In contemporary society, organochlorines are extensively utilized across agricultural, industrial, and household applications, including pesticides and plastics, due to their advantageous chemical properties^[1,2]. During the latter half of the 20^th century, global consumption of organochlorine pesticides reached a staggering 2 million tons^[3]. As one of the world’s leading agricultural nations, China plays a crucial and undeniable role in both the production and consumption of organochlorines^[4,5]. Despite the evident benefits these compounds offer, their potential for causing environmental contamination and ecological disruption has led to the prohibition of many organochlorines under the Stockholm Convention^[6]. However, the legacy of their extensive use has left a lasting imprint on the environment, presenting ongoing challenges for environmental management and posing a significant threat to human health^[7-9]. In regions such as the Yangtze River Delta of China, atmospheric concentrations of organochlorines range from 17.9 to 168 pg/m^3[10], while areas more dramatically affected, such as the pesticide-contaminated southwestern regions of China, concentrations can reach as high as 195 ng/m^3[11]. These persistent environmental pollutants elevate the likelihood that these harmful substances will enter the human body, amplifying concerns regarding their health implications^[12].

Extensive research has demonstrated a link between exposure to organochlorines and risks of developing chronic diseases^[13,14]. The elderly population, given their physiological decline and cumulative environmental exposures, manifests heightened vulnerability to the detrimental effects of these pollutants^[15,16]. The respiratory system, particularly the lungs, serve as the primary interface for interaction with airborne pollutants, rendering it especially susceptible to the detrimental effects of these compounds^[17,18]. The negative impact of lung impairment on the general health and overall quality of life of the elderly cannot be ignored. While existing studies on effects of organochlorines on the lung function have predominantly concentrated on pediatric and adult populations^[19,20], the relationship between these compounds and lung function in the elderly remains relatively underexplored. This knowledge gap underscores the critical need for targeted research on the impact of organochlorines on lung health, especially in the context of a rapidly aging global population.

The weakening of lung function generally involves multiple biological processes, with inflammatory responses playing a pivotal role^[21,22]. The degeneration of lung tissue is frequently accompanied by the onset of inflammation, which tends to intensify when triggered by external stimuli^[23,24]. This amplified inflammatory response is particularly concerning in the context of environmental pollutant exposures. In addition, thyroid hormones, recognized as crucial endocrine regulators, not only modulate metabolic processes but also significantly influence lung development and function^[25,26]. However, the specific role of thyroid hormones on the association between organochlorine exposure and lung function remains largely unknown. Our prior research has identified the detrimental effects of organochlorines on lung function among 26 airborne organic pollutants^[27]. Building upon these findings, this study aimed to investigate the complex interplay among organochlorine exposure, inflammatory factors, and thyroid hormone levels in relation to lung function, and to offer new insights into the mechanisms through which organochlorines affected lung health in the elderly.

This research constitutes a segment of the China Biomarkers of Air Pollutant Exposure (BAPE) Study, involving the recruitment of 76 healthy older adults (50% male), with ages from 60 to 69, from Jinan, Shandong Province^[28]. The enrollment flowchart and the specific times of exposure measurements for the study participants have been thoroughly documented in our prior publications^[28]. The initial assessment was performed at Ankang Community Hospital in September 2018, with subsequent five monthly follow-ups until January 2019. Data regarding sociodemographic factors were collected by face-to-face interviews through electronic questionnaires. In parallel, physical examinations were conducted to obtain critical metrics such as participants’ height and weight. Fasting venous blood samples were also collected for subsequent analysis. It is essential to highlight that during each follow-up, participants’ information underwent a comprehensive re-collection, which encompassed the measurement of exposure levels, physical examinations, and sample collection. Consequently, each participant contributed multiple data measurements for every variable assessed throughout the study. This research was approved by the Ethics Review Committee of the National Institute of Environmental Health, Chinese Center for Disease Control and Prevention (NIEH, China CDC, No. 201816), and informed consent was obtained from all participants. Detailed research protocols have been documented in prior literature^[28-30].

