
==== Front
BMC Pulm Med
BMC Pulm Med
BMC Pulmonary Medicine
1471-2466
BioMed Central London

39289625
3269
10.1186/s12890-024-03269-2
Research
Blood cadmium concentration and pulmonary function injury: potential mediating role of oxidative stress in chronic obstructive pulmonary disease patients
Xu Juan 12
Zhu Feng-Min 12
Liu Ying 12
Fang Pu 12
Sun Jing 12
Liu Ming-Yan 12
Tang Min-Min 12
Zhao Hui 123
Fu Lin fulindev@126.com

123
Yang Jin yangqj1015@foxmail.com

1234
1 grid.452696.a 0000 0004 7533 3408 Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601 China
2 grid.452696.a 0000 0004 7533 3408 Institute of Respiratory Diseases, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601 China
3 grid.452696.a 0000 0004 7533 3408 Centre for Big Data and Population Health of IHM, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601 China
4 grid.452696.a 0000 0004 7533 3408 Information Management Centre, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230601 China
17 9 2024
17 9 2024
2024
24 45915 1 2024
4 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Exposure to cadmium (Cd) is associated with a reduction in lung function among patients with chronic obstructive pulmonary disease (COPD). The longitudinal relationship and mechanism underlying the link between Cd exposure and lung function changes among COPD patients are yet unknown.

Methods

The cohort study included 259 eligible patients who underwent regular professional follow-ups. Blood Cd levels and serum 8-iso-prostaglandin F2 alpha (8-iso-PGF2α) levels were assessed. Lung function was determined at baseline and follow-up research. The associations between changes in lung function and blood Cd concentration were analysed using multivariate linear and logistic regression models.

Results

Each 1-ppb elevation in blood Cd content resulted in a 0.420 L decrease in forced vital capacity (FVC), a 0.424 L decrease in forced expiratory volume in 1 s (FEV1), a 4.341% decrease in FEV1/FVC%, and a 8.418% decrease in FEV1% predicted in patients with COPD. Blood Cd concentration showed a positive correlation with serum 8-iso-PGF2α levels in a specific range. The relative contribution of increased serum levels of 8-iso-PGF2α to Cd-induced declines in FEV1, predicted FEV1%, and FEV1/FVC% were 2.08%, 8.08%, and 13.19%, respectively.

Conclusion

Blood Cd levels are associated with lung function changes in COPD patients. Oxidative stress is thought to be an important mediator in Cd-induced reduction of pulmonary function.

Keywords

Cadmium
Pulmonary function
8-Iso-prostaglandin F2 alpha
Chronic obstructive pulmonary disease
Oxidative stress
National Natural Science Foundation of China82100078, 82270071 http://dx.doi.org/10.13039/501100009558 University Natural Science Research Project of Anhui Province 2023AH030117 Major Scientific Research Project of the Department of Education of Anhui Province2022AH040098 Research Foundation of Anhui Medical University2022xkj170 issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Chronic obstructive pulmonary disease (COPD) is a progressive disease that comes with a substantial clinical and financial burden [1]. More than three million people die from COPD each year worldwide. Although there have been improvements in controlling its symptoms and preventing acute exacerbations, progress in slowing disease progression has been limited [2]. COPD is characterised by an airflow limitation that cannot be reversed completely [3]. It is often accompanied by comorbidities, which greatly impact patients’ quality of life [4]. Heavy metal exposure, cigarette smoking, and air pollution are important risk elements for the decline in pulmonary function [5, 6]. The longitudinal relationship between lung function and exposure to heavy metals has not yet been fully investigated to date.

Metals and metal-like groups with atomic densities greater than 4 g/cm are collectively referred to as heavy metals, such as cadmium (Cd), plumbum (Pb), chromium (Cr), and cobalt (Co) [7]. Cd is a highly toxic heavy metal found predominantly in industrial and agricultural waste [8]. The public is primarily exposed to Cd through the consumption of specific foods and inhalation of cigarette smoke [9], which can cause permanent organ damage and pose a significant threat to humans [10]. The primary organs affected by both short-term and prolonged exposure to Cd are the lungs, bones, and kidneys in the human body [11]. Studies have found that the levels of Cd in the blood and urine are negatively correlated with lung function and may increase the risk of adult COPD [12]. In addition, our team previously found a significant negative correlation between blood Cd concentrations and lung function in patients with COPD [13–15]. However, few longitudinal studies have explored the association between exposure to Cd and alterations in lung function among COPD patients. In addition, the specific mechanisms underlying the change of lung function induced by Cd are not yet clear.

Oxidative stress is closely linked to the onset and progression of COPD [16]. The imbalance between oxidants and antioxidants is an important mechanism of oxidative stress [17]. Lipids are the most influenced class of macromolecules among the different biological targets of oxidative stress. Lipid peroxidation produces numerous secondary products, such as 8-iso-prostaglandin F2 alpha (8-iso-PGF2α), hydroxy nonenal alkyne, malondialdehyde, and lipoperoxides [18]. Arachidonic acid is peroxidized nonenzymatically by free radicals in vivo to create the molecule 8-iso-PGF2α [19]. Currently, 8-iso-PGF2α is the most widely accepted biomarker of oxidative stress due to its sensitivity and specificity [20]. Cd exposure can induce oxidative stress by reducing antioxidant enzymes and increasing lipid peroxidation [21]. Studies have shown that Cd induces reactive oxygen species (ROS) and triggers cellular lipid peroxidation, leading to damage to the epithelial cells of the lungs [22]. Furthermore, there is a significantly positive connection between Cd concentration and human 8-iso-PGF2α levels [23]. However, the role of 8-iso-PGF2α on the connection between pulmonary function changes and Cd exposure in COPD patients remains unknown.

