多环芳烃暴露对端粒长度的影响及易感性生物标志研究
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摘要
多环芳烃(Polycyclic aromatic hydrocarbons,PAHs)已被国际癌症研究署(International Agency for Research on Cancer,IARC)归为“Ⅰ类致癌物”。长期暴露于PAHs可致多种损伤发生,其中焦炉工肺癌是职业性PAHs暴露导致的不良后果中最令人关注的问题。我国已将焦炉工肺癌列入八种法定职业肿瘤之一。DNA/染色体损伤是PAHs暴露到肺癌发生间的重要生物学事件。据文献报道,端粒长度缩短也是DNA/染色体损伤早期效应的重要指标。迄今,尚未见有关职业性PAHs暴露人群端粒长度的分子流行病学研究。探讨端粒长度作为PAHs暴露早期效应标志物,研究PAHs暴露人群端粒长度的暴露-效应-损伤易感性生物学标志的关系有助于更深入地阐明PAHs致癌机制,对提高焦炉作业工人PAHs暴露水平和健康损伤程度的评价,减少PAHs暴露相关健康危害提供科学依据。
本研究采用实时定量聚合酶链反应(Real time polymerase chain reaction,RT-PCR)的方法,测定研究对象外周血全基因组DNA端粒长度,并探讨其与PAHs代谢酶(CYP1A1和mEH)及代谢相关基因(AHR)和DNA修复基因(XRCC1、FEN1、ERCC1、XPF和XPA)多态性的关系。研究结果如下:
一、外周血全基因组DNA端粒长度与多环芳烃暴露的关联研究
采用了横断面分子流行病学设计,探讨了145名PAHs暴露工人和68名非暴露者的外周血全基因组DNA端粒长度,分析了端粒长度与多环芳烃暴露水平的关系及可能的影响因素。结果显示,暴露组端粒长度显著短于非暴露组(1.10±0.75 vs.1.43±1.06,P=0.026)。以全部研究对象的尿1-OHPyr浓度、CBMN率和端粒长度的中位数为界值,进一步分析它们之间的关系,发现端粒长度与尿1-0HPyr浓度或CBMN率有负相关性(r分别为-0.136和-0.154),端粒长度有随尿1-OHPyr浓度或CBMN率增高而变短的趋势。同时,未发现年龄、性别、吸烟、饮酒和PAH外暴露等级对暴露组端粒长度的显著影响。
二、多环芳烃暴露工人端粒长度与PAH代谢基因多态性的关联研究
1.校正了性别、年龄、每日吸烟量和尿1-OHPyr后,暴露组CYP1A1基因3801T＞C位点CT基因型个体端粒长度(1.25±0.93)显著长于TT基因型(0.93±0.51,P=0.043),mEH基因Tyr~(113)His位点Tyr/His基因型个体端粒长度(1.25±0.93)显著短于Tyr/Tyr基因型(0.93±0.51,P=0.043);
2.校正了性别、年龄、每日吸烟量和PAHs外暴露等级后,暴露组AHR基因rs10250822位点和rs2282885位点CT基因型个体尿1-OHPyr水平显著低于TT基因型(分别为9.83±1.05 vs.14.48±1.29μmol/mol Cr,P=0.032:10.37±1.01 vs.13.51±1.23μmol/mol Cr,P=0.044),具有1条T_A_A_G_A单体型的个体尿1-OHPyr水平(14.06±1.20)显著高于具有0条该种单体型的个体(10.82±1.12,P=0.037);趋势性检验发现,rs2282885位点个体尿中1-OHPyr水平有随着基因型TT→CT→CC逐渐降低的趋势(P_(trend)=0.041)。校正了性别、年龄、每日吸烟量和尿1-OHPyr后,暴露组AHR基因rs10250822位点CT基因型个体端粒长度(1.02±0.64)显著短于TT基因型(1.36±1.14,P=0.044);rs10247158位点AT基因型个体端粒长度(0.93±0.54)显著短于AA基因型(1.19±0.84,P=0.047),趋势性检验发现,rs2282885位点个体外周血全基因组DNA端粒长度有随着基因型TT→CT→CC逐渐缩短的趋势(P_(trend)=0.040)。
三、多环芳烃暴露工人端粒长度与DNA修复基因多态性的关联研究
