly higher by 40% in the group of workers chronically exposed to lead than in the control group.

Results of the present study showed that chronic lead exposure is associated with elevated levels of sVEGFR-1 and FGF-basic. FGF-basic is a strong positive modulator of angiogenesis, while sVEGFR-1 acts as an antiangiogenic molecule.³⁵ Additionally, overexpression of sVEGFR-1 may lead to hypertension or defects in developmental angiogenesis.^37,38 Consistently, some studies have identified a positive association between lead exposure and cardiovascular disorders, such as hypertension.³⁹ Observed in the present study increase of sVEGFR-1 level could be interpreted as a result of compensatory mechanism against lead toxicity. In vitro studies demonstrated that lead acetate (1–100 µM) inhibits tube formation by cultured human umbilical vascular endothelial cells in a dose- and time-dependent manner.^40,41 In light of this, it is possible to conclude that lead is able to modulate mechanisms associated with angiogenesis depending on the exposure profile.

The results of the present research should be evaluated in the context of its limitations. The possible confounding role of the inorganic elements such as other metal ions were not taken into consideration, probably this was the major limitation of our study. Besides, the next limitation applies to the number of selected angiogenic factors. In light of this, the present study should be regarded as a pilot study. Obtained results encourage us to continue researches in this field.

Conclusions

Results of the present study indicate that chronic occupational lead exposure promotes inflammatory processes via induction of pro-inflammatory cytokines, modulating angiogenesis, and by eliciting interdependencies between the immune response and angiogenic factors which were not observed in healthy unexposed subjects.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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The influence of occupational chronic lead exposure on the levels of selected pro-inflammatory cytokines and angiogenic factors

Abstract

Keywords

Introduction

Material and methods

Study population

Laboratory procedures

Statistical analysis

Results

Epidemiologic data and lead exposure indices

The study parameter concentrations

Discussion

Conclusions

Footnotes

Declaration of Conflicting Interests

Funding

References