This cohort study’s objective was to explore the potential mechanisms underlying this relationship between environmental Cd exposure and changes in lung function. Blood samples and clinical characteristics were collected from COPD patients. Serum 8-iso-PGF2α and blood Cd levels were measured. The relationships among lung function parameters, Cd levels, and 8-iso-PGF2α levels were investigated. Additionally, the role of 8-iso-PGF2α in the relationship between Cd exposure and lung function changes was analysed.

Materials and methods

Study population

All participators were selected from Anhui COPD cohort (AHCC) in accordance with the previous studies [24, 25]. To ensure that the subjects had similar daily behaviours and surroundings, patients with comparable lifestyles and exposure levels who had resided in Hefei, Fuyang, or Bozhou for more than five years were enlisted. All subjects were enrolled from Second Affiliated Hospital of Anhui Medical University, Bozhou People’s Hospital, and Fuyang People’s Hospital. From September 2020 to June 2022, a total of 259 patients were included based on the exclusion and inclusion criteria. The followings were the inclusion criteria: (1) COPD diagnosis was defined by the American Thoracic Society and the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD); (2) agreed to undergo peripheral blood collection and lung function tests; (3) agreed to participate in the follow-up studies. The followings were the exclusion criteria: (1) Subjects had lung cancer, bronchial asthma, tuberculosis; (2) presence of malignant tumours or autoimmune diseases; (3) physical or mental conditions that may hinder cooperation with relevant examinations and tests. All participants provided blood samples, underwent lung function examinations, and were followed up annually. An informed consent form was signed by all participants.

Measurement of blood Cd

Fasting peripheral blood were obtained from all cases. Prior to venous blood sampling, patients were instructed to fast for at least 6 h. Before analysis, blood samples were centrifuged and kept in a cryogenic refrigerator. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the baseline concentration of blood Cd. A dilution solution (180 µL of blood sample diluted with 3820 µL of solution) was used to dilute the whole blood samples (400 µL). The blood Cd detection limit was 0.001 ppb. According to the tripartite technique for determining blood Cd concentration, the participants were divided into low-Cd (Tertile 1: Cd < 0.296 ppb), medium-Cd (Tertile 2: Cd, 0.296 ~ 0.9 ppb), and high-Cd groups (Tertile 3: Cd > 0.9 ppb).

Determination of serum 8-iso-PGF2α concentration

An enzyme-linked immunosorbent test (ELISA) was used to measure the level of serum 8-iso-PGF2α. Cusabio, Wuhan, China, supplied the human 8-iso-PGF2α ELISA kits. The experimental procedures were carried out as described previously [26, 27].

Pulmonary function test

Professional nurses conducted lung function tests in all COPD patients. Before the test, patients were instructed to practice inhaling and exhaling. To minimize technical variability, calibration checks were performed each morning before the test. The test was performed under the supervision of an experienced technician. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1% predicted, and FEV1/FVC% were determined.

Statistical analyses

Continuous data were shown as means or medians, and categorical data were shown as frequencies (percentages). The distinctions between two or more continuous variable groups were analysed using one-way analyses of variance (ANOVA) or independent sample t-tests. The difference of categorical data was compared by Fisher’s exact test. Blood Cd concentration, serum 8-iso-PGF2α, and pulmonary function parameters were continuous variables. Therefore, the associations among blood Cd concentration, serum 8-iso-PGF2α, and pulmonary function parameters were analysed by linear regression models. Age, gender, smoking status, and smoking amount are the risks of COPD process. Basic complications and therapy methods can affect the progression of COPD. Therefore, those confounding factors were adjusted and controlled in the different models. Besides, COPD patients were divided into three subgroups in the basis of the tertile of blood Cd concentration. Then, the associations among the subgroups of COPD patients, pulmonary function parameters were further estimated by logistic regression model. In order to assess the correlations through visualization, smooth curve fitting (penalized splines) and generalized additive model (GAM) were the fittest manner to analyse the associations. In the event that a non-linear correlation was identified, the inflection point was identified using a recursive algorithm that started with random initialization and included a smoothing step or filtering. The role of 8-iso-PGF2α on the relationship between blood Cd concentration elevation and pulmonary function decline within 2 years was explored by mediating effect in COPD patients. To evaluate the predictive impact of variables and estimate odds ratios (OR) with 95% confidence intervals (CI), univariate and multivariate linear and logistic regression models were carried out. Age, gender, smoking status, smoking amount, comorbidities, inhaled therapy for COPD, and pulmonary function indicators were adjusted. The significance levels were set at P < 0.05.

Results

Baseline information

The general information, pulmonary function indicators, and clinical data of the 259 subjects from the three medical institutions are presented in Table 1. No prominent differences were observed in age, hypertension, gender, diabetes, coronary disease, cerebrovascular disease, glucocorticoid use, or inhaled preparations among the patients. In addition, in different subgroups of patients, blood Cd levels were significantly correlated with levels of current smoking, white C-reactive protein (CRP), interleukin-6 (IL-6). Conversely, pulmonary function indicators showed a reverse association.