Personal exposure to organochlorines was monitored using a Fresh Air wristband^[31]. At each stage of the survey, participants wore these wristbands continuously for three days continuously, only removing them when showering. At the end of the exposure period, we extracted the polydimethylsiloxane sorbent bars from each wristband and transported them to the Yale School of Public Health with cold chain preservation for chemical analysis^[31,32]. In this study, five specific organochlorines, namely bis (2-chloro-1-methylethyl) ether (BCIE), hexachlorobutadiene (HCBD), 4-chloroaniline, 1,3-dichlorobenzene, and 1,4-dichlorobenzene were evaluated.

Lung function of all participants was assessed by trained medical personnel using a spirometer (SP10BT, Oranger Technology Co. Ltd., Tianjin, China). To warrant the reliability of the results, multiple measurements were obtained for each participant, using the quality control standards outlined by the ATS/ERS guidelines^[33]. This rigorous process continued until we obtained three measurements that met the predefined criteria. Subsequently, the best value was selected as the definitive result for the lung function assessment among these measurements. We evaluated four pulmonary function indicators, namely forced vital capacity (FVC), forced expiratory volume in 1 s (FEV₁), the ratio of FEV₁ to FVC (FEV₁/FVC), and peak expiratory flow (PEF)^[34].

The serum concentrations of inflammatory factors were determined using the Luminex MagPix system with a Milliplex Mitogen-Activated Protein (MAP) High-sensitivity Human Cytokine Panel (HSCYTO-60, Millipore Corp.), adhering to the protocol of the manufacturer^[30]. The concentrations of the following 13 inflammatory factors were assessed, including interleukin (IL)-1β, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17A, IL-21, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ.

The serum concentrations of thyroid-stimulating hormone (TSH), triiodothyronine (T₃), and thyroxin (T₄) were quantified using fluorescence detection system (Magpix®, Luminex Corporation, Austin, TX, USA)^[35]. This assay employed carboxyl-modified microspheres as reaction carrier, coupled with fluorescence-based quantification, to facilitate the simultaneous analysis of multiple analytes.

Information on covariates such as age (years), gender (male, female), income (10,000 yuan/year), and educational attainment (below primary school, primary, junior and senior high school, and university and above) was gathered through face-to-face follow-up assessments. Body mass index (BMI, kg/m²) was calculated using participants' height and weight measured during physical examinations, employing the formula where weight is divided by height squared. Additionally, blood samples were analyzed to determine cotinine levels (ng/mL) as an indicator of passive tobacco exposure using Hypersil GOLD C18 Selectivity HPLC Columns (ThermoFisher Scientific) interfaced with an LC-Q-Exactive Orbitrap Mass Spectrometer (ThermoFisher Scientific)^[29].

