Effects Of PAHs Exposure On The Malignant Progression Of Low-Grade Cervical Intraepithelial Neoplasia,Based On Community Cohort Study

Objective:Cervical cancer is the fourth most malignant cancer among women worldwide,and shows a substantial increasing trend with cervical cancer incidence.Low-grade cervical intraepithelial neoplasia（CIN I）,an early stage in the natural process of cervical cancer,develops slowly and reversibly.Hence,it is of great significance to find out the key factors influencing the progression of CIN I for cervical cancer prevention.High-risk human papillomavirus（HR-HPV）infection is necessarily a causal factor in cervical carcinogenesis,not the only factor.In recent years,industrial production has a rapidly increasing trend.Polycyclic aromatic hydrocarbons（PAHs）,as the major environmental pollutants with carcinogenicity,its effects on cancer are increasingly attracting attention from scholars worldwide.However,it has been never reported regarding the effects of PAHs exposure on the occurrence and progression of cervical lesions.Our previous studies based on the cross-sectional study revealed that PAHs high exposure increased the risks of cervical cancer and precancerous lesions,especially,a stronger risk when it combined with HR-HPV infection.Given it,we hypothesized that PAHs exposure might affect the progression of early cervical lesions.We used a prospective cohort study to evaluate the role of PAHs exposure on the malignant progression of CIN I.Meanwhile,with interaction analysis and Cox regression analysis,we also further evaluate the effect of PAHs exposure combined with HPV infection on the malignant progression of CIN I so as to provide scientific basis for the formulation of strategies regarding preventing and controlling malignant transformation of the malignant progression of CIN.Methods:The participants were from a large community cohort established in two counties（Jiexiu and Yangqu）of Shanxi Province from June to December 2014.A total of 2,304women were diagnosed by colposcopy and pathology,including cervical carcinoma（CC）,high-grade cervical intraepithelial neoplasia（CINⅡ/Ⅲ）,low-grade cervical intraepithelial neoplasia（CINⅠ）and normal cervical（NC）.564 women with CIN I were eventually enrolled into this study.The baseline information of demographic characteristics and related factors was collected from all the participants using a structured questionnaire.HPV genotypes were detected by flow-through hybridization technology.1-hydroxypyrene（1-OHP）was detected by high-performance liquid chromatography.The follow-up was carried out for a period of 2 years.The outcomes were assessed at baseline and at 3follow-ups times（after 6,12 and 24 months）.The observed ending was that CIN I progressed to CIN II/III or cervical cancer.Data analyses were performed by the SPSS（version20.0）statistical software.The counting card information was assessed by chi-square test and trend chi-square test.The risks ratio（RR）and 95%confidence interval（95%CI）,AR,AR%were estimated the effects of PAHs exposure on the outcomes of CIN I by unconditional logistic regression models.Additive model was used to analyze interaction between two factors.Cox regression analysis was conducted to determine the HR and 95%CI of PAHs exposure with the persistence/progression of CIN I,through proportional hazard models.Statistical significance was set atα=0.05.Results:1.Outcome of CIN I:Three different outcomes occurred for 564 women with CIN I during follow-up period in this study,including reverse,persistence and progression.Our results showed that the reverse rates of CIN I with 84.6%,83.5%,79.5%,the persistence rates with 13.6%,13.2%,15.2%and the progression rates with 1.8%,3.3%and 5.3%at 6,12 and 24 months,respectively.With the extension of the follow-up times,both the persistence and progression rates of lesion gradually increased.2.The effects of PAHs exposure on the outcome of CIN I:A prospective cohort study was adopted in this study to evaluate the effects of PAHs exposure on the outcome of CIN I by detecting 1-OHP levels in urine.We observed that at each follow-up time,the persistence/progression rates of CIN I in the high exposure group were significantly higher than that in the low exposure group,and PAHs high exposure increased the risks of CIN I persistence/progression（at 6 months:aRR=1.95,95%CI:1.17³.28;at 12 months:aRR=3.96,95%CI:2.14⁷.31;at 24 months:aRR=4.55,95%CI:2.43⁸.53）.With the extension of follow-up times,the risks of CIN I