Table 1 Demographic characteristics of participators at baseline

Characteristic	Tertile of blood Cd	P	
Tertile 1 (<0.296 ppb)	Tertile 2 (0.296 ~ 0.9 ppb)	Tertile 3 (>0.9 ppb)	
N	86	88	85		
Age, years	74.2 ± 1.01	74.5 ± 0.90	73.7 ± 0.81	0.652	
Male, n (%)	64 (74.4)	62 (69.7)	67 (78.8)	0.456	
Smoking status, n (%)				0.818	
None	33 (38.4)	32 (36.0)	36 (42.4)		
Former	40 (46.5)	39 (43.8)	33 (38.8)		
Current	13 (15.1)	17 (19.1)	16 (18.8)		
Smoking amount, pack-year	20.0 (15.0, 39.5)	40.0 (30.0, 50.0)	54.0 (30.0, 60.0)	<0.001	
Comorbidities, n (%)					
Hypertension	37 (43.0)	44 (49.4)	35 (41.2)	0.510	
Diabetes mellitus	6 (7.0)	8 (9.0)	9 (10.6)	0.264	
Coronary disease,	12 (14.0)	11 (12.4)	9 (10.6)	0.817	
Cerebrovascular diseases	7 (8.1)	6 (6.7)	6 (7.1)	0.956	
Inhaled therapy for COPD, n (%)					
SABA	22 (25.6)	31 (34.8)	29 (34.1)	0.126	
SAMA	5 (5.8)	6 (6.7)	7 (8.2)	0.829	
LABA	22 (25.6)	27 (30.3)	27 (31.8)	0.633	
LAMA	14 (16.3)	19 (21.3)	16 (18.8)	0.606	
Inhaled corticosteroids	64 (74.4)	74 (83.1)	69 (81.2)	0.277	
IL-6 (pg/mL)	18.5 (10.5, 41.0)	22.3 (12.9, 48.0)	115.5 (92.8, 158.1)	<0.001	
CRP (mg/L)	22.1 (10.2, 34.3)	33.9 (20.2, 53.5)	70.8 (29.3, 130.0)	<0.001	
FVC (L)	2.6 ± 0.10	2.3 ± 0.10	1.8 ± 0.10	<0.001	
FEV1 (L)	2.6 ± 0.11	2.3 ± 0.11	1.7 ± 0.09	<0.001	
FEV1/FVC (%)	70.2 ± 1.72	64.9 ± 1.82	56.7 ± 1.71	0.002	
Predicted FEV1 (%)	75.2 ± 3.14	67.9 ± 2.75	59.0 ± 3.23	<0.001	
Bold values indicate statistical significance

Values were expressed as n (%), mean ± S.E.M. or median (IQR)

Association of blood cd concentration with lung function indicators

The relationship between lung function and Cd concentration was analysed in COPD patients using a linear regression model. Smoking status and smoking amount were adjusted in Model 1. According to linear regression studies, each 1-ppb increase in blood Cd levels was associated with a 0.630 L decrease in FVC, a 0.544 L decline in FEV1, a 6.671% decline in FEV1/FVC%, and a 12.038% decline in predicted FEV1% (Table 2). Higher blood Cd levels elevated the risk of a reduction in pulmonary function (Table 2). Our findings showed that lung function and blood Cd levels were inversely associated (Table 2). In Model 2, the results were consistent with those obtained with Model 1 (Table 2).

Table 2 Associations between blood cd and pulmonary function parameters in COPD patients

Variables	Estimated changes by continuous Cd	Estimated changes (95% CI) by tertile of Cd	P trend	
Low (<0.296 ppb)	Medium (0.296 ~ 0.9 ppb)	High (>0.9 ppb)	
Model 1						
FVC (L)	-0.630 (-0.891, -0.370)	1.0 (Ref)	0.652 (0.260, 1.636)	0.185(0.069, 0.498)	0.003	
FEV1 (L)	-0.544 (-0.814, -0.275)	1.0 (Ref)	1.172 (0.460, 2.986)	0.157(0.053, 0.463)	0.038	
FEV1/FVC (%)	-6.671(-11.068, -2.275)	1.0 (Ref)	0.935(0.378, 2.312)	0.241(0.085, 0.680)	0.009	
Predicted FEV1 (%)	-12.038(-19.523, -4.554)	1.0 (Ref)	1.923(0.737, 5.019)	0.334(0.125, 0.894)	0.033	
Model 2						
FVC (L)	-0.420(-0.925, -0.353)	1.0 (Ref)	0.356(0.118, 1.075)	0.139(0.043, 0.445)	0.041	
FEV1 (L)	-0.424(-0.718, -0.131)	1.0 (Ref)	1.360(0.458, 4.034)	0.149(0.044, 0.506)	0.023	
FEV1/FVC (%)	-4.341(-9.276, 0.595)	1.0 (Ref)	0.878(0.315, 2.448)	0.247(0.078, 0.782)	0.033	
Predicted FEV1 (%)	-8.418 (-16.676, -0.160)	1.0 (Ref)	2.374(0.793, 7.102)	0.367(0.120, 0.922)	0.122	
Model 1 was adjusted for smoking status and smoking amount

Model 2 was adjusted for age, gender, smoking status, smoking amount, hypertension, diabetes mellitus, coronary disease, cerebrovascular diseases, SABA, SAMA, LABA, LAMA, and inhaled corticosteroids

Bold values indicate statistical significance

Association of blood Cd concentration with serum 8-iso-PGF2α levels

The relationship between serum 8-iso-PGF2α levels and blood Cd concentration in patients with COPD was investigated using smooth curve fitting (penalized spline method) and GAM in this study. As shown in Fig. 1A–B, a nonlinear association between serum 8-iso-PGF2α indicators and blood Cd concentration was observed. The results showed that the turning points of serum 8-iso-PGF2α were 0.183 ppb, 0.295 ppb, and 1.241 ppb. Figure 1A shows that the blood Cd concentration between the inflection points is positively associated with the serum 8-iso-PGF2α levels. As depicted in Fig. 1B, serum 8-iso-PGF2α levels and blood Cd concentration were positively associated on the right side of the inflection points.