Preceding the analysis, the concentrations of organochlorines were Log₂-transformed to improve the normality of the data. For continuous variables, the mean and standard deviation (SD) were used for description, and categorical variables were characterized by percentages. And organochlorines’ distribution characteristics were described employing the median and interquartile range (IQR). The inter-correlations among the 5 organochlorines were evaluated using Spearman's correlation analysis. We employed the latent profile analysis (LPA) to partition the study samples into distinct subgroups based on TSH, T₃, and T₄ levels. LPA is a robust statistical technique grounded in a mixed distribution model, aiming to discern latent, unobserved subgroups within the data^[36,37]. LPA posits that the sample data originates from a mixture of distributions corresponding to distinct potential groups, each characterized by its own unique mean and variance. Specifically, LPA leveraged Bayes' theorem to assign each sample to the thyroid hormone spectrum most likely to be a member based on the relative similarity of participants’ thyroid hormone characteristics. Our analysis ultimately identified two distinct categories. One group was characterized by elevated levels of TSH, T₃, and T₄ compared to the other, leading us to designate it as the “high” group, with the other group being labeled as the “low” group. This classification was determined by comparing the relative characteristics of the thyroid hormone profiles across two groups. Subsequent analyses, including association and mediation analyses, were conducted within these two groups, both derived through the LPA method, to probe the intricate relationship between organochlorines exposure and various physiological indicators. We selected several covariates for inclusion in our analysis, specifically age, gender, income, educational attainment, BMI, and serum cotinine. The rationale for considering these covariates is multifaceted. Firstly, age and gender are fundamental demographic variables known to significantly influence both thyroid function and lung health^[38-40]. Socioeconomic factors such as income and educational attainment are critical as they affect healthcare access, lifestyle choices, and exposure to environmental pollutants^[41-43]. Furthermore, BMI serves as an important health indicator, closely associated with respiratory function and overall health status^[44]. To control for the effect of passive smoking on the results, serum cotinine was also included as a covariate. Subsequent analyses were conducted in three stages. First, a linear mixed-effect model (LMM) was employed to examine the relationship between 5 organochlorines and 4 pulmonary function indicators, after taking into account covariates such as age, gender, income, educational attainment, BMI, and serum cotinine. Participants’ ID was incorporated as a random intercept term to account for individual variations, with a false discovery rate (FDR) less than 0.05 determined statistically significant. Second, a similar approach investigated associations between 5 organochlorines and 13 inflammatory factors. Finally, mediation analyses were performed to evaluate the mediating impact of inflammatory factors on the relationship between exposure to organochlorines and lung function. Specifically, the assessment of mediating effects was based on the construction of the following two models: 1) the mediation model, which utilized a LMM to investigate the association between organochlorine exposure and inflammatory factors; 2) the outcome model, which also based on a LMM to assess the effects of both organochlorine exposure and inflammatory factors on lung function. Both models incorporated previously identified covariates. The mediation proportion was calculated using nonparametric bootstrapping (500 resampling). All data analyses were conducted using R (version 4.2.3).

After excluding missing values, we integrated 290 measurements from 75 healthy older adults into the analysis. The participants, with an average age of 65.0 ± 2.8 years, consisted of 37 males (49.3%). Table 1 presents the participant characteristics, including lung function, thyroid hormone levels, inflammatory factor concentrations, and other relevant variables. The detailed results of the five measurements of physiological indicators are provided in Supplementary Table S1. Furthermore, Supplementary Table S2 presents the organochlorine exposure levels of the participants. Consistent with previous studies^[27,31], among the five organochlorines examined, 1,3-dichlorobenzene displayed the highest concentration, with a median value of 2.36 ng/m³, while 4-chloroaniline exhibited the lowest concentration at 0.43 ng/m³. Generally, there were positive inter-correlations among the 5 organochlorines assessed (Supplementary Table S3).

Figure 1 illustrates the associations between personal exposure to 5 organochlorines and lung function by two groups with different levels of thyroid hormones. The results indicate that only one organochlorine, BCIE, was significantly associated with a pulmonary function indicator of FVC. This result aligns consistently with previously findings^[27]. However, this association was only observed in the low thyroid hormone group. Specifically, an increase of one IQR in BCIE concentration was associated with a decrease of 2.05% (95% CI: –3.11%, –0.97%) in FVC.

Figure 1.  Associations between personal exposure to organochlorines and changes in lung function by different groups of thyroid hormones. *represents FDR < 0.05. BCIE, Bis (2-chloro-1-methylethyl) ether; HCBD, Hexachlorobutadiene; FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 s; FEV₁/FVC, the ratio of FEV₁ to FVC; PEF, peak expiratory flow.

Figure 2 and Supplementary Table S4 show the associations between personal exposure to various organochlorines and inflammatory factors, stratified by thyroid hormone levels. Our findings reveal that 1,3-dichlorobenzene, 4-chloroaniline, BCIE, and HCBD induced alterations in the levels of several inflammatory factors. Particularly, the low thyroid hormone group exhibited greater sensitivity to the inflammatory factors induced by organochlorine exposure. Specifically, BCIE was associated with significant changes in the levels of IL-2, IL-7, IL-8, and IL-13 within the low thyroid hormone group. Contrastingly, no significant association between BCIE and inflammatory factors was observed in the high thyroid hormone group.