persistence/progression in the high-exposure group gradually increased.Furthermore,we found that compared to Q1（≤0.05μmol/molCr）levels of 1-OHP,women with Q4（≥0.15μmol/molCr）had a greater persistence/progression rates of CIN I.The risks of CIN I persistence/progression showed an increasing trend with the levels of 1-OHP increased.3.The risks of PAHs exposure combined with HPV infection on the persistence/progression of CIN I:At each follow-up time,the infection rates of HPV and HR-HPV in the CIN I persistence/progression group were significantly higher than that in the reversal group（P<0.001）.Before and after adjusting for factors related with the outcome of CIN I,both HPV and HR-HPV infection increased the risks of CIN I persistence/progression.In addition,at 12 months and 24 months,there was a positive additive interaction between PAHs high exposure and HPV or HR-HPV infection on the persistence/progression of CIN I,while we did not observe the same results at 6 months.4.Multivariate Cox regression analysis for CIN I persistence/progression:Multivariate in the persistence/progression of CIN I was introduced into Cox regression model to reveal the main factors and the risk prediction of the outcome of CIN I at different follow-up times.The results showed that HR-HPV infection was the main factor in the persistence/progression of CIN I at 6 months（h（t）=h₀（t）exp（0.901×HR-HPV））,while the effects of PAHs exposure and HR-HPV infection were more pronounced at 12months（h（t）=h₀（t）exp（0.812×PAHs+1.398×HR-HPV））and 24 months（h（t）=h₀（t）exp（0.834×PAHs+0.952×HR-HPV））.Conclusion:1.This study revealed the natural transformation characteristics of CIN I without clinical treatment.Despite the fact that 79.5%of 564 with CIN I patients occurred lesion reversal,20.5%of the patients still had lesions that persisted or even progressed.And the persistence/progression rates of CIN I showed an increasing trend with the extension of follow-up times.Therefore,It is of great significance to actively seek to the factors of CIN I persistence/progression and early intervene CIN I patients for effectively blocking the process and malignant transformation of cervical carcinogenesis.2.Compared to women with PAHs low exposure,the persistence/progression rates of CIN I was significantly higher in those with high exposure.The increase of 1-OHP levels can promote the persistence of CIN I lesions and even the development of high-grade lesions.In addition,the risks of CIN I persistence/progression gradually increased with the extension of follow-up time,suggesting that PAHs exposure could be considered as an early warning sign for the discovery of cervical precancerosis.It plays an important role for controlling the progression of CIN I to early detect CIN I patients and reduce PAHs exposure levels for them.3.There was a positive additive interaction between PAHs high exposure and HPV or HR-HPV infection on the persistence/progression of CIN I.It suggested that PAHs high exposure on the persistent or malignant transformation of CIN I may be an important promoter independent of HPV infection.Especially,PAHs high exposure with HPV or HR-HPV infection can obviously promote the persistence and even progression of CIN I.In addition,the combined effects of PAHs exposure with HPV or HR-HPV infection were not found in patients at the early stage of the lesion,while manifesting when the lesion progressed to 12 months.So it is of great significance to pay more attention to monitor HPV infection,and meanwhile to strengthen the detection of PAHs levels of these women with HPV infected,for early discovering the progression of cervical lesions,hindering the malignant process of cervical lesions and reducing the morbidity and mortality of cervical cancer.4.Both PAHs exposure and HR-HPV infection played an important early warning role for the persistence/progression of CIN I.When CIN I patients were in the early stage of the lesions,HR-HPV infection had a significant effect on the persistence or malignant transformation of the lesions.When the lesions progressed to 12 months,HR-HPV infection and accumulated PAHs exposure in the environment have the more obvious effects on the malignant transformation of CIN I.It was confirmed again that the key role of HR-HPV infection in cervical carcinogenesis.Meanwhile,PAHs in the environment,a carcinogenic factor commonly exposed in the population,played a significant role in the malignant transformation of cervical lesions with the severity of cervical lesions.