Fig. 1 Nonlinear relationship between serum 8-iso-PGF2α levels and blood Cd concentration. The relationship between serum 8-iso-PGF2α levels and blood Cd concentration in COPD patients was investigated using smooth curve fitting and GAM in this study. (A) Low serum Cd concentration (lower than 0.296 ppb) and serum 8-iso-PGF2a. (B) High blood Cd concentration (higher than 0.9 ppb) and serum 8-iso-PGF2a

Associations among blood Cd concentration, serum 8-iso-PGF2α levels, and indicators of pulmonary function

The relationship among blood Cd concentration, serum 8-iso-PGF2α levels, and lung function were analysed using linear regression model. Smoking status and smoking amount were adjusted. Model 1 showed that an increase in serum 8-iso-PGF2α levels enhanced the likelihood of pulmonary function reduction with FVC (Tertile 2: OR, -0.411; 95% CI, -1.121 to 0.102. Tertile 3: OR, -0.699; 95% CI, -1.686 to 0.088), FEV1 (Tertile 2: OR, -0.314; 95% CI, -0.833 to 0.204. Tertile 3: OR, -0.404; 95% CI, -0.831 to 0.023), FEV1/FVC (%) (Tertile 2: OR, -3.217; 95% CI, -11.109 to 4.675. Tertile 3: OR, -5.786; 95% CI, -10.063 to 4.492) and predicted FEV1% (Tertile 2: OR, -10.258; 95% CI, -25.546 to 5.030. Tertile 3: OR, -12.752; 95% CI, -24.842 to -0.663). In Model 2, the results were consistent with those obtained with the Model 1 (Table 3). To investigate the long-term effect of environmental Cd on lung function, the clinical data of the patients during hospitalisation and follow-up were retrospectively collected and analysed. As shown in Fig. 2, restricted cubic spline function was utilized to assess the relationships between pulmonary function changes and blood Cd concentration with different serum 8-iso-PGF2α levels. The results showed that lung function decline and blood Cd levels with different serum 8-iso-PGF2α levels were positively correlated.

Table 3 Associations between blood Cd and pulmonary function parameters in COPD patients

Variables	Estimated changes (95% CI) by continuous Cd	
Levels of serum 8-iso-PGF2α	
Low (<3.201 pg/mL)	Medium (3.201 ~ 3.392 pg/mL)	High (>3.392 pg/mL)	
Model 1				
FVC (L)	-0.643 (-1.443, 0.157)	-0.411 (-1.121, 0.102)	-0.699 (-1.686, 0.088)	
FEV1 (L)	-0.464 (-1.240, 0.312)	-0.314 (-0.833, 0.204)	-0.404 (-0.831, 0.023)	
FEV1/FVC (%)	-7.840 (-19.730, 4.049)	-3.217 (-11.109, 4.675)	-5.786 (-10.063, 4.492)	
Predicted FEV1 (%)	1.415 (-17.193, 20.023)	-10.258 (-25.546, 5.030)	-12.752 (-24.842, -0.663)	
Model 2				
FVC (L)	-0.378 (-2.485, -0.270)	-0.494 (-1.416, 0.027)	-0.509 (-0.938, -0.080)	
FEV1 (L)	-0.688 (-1.792, 0.417)	-0.423 (-1.106, 0.259)	-0.639 (-1.118, -0.161)	
FEV1/FVC (%)	-8.470 (-25.375, 8.435)	-5.374 (-14.539, 3.792)	-6.654 (-15.138, 1.831)	
Predicted FEV1 (%)	0.255 (-25.110, 25.620)	-18.576 (-37.860, 0.708)	-16.134 (-30.241, -2.026)	
Model 1 was adjusted for smoking status and smoking amount

Model 2 was adjusted for age, gender, smoking status, smoking amount, hypertension, diabetes mellitus, coronary disease, cerebrovascular diseases, SABA, SAMA, LABA, LAMA, and inhaled corticosteroids

Bold values indicate statistical significance

Fig. 2 Nonlinear relationship between pulmonary function alteration and blood Cd concentration.Restricted cubic spline function was utilized to assess the correlation between changes in pulmonary function and blood Cd concentration with different serum 8-iso-PGF2α levels. COPD patients were classified into three groups based on serum 8-iso-PGF2α tertiles: low (below 3.201 pg/mL), medium (3.201-3.392 pg/mL) and high (above 3.392 pg/mL). (A-C) Correlation between FEV1 and blood Cd concentration with different serum 8-iso-PGF2a levels. (A) Low 8-iso-PGF2a levels; (B) Medium 8-iso-PGF2α levels; (C) High 8-iso-PGF2a levels. (D-F) Correlation between FVC and blood Cd concentration with different serum 8-iso-PGF2a levels. (D) Low 8-iso-PGF2α levels; (E) Medium 8-iso-PGF2α levels; (F) High 8-iso-PGF2α levels. (G-I) Correlation between FEV1/FVC% and blood Cd concentration with different serum 8-iso-PGF2α levels. (G) Low 8-iso-PGF2α levels; (H) Medium 8-iso-PGF2α levels; (I) High 8-iso-PGF2α levels. (J-L) Correlation between FEV1% and blood Cd concentration with different serum 8-iso-PGF2α levels. (J) Low 8-iso-PGF2α levels; (K) Medium 8-iso-PGF2α levels; (L) High 8-iso-PGF2α levels.

Mediating role of 8-iso-PGF2α in the association between blood higher Cd and pulmonary function decline

The mediating role of 8-iso-PGF2α in the relationship between blood Cd concentration increase and pulmonary function decline after 2 year was assessed in COPD patients. As shown in Fig. 3, blood Cd increase can directly evoke pulmonary function parameters reduction after two years. In addition, 8-iso-PGF2α acted as a partially mediating role on Cd-induced pulmonary function decline among COPD patients. The increasing 8-iso-PGF2α mediated 1.90%, 2.08%, 13.19%, and 8.08% of Cd-related with decreases in FVC (P<0.05), FEV1 (P<0.05), FEV1/FVC% (P<0.01), and FEV1% (P<0.01), respectively.