校正了性别、年龄、每日吸烟量和尿1-OHPyr后,XRCC1基因C26304TArg~(194)Trp位点CT基因型个体端粒长度(0.98±0.62)显著短于CC基因型(1.27±0.83,P=0.025);XRCC1基因G27466A Arg~(280)His位点GA基因型个体端粒长度(1.50±1.02)显著长于GG基因型(1.01±0.64,P=0.004);FEN1基因rs174538位点AA基因型个体端粒长度(2.16±1.44)显著长于GG基因型(1.17±0.83,P=0.029);XPA基因A-4G(rs1800975)位点AG基因型个体端粒长度(0.99±0.65)显著短于AA基因型(1.40±0.93,P=0.005)。趋势性检验发现,XRCC1基因G27466A Arg~(280)His和XPA基因A-4G(rs1800975)位点的个体外周血全基因组DNA端粒长度有随着突变等位基因增多而改变的趋势(P_(trend)=0.002和P_(trend)=0.033)。未发现ERCC1 Asn~(183)Asn位点和XPF基因Ser~(835)Ser位点多态性与外周血全基因组DNA端粒长度有显著性关联(P＞0.05)。
总之,本研究在PAHs暴露工人中开展了外周血全基因组DNA端粒长度的研究。系统地研究了AHR基因多态性与尿1-OHPyr水平和外周血全基因组DNA端粒长度的关系,揭示了AHR基因变异对PAHs代谢通路及DNA/染色体损伤效应的影响。探讨了PAHs代谢酶基因和DNA修复酶基因多态性对端粒长度的影响。发现端粒长度缩短可能是DNA/染色体损伤效应的早期生物标志物,也可能是PAHs致癌过程中的重要生物学事件,为PAHs暴露工人遗传损伤效应易感性研究以及人群危险度评价提供了新的效应指标。
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 exposure
A 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 gene
After 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 Tyr~(113)His 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_A_A_G_A haplotype carriers were higher than null-T_A_A_G_A 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 gene
After 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 Arg~(194)Trp,XRCC1 gene at locus G27466A Arg~(280)His,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 Arg~(280)His 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 Asn~(118) Asn and XPF Ser~(835)Ser.
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.
本研究采用实时定量聚合酶链反应(Real time polymerase chain reaction,RT-PCR)的方法,测定研究对象外周血全基因组DNA端粒长度,并探讨其与PAHs代谢酶(CYP1A1和mEH)及代谢相关基因(AHR)和DNA修复基因(XRCC1、FEN1、ERCC1、XPF和XPA)多态性的关系。研究结果如下:
一、外周血全基因组DNA端粒长度与多环芳烃暴露的关联研究
采用了横断面分子流行病学设计,探讨了145名PAHs暴露工人和68名非暴露者的外周血全基因组DNA端粒长度,分析了端粒长度与多环芳烃暴露水平的关系及可能的影响因素。结果显示,暴露组端粒长度显著短于非暴露组(1.10±0.75 vs.1.43±1.06,P=0.026)。以全部研究对象的尿1-OHPyr浓度、CBMN率和端粒长度的中位数为界值,进一步分析它们之间的关系,发现端粒长度与尿1-0HPyr浓度或CBMN率有负相关性(r分别为-0.136和-0.154),端粒长度有随尿1-OHPyr浓度或CBMN率增高而变短的趋势。同时,未发现年龄、性别、吸烟、饮酒和PAH外暴露等级对暴露组端粒长度的显著影响。
二、多环芳烃暴露工人端粒长度与PAH代谢基因多态性的关联研究
1.校正了性别、年龄、每日吸烟量和尿1-OHPyr后,暴露组CYP1A1基因3801T＞C位点CT基因型个体端粒长度(1.25±0.93)显著长于TT基因型(0.93±0.51,P=0.043),mEH基因Tyr~(113)His位点Tyr/His基因型个体端粒长度(1.25±0.93)显著短于Tyr/Tyr基因型(0.93±0.51,P=0.043);