Figure 2.  Associations between organochlorines and changes in inflammatory factors by different groups of thyroid hormones. *, **, and *** represents FDR < 0.05, 0.01 and 0.001, respectively. BCIE, Bis (2-chloro-1-methylethyl) ether; HCBD, Hexachlorobutadiene; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon.

Based on the mediation analysis, we found that IL-2 and IL-13 significantly mediated the relationship between BCIE exposure and FVC, with 15.63% (95% CI: 0.91%, 44.64%) and 13.94% (95% CI: 0.52%, 41.07%) of mediating effects, respectively (Figure 3 and Supplementary Table S5).

Figure 3.  The mediation effect of inflammatory factors on the association between BCIE and FVC among healthy older adults. BCIE, Bis (2-chloro-1-methylethyl) ether; FVC, forced vital capacity; IL, interleukin.

As far as we know, this is the first study to explore the complex interplay among organochlorines exposure, inflammatory factors, and alterations in lung function, after taking into account the modulatory role of thyroid hormone levels. Our findings suggest that organochlorine exposure led to a decline of lung function by the induction of inflammatory factors. Importantly, low thyroid hormone levels may amplify this adverse effect, suggesting an increased vulnerability to the impacts of organochlorine exposure under hypothyroid conditions.

Inflammation is a fundamental immune response triggered by various stimuli, including exposure to environmental pollutants^[45]. Numerous studies have demonstrated that organochlorines can induce inflammatory disorders within the body^[46-48]. For instance, a cross-sectional study conducted in Portugal revealed a positive correlation between blood concentrations of hexachlorocyclohexane and levels of IL-10 among women aged 22 to 59 years^[46]. Similarly, in vitro experiments performed by Thota et al. indicated that pentachlorophenol exposure resulted in elevated levels of inflammatory mediators, including IL-1β, IL-6, TNF-α, and IL-8^[48]. Research by Jang et al. on Sprague-Dawley rats identified a positive correlation between endosulfan exposure with increased TNF-α and IL-1β levels^[47]. Aligning with these previous reports, our study uncovered a significant association between organochlorine exposure and altered inflammatory profiles, highlighting that inflammation may play a key role in lung function impairment associated with organochlorine exposure. It is widely acknowledged that the dysregulation of inflammatory factors contributes to the impairment of lung function^[49,50]. Specifically, Lee et al. and Kubysheva et al. proposed that IL-2, IL-13, IL-18, and TNF-α may be associated with the decline in lung function^[51,52]. While this study identified only two significant inflammatory mediators, IL-2 and IL-13, it is important to recognize the importance of the overall inflammatory environment, which encompasses additional inflammatory factors, even though they were not statistically significant in our analysis. The inflammatory process is pervasive within lung tissues, and immune cells like macrophages and lymphocytes are abundant throughout the lung parenchyma^[53]. When pollutants infiltrate the lungs, inflammatory homeostasis can be disrupted, leading to the secretion of a plethora of inflammatory factors^[54]. Persistent inflammation can result in the degradation of elastin and the destruction of alveolar cells, leading to a decline in lung function^[55,56]. While research specifically examining inflammation-mediated organochlorine damage to lung function remains limited, existing studies have substantiated the critical role of inflammatory factors in the impairment of lung function caused by other environmental pollutants. For instance, Xiao et al. utilized data from the National Health and Nutrition Examination Survey (NHANES) to investigate the mechanisms linking polycyclic aromatic hydrocarbons (PAHs) to chronic obstructive pulmonary disease (COPD)^[57]. Their findings revealed that PAHs increased the risk of COPD by influencing systemic inflammation. Similarly, Zheng et al. demonstrated that systemic inflammation mediated the relationship between dust exposure and the decline in FEV₁^[58]. Furthermore, immune cells closely associated with inflammatory responses, such as lymphocytes and white blood cells, were also found to be vital mediators of lung diseases induced by air pollution^[59]. These findings support our observations and underscore the underlying mechanism for the intricate relationship between inflammatory responses and respiratory health. Collectively, our study offers novel insights into the complex interplay among organochlorine exposure, inflammatory responses and lung function impairment, and emphasizes the importance of sustaining pulmonary inflammatory homeostasis for maintaining respiratory health in the elderly population.