Fig. 3 Mediating effect of 8-iso-PGF2α on the association between Cd exposure and reduction in pulmonary function. (A-D) Estimated proportion of association between reduction in pulmonary function and blood Cd concentration mediated by 8-iso-PGF2α. (A) FVC decline; (B) FEV1 decline; (C) FEV1/FVC% decline; (D) FEV1% decline. *P < 0.05; ** P < 0.01.

Discussion

This objective of this cohort study was to explore the link between exposure to Cd and changes in lung function in COPD patients, as well as the potential mediating influence of 8-iso-PGF2α on this connection. The results indicated a positive association between serum 8-iso-PGF2α levels and blood Cd concentration in a specific range, as well as an association between decreased lung function and blood Cd concentration. Lung function parameters were inversely associated serum 8-iso-PGF2α levels. Thus, there is a clear inverse relationship between blood Cd concentrations and lung function in COPD patients, which is mediated through 8-iso-PGF2α.

Cd is a common toxic heavy metal and pollutant in the environment. Exposure to Cd in the environment can lead to various respiratory diseases in humans [28]. A previous study found that higher blood Cd levels are linked to a reduction in lung function [29], and an animal experiment suggested that exposure to Cd can cause pulmonary toxicity in rats through increased lipid peroxidation [30]. However, most published studies on the relationship between lung function alteration and Cd exposure are cross-sectional, with very few longitudinal studies investigating the association in COPD patients. In short, the connection between blood Cd levels and alterations in lung function in COPD patients remains unclear. Therefore, we measured the concentration of Cd in blood samples and analysed its association with changes in lung function in COPD patients by means of a cohort study. We discovered that in COPD patients, an increase in blood Cd concentration was positively correlated with lung function decline. Further multivariable logistic and linear regression analyses showed that, even after adjusting for various confounding factors, blood Cd concentration remained negatively correlated with lung function. In addition, further follow-up studies showed a positive association between lung function decline and blood Cd concentration among COPD patients over two years. These findings indicate that there is a negative relationship between lung function and blood Cd concentration in COPD patients and that it further exacerbates the decline in lung function over two years.

Oxidative stress is associated with an imbalance between antioxidants and oxidants, which may result in cellular damage caused by ROS or reactive nitrogen species (RNS) [31]. Studies conducted in vivo and in vitro have demonstrated that exposure to Cd can result in functional disruption of the mitochondrial electron transport chain, which produces ROS and activates the body’s antioxidant defence system [32]. The compound 8-iso-PGF2α has received widespread recognition as a reliable biomarker of oxidative stress, and its use in clinical research has been extensively validated [33]. In males, 8-iso-PGF2α levels have been observed to positively correlate with higher urinary Cd concentrations in recent investigations [34]. This discovery supports our observations, which showed that 8-iso-PGF2α levels in COPD patients parallelly increased with blood Cd concentrations within a certain range. Furthermore, according to a mediation analysis, 8-iso-PGF2α mediates the association between lung function decline and ambient Cd exposure in COPD patients. These results suggest that oxidative stress probably plays a significant role in the Cd-induced decline in lung function in COPD patients.

Several significant conclusions emerged from this study. First, our study highlighted a clear association between Cd levels and pulmonary function reduction among COPD patients within two years. Second, we explored the potential mechanisms underlying the Cd-related decline of lung function. The significant mediating influence of 8-iso-PGF2α on the connection between lung function decline and Cd exposure provides important clues to the pathogenesis of COPD in these patients. Third, this COPD-based longitudinal study contributes to the investigation of the causal link between ambient Cd exposure and lung function. Lastly, this was a multicentre study with a relatively large sample size, including patients from three separate tertiary hospitals in Anhui Province.

However, there were some limitations in this research. This study was only an epidemiological investigation, and it is yet unknown how exactly Cd exposure causes lung function detriment. Further validation is needed through in vitro and in vivo experiments to determine the precise mechanism. In addition, this study only measured the concentration of Cd in blood samples at a single time point rather than testing Cd levels in 24-h blood specimens. This may not fully represent the Cd burden in COPD patients, we also do not collect venous blood samples from COPD patients every day. Therefore, future studies should collect urine and blood samples at multiple time points. Finally, in the real world, people are exposed to various metals, but this study only focused on Cd. The possible impacts of additional metals on the development and progression of COPD should be further studied.

Conclusions

Overall, this cohort study primarily indicates a strong correlation between decreased lung function and Cd exposure in patients with COPD, partly mediated by 8-iso-PGF2α. These findings support the damaging effect of daily ambient Cd exposure on lung function in COPD patients through oxidative injury. Subsequent follow-up can assist clinical researchers in tracking the progression and changes in lung function in COPD patients after Cd exposure and provide evidence on the long-term impacts of Cd exposure.

Acknowledgements

We would like to thank all of the study participants and the nurses and doctors from the three tertiary hospitals who helped with subject recruitment.

Author contributions

JX: Investigation, Methodology, Conceptualization, Writing - Original Draft, Data Curation, Resources, Visualization. FZ: Supervision, Resources, Investigation. YL: Resources, Supervision, Investigation. PF: Supervision, Investigation, Resources. JS: Resources, Supervision, Investigation. ML: Supervision, Investigation, Resources. MT: Supervision, Investigation. HZ: Project administration, Resources, Investigation. LF: Formal analysis, Validation, Methodology, Conceptualization, Supervision, Resources, Writing - Review & Editing, Data Curation, Investigation. JY: Formal analysis, Methodology, Conceptualization, Funding acquisition, Resources, Supervision, Writing - Review & Editing. The article’s submission was reviewed and approved by all authors.

