The Influence Of Polycyclic Aromatic Hydrocarbons On Telomere Length And Biomarkers Of Susceptibility

Polycyclic aromatic hydrocarbons(PAHs),as the human carcinogen(Group 1), are primary compounds in coke oven emissions(COEs) generated in the coking process.Long-time exposed to PAHs can lead to several damages.Both epidemiological and experimental studies have shown that PAHs are causally associated with lung cancer among coke-oven workers.Therefore,lung cancer of coke-oven workers has been classified as one of the eight prescribed occupational cancers in China.Prevention of occupational lung cancer is a critical issue. DNA/chromosome damage is an important biologic event of PAH induced carcinogenesis.The variation of telomere length is an important indicator of DNA/chromosome damage early effect.Presently,there are no epidemiological reports on telomere length in peripheral blood among PAH exposed population. Potentially as an early effect-biomarker PAH exposure,the telomere length may play a key role in investigating the association of biomarkers exposure,effect and susceptibility.Studies of biomarkers will be of great importance in understanding of PAH carcinogenesis and improvement of risk assessment.This paper used a real time polymerase chain reaction(RT-PCR) method to determine the DNA telomere length in peripheral blood.The association of telomere length and polymorphisms of CYP1A1,mEH,AHR,XRCC1,FEN1,ERCC1,XPF and XPA gene were studied.The main results are as follows:1.The association between telomere length and PAH exposureA cross-sectional epidemiological design was used to explore the relationship between the telomere length and PAH exposure level in 145 PAH-exposure workers and 68 non-exposure workers.The potential influence on telomere length was analyzed.The telomere length was significantly shorten in PAH exposed workers than that in non-exposure workers(1.10±0.75 vs.1.43±1.06,P=0.026).By respectively using median of urinary 1-OHPyr,CBMN frequency and telomere length as a cut-off value,we have found that the telomere length had a weak correlation with urinary 1-OHPyr and CBMN frequency.The telomere length has shown a linear correlation with urinary 1-OHPyr and CBMN frequency among subjects.We have not found that age,sex,smoking and drinking status and external exposure categories have influence on the DNA telomere length in peripheral blood.2.The association of telomere length and genetic polymorphisms of PAH metabolic geneAfter adjusting for sex,age,cigarettes and 1-OHPyr levels,multivariate analysis of covariance has revealed that there was a significant association between CYP1A1 gene at locus 3801 T＞C,mEH gene at locus Tyr¹¹³His among PAH exposed workers. There was a significant association between at locus rs10250822,rs2282885 of AHR gene polymorphisms and urinary 1-OHPyr.The urinary 1-OHPyr levels of one T_AAGA haplotype carriers were higher than null-T_AAGA carriers.In PAH-exposed workers,the urinary 1-OHPyr levels have shown a linear correlation with the genotypes at locus rs2282885 with adjustment for the same variables.After adjusting for sex,age,cigarettes and 1-OHPyr levels,multivariate analysis of covariance revealed that among coke-oven workers,there was a significant association between locus rs10250822,rs10247158 of AHR gene polymorphisms and telomere length.In PAH-exposed workers,the telomere length has shown a linear correlation with the genotypes at locus rs2282885 with adjustment for the same variables.3.The association of telomere length and genetic polymorphisms of DNA repair geneAfter adjusting for sex,age,cigarettes and 1-OHPyr levels,multivariate analysis of covariance revealed that there was a significant association between polymorphisms of XRCC1 gene at locus C26304T Arg¹⁹⁴Trp,XRCC1 gene at locus G27466A Arg²⁸⁰His,XPA gene at locus A-4G(rs1800975),FEN I gene at locus rs174538 and telomere length among PAH-exposure workers.The multivariate linear regression analysis has revealed that only XRCC1 gene at locus G27466A Arg²⁸⁰His and XPA gene at locus A-4G(rs1800975) polymorphisms were associated with telomere length.We have not found significant difference in telomere length with genotypes at locus ERCC1 Asn¹¹⁸ Asn and XPF Ser⁸³⁵Ser.In summary,the association between DNA telomere length in peripheral blood and PAH exposure was studied.The study of the influence of polymorphisms PAH metabolism and DNA repair gene on the telomere length among coke-oven workers exposed to high level PAHs has suggested that short telomere length may be an early biomarker of effect for DNA/chromosome damage.The change of telomere length is an important biological incident of PAHs carcinogenesis.The result is important for future studies in genetic susceptibility of occupational or environmental diseases and will facilitate developing biomarkers for improvement of risk assessment.