Association Of Polycyclic Aromatic Hydrocarbon Exposure-gene Polymorphism Interaction With Lung Cancer Risk

Polycyclic aromatic hydrocarbons(PAHs),one of the largest proporton of environmental poisons in the world.Forest fire,vehicle exhaust emissions,coal,oil and natural gas combustion can all emit PAHs into the surrounding environment.The human can be exposed to PAHs in the environment through respiratory inhalation,dietary intake and skin contact.Toxicological evidence and epidemiological studies indicated that,PAHs exposure is closely associated with decreased lung function,chronic obstructive pulmonary disease,asthma,decreased semen quality in men,and the development of a variety of malignancies.However,there are few epidemiological studies indicate the association between PAHs exposure and lung cancer.Many epidemiological studies focus on the occupational population,which exposed to high concentrations of PAHs.Studies on the association between PAHs exposure and lung cancer risk in the general population are rare and inconsistent.The general population is exposed to lower levels of PAHs than the occupational population.It is necessary to further explore the association between PAHs exposure and lung cancer risk in the general population.The development of lung cancer is the result of the interaction between environmental factors and genetic factors.PAHs can be metabolized and activated by the cytochrome P450 enzyme family when PAHs entering the lung tissue.PAHs can form PAHs-DNA adducts and reactive oxygen species,which can lead to gene mutation,base aging,DNA chain break and to lung cancer.DNA damage can be effectively removed or repaired by Base excision repair(BER),Nucleotide removal repair(NER)and chain breaking repair.Thus,Single nucleotide polymorphism(SNP)of the PAHs metabolic enzyme genes and DNA damage repair genes may modify the association between PAHs exposure and lung cancer risk.Therefore,we conducted a case-control study of 122 lung cancer and 244 healthy controls.Our study collected the epidemiological data of the study subjects,urine and blood samples,detected the concentrations of 10 PAHs metabolites in urine and so on.The objectives of this study are: 1)To investigate levels of urinary PAHs metabolites amo ng the study subjects;2)To explore the possible associations between urinary PAHs metabolites and the risk of lung cancer;3)To explore the associations between gene polymorphism-PAHs exposure interaction and lung cancer risk.This study included two parts as following:PartⅠEnvironmental exposure to PAHs and the risk of lung cancerObjective: The case-control study was designed to assess the associations between environmental exposure to PAHs and the odds of lung cancer using urine samples in a Chinese general population.Methods: The matched case-control study used the concentration of 10 PAHs metabolites in urine samples as biomarkers to reflect the levels of environmental exposure to PAHs.The concentrations of 10 PAHs metabolites in urine were measured by Gas C hromatography-Mass Spectrometry.Multivariate Logistic regression models were used to evaluate the potential association,and a dose-response relationship between exposure and outcome was further explored using the restricted cubic spline curve(RCS).Results: Based on the results from different statistical models,positive associations for increased odd of lung cancer with increasing tertiles of1-hydroxyphenanthrene(1-OHPh),3-hydroxyphenanthrene(3-OHPh),and ∑OHPh were suggested(P trend < 0.05).Compared with the lowest tertile,participants in the highest tertile of 1-OHPh,3-OHPh and ∑OHPh have a 3.55-fold,6.74-fold,and2.45-fold increased odds of suffering lung cancer,respectively.However,only the monotonously rising trend o f significant association with 1-OHPh was further demonstrated in the RCS model.Conclusions: Our findings reveal that the levels of 1-OHPh may be associated with an elevated risk of lung cancer.Part Ⅱ The association of inte raction between PAHs exposure and genetic polymorphis m with the risk of lung cancerObjective: The purpose of this study is to investigate the potential association between gene polymorphism and the risk of lung cancer,and the association of interaction between PAHs exposure and genetic polymorphism with the risk of lung cancer.Methods: The current study was a 1:2 matched case-control study.The case and control groups included in this study were completely consistent with the PartⅠ.We explore the association between 14 SNPs of 10 genes and the risk of lung cancer.In the PartⅠ,we measured the levels of 10 metabolites of PAHs,which can be classified into four categories.Therefore,we used the concentrations of 1-OHP,∑OHNa,∑OHFlu,and ∑OHPh to represent the exposure of four PAHs in this study population.The relationships between genetic polymorphism and lung cancer were evaluated using logistic models based on different genetic models.The interactions between exposure to pyrene,naphthalene,fluorene,and phenanthrene and genetic polymorphism were investigated on the multiplicative scale.Results: Of the 14 SNPs in 10 genes,significant associations were found between rs17655 in ERCC5 and the risk of lung cancer.Multiplicative interactions between rs4646422 in CYP1A1,rs17655 in ERCC5,rs25487 in XRCC1,rs1801320 in RAD51,and naphthalene exposure for lung cancer were observed.Multiplicative interactions between rs4646422 in CYP1A1,and rs17655 in ERCC5,and rs1801320 in RAD51,and phenanthrene exposure for lung cancer were observed.The above interaction was still statistically significa nt after FDR correction(PFDR<005).Conclusion: Associations between naphthalene exposure and the risk of lung cancer may be modified by genetic variants in CYP1A1,ERCC5,XRCC1,and RAD51.Associations between phenanthrene exposure and the risk of lung cancer may be modified by genetic variants in CYP1A1,ERCC5,and RAD51.