Funding

This work was supported by National Natural Science Foundation of China (82100078, 82270071), University Natural Science Research Project of Anhui Province (2023AH030117), Major Scientific Research Project of the Department of Education of Anhui Province (2022AH040098), Research Foundation of Anhui Medical University (2022xkj170).

Data availability

The datasets used and analysed during the current study available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The Anhui Medical University Ethics Committee (YX2021-146) approved this study. An informed consent form was signed by all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

Cd Cadmium

COPD Chronic Obstructive Pulmonary Disease

8-Iso-PGF2α 8-Iso-prostaglandin F2 alpha

FVC Forced Vital Capacity

FEV1 Forced Expiratory Volume in 1 s

Pb Plumbum

Cr Chromium

Co Cobalt

ROS Reactive Oxygen Species

AHCC Anhui Chronic Obstructive Pulmonary Disease Cohort

GOLD Chronic Obstructive Pulmonary Disease

ICP-MS Inductively Coupled Plasma Mass Spectrometry

ELISA Enzyme-Linked Immunosorbent Test

ANOVA Analyses Of Variance

GAM Generalized Additive Model

OR Odds Ratios

CI Confidence Intervals

WBC White Blood Cells

ALT Alanine Aminotransferase

CRP C-Reactive Protein

IL-6 Interleukin-6

RNS Reactive Nitrogen Species

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Juan Xu, Feng-Min Zhu and Ying Liu contributed equally to this work.
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References

