China is the world's largest coke producer, accounting for 60% of the world's total coke production (Liu et al., 2009). Shanxi Province is the largest coke-producing area in the world (Xu et al., 2006). During the coking process, a large amount of coke oven emissions are produced, of which polycyclic aromatic hydrocarbons (PAH) are the main component (Cavallo et al., 2008). Therefore, as an important base of the coal chemical industry, public health problems caused by coal-fired pollution in Shanxi province have attracted great attention from scholars and the government.

Coke oven workers are predominantly male, comprising a high number of smokers; thus, there is considerable tobacco smoke exposure, in addition to long-term exposure to PAH. Numerous studies have shown that long-term PAH exposure is closely related to the occurrence of various respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma (Al-Daghri et al., 2013; Burstyn et al., 2003). Previous studies have found that smoking (including passive smoking) is an important risk factor for respiratory disease, with approximately 30% of smokers developing COPD and 15% developing lung cancer, whereas only 10% of patients with COPD or lung cancer have no clear history of smoking (Govindan et al., 2012). Self-reported smoking levels have been widely used to assess the health effects of smoking; however, they may be inaccurate. Actual smoke inhalation and absorption depend on the mode of smoking and the level of exposure to secondhand smoke, making it particularly important to detect the levels of internal exposure to tobacco (Connor Gorber et al., 2009; Reynolds et al., 2017). A cross-sectional study showed that the interaction between PAH exposure and smoking led to decreased lung function in coke oven workers, suggesting that long-term exposure to PAH and smoking can lead to early lung impairment in workers (Hu et al., 2006). However, the underlying mechanisms linking tobacco smoking and PAH exposure to decreased lung function remain unclear. PAH and tobacco disrupt the structural integrity of lung epithelial cells by oxidative stress and inflammatory responses, which may play an important role in the pathogenesis of reduced lung function (Farzan et al., 2016).

Exposure to several environmental pollutants affects the level of Club cell secretory protein (CC16), a 16 kDa homodimeric protein secreted by cilia-free bronchial Club cells (Wang et al., 2017; Zhou et al., 2018). Some studies have confirmed that CC16 is an important lung epithelial marker because it reflects the process of air-blood barrier disruption and altered lung epithelial permeability (Broeckaert and Bernard, 2000; McAuley and Matthay, 2009). When stimulated by exogenous substances, the airways locally produce large amounts of reactive oxygen species (ROS) and inflammatory factors. Simultaneously, the Club cells secrete CC16 to counteract the oxidative stress and inflammatory responses (Van Vyve et al., 1995). However, the long-term presence of contaminants may lead to a decrease in Club cells as well as mRNA and protein expression of CC16, resulting in a decrease in CC16 levels (Lam et al., 2018). Therefore, CC16 levels may have great potential in assessing the health risks of pollutants and early impairment of lung function. Several epidemiological and clinical studies have shown reduced serum CC16 levels in patients with lung function defects, asthma, and COPD (Guerra et al., 2016; Lomas et al., 2008; Rava et al., 2013). However, some epidemiological cohorts have found that low serum concentrations of CC16 predict an accelerated decline in lung function in adulthood (Guerra et al., 2015). Therefore, although CC16 may reflect the degree of lung epithelial damage, a causal relationship between its concentration and altered lung function has been difficult to establish.

Therefore, we hypothesized that exposure to PAH and tobacco smoke in coke oven workers might reduce lung function via decreasing CC16 concentrations. To investigate the associations between PAH and tobacco smoke exposure and the levels of CC16 and lung function, we measured urinary nicotine and PAH metabolite levels, lung function indicators and plasma CC16 levels at baseline among 313 occupational workers in a coke oven plant in Shanxi province, with follow-up after 5 years. We further conducted a cross-lagged panel analysis to demonstrate the causal relationship between CC16 levels and decreased lung function. Finally, a causal mediation model was used to assess the mediating role of plasma CC16 levels in the association of PAH and tobacco smoke exposure with decreased lung function.