2.校正了性别、年龄、每日吸烟量和PAHs外暴露等级后,暴露组AHR基因rs10250822位点和rs2282885位点CT基因型个体尿1-OHPyr水平显著低于TT基因型(分别为9.83±1.05 vs.14.48±1.29μmol/mol Cr,P=0.032:10.37±1.01 vs.13.51±1.23μmol/mol Cr,P=0.044),具有1条T_A_A_G_A单体型的个体尿1-OHPyr水平(14.06±1.20)显著高于具有0条该种单体型的个体(10.82±1.12,P=0.037);趋势性检验发现,rs2282885位点个体尿中1-OHPyr水平有随着基因型TT→CT→CC逐渐降低的趋势(P_(trend)=0.041)。校正了性别、年龄、每日吸烟量和尿1-OHPyr后,暴露组AHR基因rs10250822位点CT基因型个体端粒长度(1.02±0.64)显著短于TT基因型(1.36±1.14,P=0.044);rs10247158位点AT基因型个体端粒长度(0.93±0.54)显著短于AA基因型(1.19±0.84,P=0.047),趋势性检验发现,rs2282885位点个体外周血全基因组DNA端粒长度有随着基因型TT→CT→CC逐渐缩短的趋势(P_(trend)=0.040)。
三、多环芳烃暴露工人端粒长度与DNA修复基因多态性的关联研究
校正了性别、年龄、每日吸烟量和尿1-OHPyr后,XRCC1基因C26304TArg~(194)Trp位点CT基因型个体端粒长度(0.98±0.62)显著短于CC基因型(1.27±0.83,P=0.025);XRCC1基因G27466A Arg~(280)His位点GA基因型个体端粒长度(1.50±1.02)显著长于GG基因型(1.01±0.64,P=0.004);FEN1基因rs174538位点AA基因型个体端粒长度(2.16±1.44)显著长于GG基因型(1.17±0.83,P=0.029);XPA基因A-4G(rs1800975)位点AG基因型个体端粒长度(0.99±0.65)显著短于AA基因型(1.40±0.93,P=0.005)。趋势性检验发现,XRCC1基因G27466A Arg~(280)His和XPA基因A-4G(rs1800975)位点的个体外周血全基因组DNA端粒长度有随着突变等位基因增多而改变的趋势(P_(trend)=0.002和P_(trend)=0.033)。未发现ERCC1 Asn~(183)Asn位点和XPF基因Ser~(835)Ser位点多态性与外周血全基因组DNA端粒长度有显著性关联(P＞0.05)。
总之,本研究在PAHs暴露工人中开展了外周血全基因组DNA端粒长度的研究。系统地研究了AHR基因多态性与尿1-OHPyr水平和外周血全基因组DNA端粒长度的关系,揭示了AHR基因变异对PAHs代谢通路及DNA/染色体损伤效应的影响。探讨了PAHs代谢酶基因和DNA修复酶基因多态性对端粒长度的影响。发现端粒长度缩短可能是DNA/染色体损伤效应的早期生物标志物,也可能是PAHs致癌过程中的重要生物学事件,为PAHs暴露工人遗传损伤效应易感性研究以及人群危险度评价提供了新的效应指标。
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 exposure
A 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 gene
After 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 Tyr~(113)His 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_A_A_G_A haplotype carriers were higher than null-T_A_A_G_A 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 gene
After 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 Arg~(194)Trp,XRCC1 gene at locus G27466A Arg~(280)His,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 Arg~(280)His 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 Asn~(118) Asn and XPF Ser~(835)Ser.
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.
引文
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