1. Jones A Causes and effects of chronic obstructive pulmonary disease Br J Nurs 2001 10 13 845 50 10.12968/bjon.2001.10.13.845 11927884
Jones A. Causes and effects of chronic obstructive pulmonary disease. Br J Nurs. 2001;10(13):845–50. 10.12968/bjon.2001.10.13.845.11927884
2. Rabe KF Watz H Chronic obstructive pulmonary disease Lancet 2017 389 10082 1931 40 10.1016/s0140-6736(17)31222-9 28513453
Rabe KF, Watz H. Chronic obstructive pulmonary disease. Lancet. 2017;389(10082):1931–40. 10.1016/s0140-6736(17)31222-9.28513453
3. Tan SL Wood AM Chronic obstructive pulmonary disease and comorbidity: a review and consideration of pathophysiology Panminerva Med 2009 51 2 81 93 19776710
Tan SL, Wood AM. Chronic obstructive pulmonary disease and comorbidity: a review and consideration of pathophysiology. Panminerva Med. 2009;51(2):81–93.19776710
4. Smith MC Wrobel JP Epidemiology and clinical impact of major comorbidities in patients with COPD Int J Chron Obstruct Pulmon Dis 2014 9 871 88 10.2147/copd.S49621 25210449
Smith MC, Wrobel JP. Epidemiology and clinical impact of major comorbidities in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2014;9:871–88. 10.2147/copd.S49621.25210449
5. Leem AY Park B Kim YS Chang J Won S Jung JY Longitudinal decline in lung function: a community-based cohort study in Korea Sci Rep 2019 9 1 13614 10.1038/s41598-019-49598-9 31541126
Leem AY, Park B, Kim YS, Chang J, Won S, Jung JY. Longitudinal decline in lung function: a community-based cohort study in Korea. Sci Rep. 2019;9(1):13614. 10.1038/s41598-019-49598-9.31541126
6. Wang M Aaron CP Madrigano J Hoffman EA Angelini E Yang J Association between Long-term exposure to Ambient Air Pollution and change in quantitatively assessed emphysema and lung function JAMA 2019 322 6 546 56 10.1001/jama.2019.10255 31408135
Wang M, Aaron CP, Madrigano J, Hoffman EA, Angelini E, Yang J, et al. Association between Long-term exposure to Ambient Air Pollution and change in quantitatively assessed emphysema and lung function. JAMA. 2019;322(6):546–56. 10.1001/jama.2019.10255.31408135
7. Jannetto PJ Cowl CT Elementary Overview of Heavy metals Clin Chem 2023 69 4 336 49 10.1093/clinchem/hvad022 36945128
Jannetto PJ, Cowl CT. Elementary Overview of Heavy metals. Clin Chem. 2023;69(4):336–49. 10.1093/clinchem/hvad022.36945128
8. Järup L Akesson A Current status of cadmium as an environmental health problem Toxicol Appl Pharmacol 2009 238 3 201 8 10.1016/j.taap.2009.04.020 19409405
Järup L, Akesson A. Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol. 2009;238(3):201–8. 10.1016/j.taap.2009.04.020.19409405
9. Turner A Cadmium pigments in consumer products and their health risks Sci Total Environ 2019 657 1409 18 10.1016/j.scitotenv.2018.12.096 30677907
Turner A. Cadmium pigments in consumer products and their health risks. Sci Total Environ. 2019;657:1409–18. 10.1016/j.scitotenv.2018.12.096.30677907
10. Wang M Chen Z Song W Hong D Huang L Li Y A review on Cadmium exposure in the Population and intervention strategies against Cadmium Toxicity Bull Environ Contam Toxicol 2021 106 1 65 74 10.1007/s00128-020-03088-1 33486543
Wang M, Chen Z, Song W, Hong D, Huang L, Li Y. A review on Cadmium exposure in the Population and intervention strategies against Cadmium Toxicity. Bull Environ Contam Toxicol. 2021;106(1):65–74. 10.1007/s00128-020-03088-1.33486543
11. Knoell DL Wyatt TA The adverse impact of cadmium on immune function and lung host defense Semin Cell Dev Biol 2021 115 70 6 10.1016/j.semcdb.2020.10.007 33158728
Knoell DL, Wyatt TA. The adverse impact of cadmium on immune function and lung host defense. Semin Cell Dev Biol. 2021;115:70–6. 10.1016/j.semcdb.2020.10.007.33158728
12. Ke HX Zhang JP Jin SH Zhou L Chai SF Ma L [Relationship between cadmium exposure and pulmonary function level and chronic obstructive pulmonary disease] Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 2023 41 4 241 6 10.3760/cma.j.cn121094-20220622-00336 37248176
Ke HX, Zhang JP, Jin SH, Zhou L, Chai SF, Ma L. [Relationship between cadmium exposure and pulmonary function level and chronic obstructive pulmonary disease]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2023;41(4):241–6. 10.3760/cma.j.cn121094-20220622-00336.37248176
13. Jiang YL Fei J Cao P Zhang C Tang MM Cheng JY Serum cadmium positively correlates with inflammatory cytokines in patients with chronic obstructive pulmonary disease Environ Toxicol 2022 37 1 151 60 10.1002/tox.23386 34652871
Jiang YL, Fei J, Cao P, Zhang C, Tang MM, Cheng JY, et al. Serum cadmium positively correlates with inflammatory cytokines in patients with chronic obstructive pulmonary disease. Environ Toxicol. 2022;37(1):151–60. 10.1002/tox.23386.34652871
14. Lv BB Yang CL Tan ZX Zheng L Li MD Jiang YL Association between cadmium exposure and pulmonary function reduction: potential mediating role of telomere attrition in chronic obstructive pulmonary disease patients Ecotoxicol Environ Saf 2023 251 114548 10.1016/j.ecoenv.2023.114548 36652742
Lv BB, Yang CL, Tan ZX, Zheng L, Li MD, Jiang YL, et al. Association between cadmium exposure and pulmonary function reduction: potential mediating role of telomere attrition in chronic obstructive pulmonary disease patients. Ecotoxicol Environ Saf. 2023;251:114548. 10.1016/j.ecoenv.2023.114548.36652742
15. Wang L-X Fei J Wang X-M Xie G-F Cao P Zhang C Environmental cadmium positively correlates with autophagy and apoptosis in chronic obstructive pulmonary disease patients Atmospheric Pollution Res 2022 13 1 101275 10.1016/j.apr.2021.101275
Wang L-X, Fei J, Wang X-M, Xie G-F, Cao P, Zhang C, et al. Environmental cadmium positively correlates with autophagy and apoptosis in chronic obstructive pulmonary disease patients. Atmospheric Pollution Res. 2022;13(1):101275.
16. Kirkham PA Barnes PJ Oxidative stress in COPD Chest 2013 144 1 266 73 10.1378/chest.12-2664 23880677
Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest. 2013;144(1):266–73. 10.1378/chest.12-2664.23880677
17. van der Pol A van Gilst WH Voors AA van der Meer P Treating oxidative stress in heart failure: past, present and future Eur J Heart Fail 2019 21 4 425 35 10.1002/ejhf.1320 30338885
van der Pol A, van Gilst WH, Voors AA, van der Meer P. Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail. 2019;21(4):425–35. 10.1002/ejhf.1320.30338885
18. Del Rio D Stewart AJ Pellegrini N A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress Nutr Metab Cardiovasc Dis 2005 15 4 316 28 10.1016/j.numecd.2005.05.003 16054557
Del Rio D, Stewart AJ, Pellegrini N. A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis. 2005;15(4):316–28. 10.1016/j.numecd.2005.05.003.16054557