Furthermore, we employed LPA to categorize samples according to thyroid hormone concentrations. This grouping methodology has been widely utilized in various researches, which substantiates its reliability and effectiveness^[60-62]. For instance, Qin et al. successfully applied LPA to delineate distinct estrogen spectra, demonstrating its ability to identify meaningful differences in hormonal profiles^[60]. Similarly, Lin et al. leveraged LPA to classify individuals into various subgroups based on diverse characteristics of the built environment, further illustrating the robustness of this analytical approach^[61]. By comparing the effects of organochlorines across different groups, this study further explored whether thyroid hormones modified the relationship between organochlorine exposure and lung function. Thyroid hormones are essential for the regulation of metabolism, energy production, and the proper functioning of tissues, including the lungs^[25]. During lung development, thyroid hormones activate relevant gene expression, promoting the formation of alveoli and vascular structures, thereby facilitating lung maturation^[63,64]. They also play a role in the synthesis of surfactant substances within the alveoli, which are essential for reducing surface tension and stabilizing the alveoli^[65]. Furthermore, thyroid hormones contribute to the maintenance of respiratory muscle endurance and strength, and influence the elasticity and compliance of lung tissue, thereby facilitating proper respiratory movements^[66,67]. Reduced sensitivity to thyroid hormones correlates with impaired lung function, while a clear link exists between hypothyroidism and decreased respiratory capacity^[68,69]. Bassi et al. revealed that thyroid hormone supplementation positively impacts lung function^[70]. Consistent with these findings, our study identified the adverse effects of low thyroid hormone levels on lung function in the elderly. Moreover, our study revealed that low levels of thyroid hormone increased the sensitivity of inflammatory factors to organochlorine exposure, likely due to the immunomodulatory role of thyroid hormones in immune cell function^[71]. Evidence suggests that hypothyroidism can induce a systemic inflammatory response, affecting various cytokines and adversely impacting overall health^[72]. Perrotta et al. have shown that T₃ can mitigate inflammation by modulating the proliferation and differentiation of macrophages^[73]. These findings provide further support for our results that thyroid hormone deficiencies elevated inflammatory sensitivity, thus exacerbating the adverse effects of organochlorine exposure on lung function. And findings may provide a foundation for targeted interventions to mitigate lung function impairments caused by environmental exposures through enhancing inflammatory homeostasis and maintaining normal thyroid hormone levels, ultimately safeguarding respiratory health among the elderly.

This study has several strengths. Firstly, it employed a panel design with multiple repeated measurements, enhancing accuracy and reliability. Secondly, the utilization of Fresh Air wristband to measure individual organochlorine exposure concentrations might offer a more accurate representation of real exposure levels. Finally, our research considered the roles of both thyroid hormones and inflammatory factors in the relationship between organochlorine exposure and lung function, adding valuable insights to the existing literature. However, there are also limitations in this research. Firstly, the study population was confined to healthy older individuals, which might limit the generalization of our results to the overall population. Secondly, the investigation only focused on short-term measurements taken over a five-month period, limiting our capacity to assess long-term effects of organochlorine exposure. Lastly, the sample size was relatively modest, requiring further large-scale epidemiological or experimental research to validate and expand our understanding of these relationships.

This study investigated the intricate interplay among organochlorine exposure, inflammatory factors, thyroid hormones, and lung function. Our findings elucidate that inflammatory factors might play a mediating role in the detrimental effects of organochlorine exposure on lung function. Furthermore, low thyroid hormone levels significantly enhanced the body’s sensitivity to organochlorine exposure, leading to the development of inflammatory disorders and compromised lung function. Our findings may improve our understanding of the biological mechanisms underpinning respiratory injuries associated with organochlorine exposure. Furthermore, we recommend that elderly individuals adopt certain measures, including adequate sleep, a balanced diet, and moderate exercise, to maintain stable levels of thyroid hormones and inflammatory factors which contribute to promoting respiratory health and mitigate risks associated with environmental exposures.