19. Basu S Radioimmunoassay of 8-iso-prostaglandin F2alpha: an index for oxidative injury via free radical catalysed lipid peroxidation Prostaglandins Leukot Essent Fat Acids 1998 58 4 319 25 10.1016/s0952-3278(98)90042-4
Basu S. Radioimmunoassay of 8-iso-prostaglandin F2alpha: an index for oxidative injury via free radical catalysed lipid peroxidation. Prostaglandins Leukot Essent Fat Acids. 1998;58(4):319–25. 10.1016/s0952-3278(98)90042-4.
20. Van’t Erve TJ Lih FB Jelsema C Deterding LJ Eling TE Mason RP Reinterpreting the best biomarker of oxidative stress: the 8-iso-prostaglandin F2α/prostaglandin F2α ratio shows complex origins of lipid peroxidation biomarkers in animal models Free Radic Biol Med 2016 95 65 73 10.1016/j.freeradbiomed.2016.03.001 26964509
Van’t Erve TJ, Lih FB, Jelsema C, Deterding LJ, Eling TE, Mason RP, et al. Reinterpreting the best biomarker of oxidative stress: the 8-iso-prostaglandin F2α/prostaglandin F2α ratio shows complex origins of lipid peroxidation biomarkers in animal models. Free Radic Biol Med. 2016;95:65–73. 10.1016/j.freeradbiomed.2016.03.001.26964509
21. Goyal T Mitra P Singh P Sharma P Sharma S Evaluation of oxidative stress and pro-inflammatory cytokines in occupationally cadmium exposed workers Work 2021 69 1 67 73 10.3233/wor-203302 33104053
Goyal T, Mitra P, Singh P, Sharma P, Sharma S. Evaluation of oxidative stress and pro-inflammatory cytokines in occupationally cadmium exposed workers. Work. 2021;69(1):67–73. 10.3233/wor-203302.33104053
22. Kiran Kumar KM Naveen Kumar M Patil RH Nagesh R Hegde SM Kavya K Cadmium induces oxidative stress and apoptosis in lung epithelial cells Toxicol Mech Methods 2016 26 9 658 66 10.1080/15376516.2016.1223240 27687512
Kiran Kumar KM, Naveen Kumar M, Patil RH, Nagesh R, Hegde SM, Kavya K, et al. Cadmium induces oxidative stress and apoptosis in lung epithelial cells. Toxicol Mech Methods. 2016;26(9):658–66. 10.1080/15376516.2016.1223240.27687512
23. Tan Q Ma J Zhou M Wang D Wang B Nie X Heavy metals exposure, lipid peroxidation and heart rate variability alteration: Association and mediation analyses in urban adults Ecotoxicol Environ Saf 2020 205 111149 10.1016/j.ecoenv.2020.111149 32829210
Tan Q, Ma J, Zhou M, Wang D, Wang B, Nie X, et al. Heavy metals exposure, lipid peroxidation and heart rate variability alteration: Association and mediation analyses in urban adults. Ecotoxicol Environ Saf. 2020;205:111149. 10.1016/j.ecoenv.2020.111149.32829210
24. Qin HY, Li MD, Xie GF, Cao W, Xu DX, Zhao H et al. Associations among S100A4, Sphingosine-1-Phosphate, and Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease. Oxid Med Cell Longev. 2022; 2022: 6041471. 10.1155/2022/6041471
25. Zheng L Jiang YL Fei J Cao P Zhang C Xie GF Circulatory cadmium positively correlates with epithelial-mesenchymal transition in patients with chronic obstructive pulmonary disease Ecotoxicol Environ Saf 2021 215 112164 10.1016/j.ecoenv.2021.112164 33756289
Zheng L, Jiang YL, Fei J, Cao P, Zhang C, Xie GF, et al. Circulatory cadmium positively correlates with epithelial-mesenchymal transition in patients with chronic obstructive pulmonary disease. Ecotoxicol Environ Saf. 2021;215:112164. 10.1016/j.ecoenv.2021.112164.33756289
26. Fu L Zhao H Xiang Y Xiang HX Hu B Tan ZX Reactive oxygen species-evoked endoplasmic reticulum stress mediates 1-nitropyrene-induced epithelial-mesenchymal transition and pulmonary fibrosis Environ Pollut 2021 283 117134 10.1016/j.envpol.2021.117134 33866216
Fu L, Zhao H, Xiang Y, Xiang HX, Hu B, Tan ZX, et al. Reactive oxygen species-evoked endoplasmic reticulum stress mediates 1-nitropyrene-induced epithelial-mesenchymal transition and pulmonary fibrosis. Environ Pollut. 2021;283:117134. 10.1016/j.envpol.2021.117134.33866216
27. Wang JL Chen X Xu Y Chen YX Wang J Liu YL The associations of serum IL-37 with the severity and prognosis in patients with community-acquired pneumonia: a retrospective cohort study Front Immunol 2021 12 636896 10.3389/fimmu.2021.636896 34025645
Wang JL, Chen X, Xu Y, Chen YX, Wang J, Liu YL, et al. The associations of serum IL-37 with the severity and prognosis in patients with community-acquired pneumonia: a retrospective cohort study. Front Immunol. 2021;12:636896. 10.3389/fimmu.2021.636896.34025645
28. Al Osman M Yang F Massey IY Exposure routes and health effects of heavy metals on children Biometals 2019 32 4 563 73 10.1007/s10534-019-00193-5 30941546
Al Osman M, Yang F, Massey IY. Exposure routes and health effects of heavy metals on children. Biometals. 2019;32(4):563–73. 10.1007/s10534-019-00193-5.30941546
29. Jakubowski M Abramowska-Guzik A Szymczak W Trzcinka-Ochocka M Influence of long-term occupational exposure to cadmium on lung function tests results Int J Occup Med Environ Health 2004 17 3 361 8 15683157
Jakubowski M, Abramowska-Guzik A, Szymczak W, Trzcinka-Ochocka M. Influence of long-term occupational exposure to cadmium on lung function tests results. Int J Occup Med Environ Health. 2004;17(3):361–8.15683157
30. Salovsky P Shopova V Dancheva V Marev R Changes in antioxidant lung protection after single intra-tracheal cadmium acetate instillation in rats Hum Exp Toxicol 1992 11 3 217 22 10.1177/096032719201100310 1352117
Salovsky P, Shopova V, Dancheva V, Marev R. Changes in antioxidant lung protection after single intra-tracheal cadmium acetate instillation in rats. Hum Exp Toxicol. 1992;11(3):217–22. 10.1177/096032719201100310.1352117
31. Hu T, Dong Y, He C, Zhao M, He Q. The Gut Microbiota and Oxidative Stress in Autism Spectrum Disorders (ASD). Oxid Med Cell Longev. 2020; 2020: 8396708. 10.1155/2020/8396708
32. Yan LJ, Allen DC. Cadmium-Induced kidney Injury: oxidative damage as a unifying mechanism. Biomolecules. 2021;11(11). 10.3390/biom11111575.
33. Ryu Y Gracia-Lor E Bade R Baz-Lomba JA Bramness JG Castiglioni S Increased levels of the oxidative stress biomarker 8-iso-prostaglandin F(2α) in wastewater associated with tobacco use Sci Rep 2016 6 39055 10.1038/srep39055 27976726
Ryu Y, Gracia-Lor E, Bade R, Baz-Lomba JA, Bramness JG, Castiglioni S, et al. Increased levels of the oxidative stress biomarker 8-iso-prostaglandin F(2α) in wastewater associated with tobacco use. Sci Rep. 2016;6:39055. 10.1038/srep39055.27976726
34. He Y Zou L Luo W Yi Z Yang P Yu S Heavy metal exposure, oxidative stress and semen quality: exploring associations and mediation effects in reproductive-aged men Chemosphere 2020 244 125498 10.1016/j.chemosphere.2019.125498 31812049
He Y, Zou L, Luo W, Yi Z, Yang P, Yu S, et al. Heavy metal exposure, oxidative stress and semen quality: exploring associations and mediation effects in reproductive-aged men. Chemosphere. 2020;244:125498. 10.1016/j.chemosphere.2019.125498.31812049
