羟基萘和3-羟基菲作为多环芳烃暴露标志物的研究
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摘要
致突变和致癌性的多环芳烃(Polycyclic aromatic hydrocarbons, PAHs)的职业暴露是职业肺癌的主要原因,例如焦炉逸散物(Coke oven emission, COE)中含有的致突变和致癌性的多环芳烃(Polycyclic aromatic hydrocarbons, PAHs)是导致焦炉工肺癌的主要原因。焦化生产已被国际癌症研究署(International Agency for Research on Cancer, IARC)归为“1类致癌物”,即“明确的人类致癌物”。反应暴露水平的生物标志物在PAHs接触工人危险度评价的危害性鉴定、剂量-反应评定、接触评定等环节起重要作用。因此,以PAHs代谢为基础,研究其外暴露标志物,寻找PAHs新的暴露标志物,对于精确的定量评价PAHs暴露水平,评价接触标志物与生物效应之间的关系,以及进行PAHs暴露危险度评价具有重要意义。
本论文建立了尿中羟基萘和3-羟基菲的液相色谱质谱检测方法,采用横断面分子流行病学设计探讨了147名PAHs暴露工人和58名非PAHs暴露工人尿中羟基萘和3-羟基菲与外暴露等级之间的关系,分析了与常用暴露标志物1-羟基芘之间的相关性；探讨了暴露标志物羟基萘和3-羟基菲与遗传损伤效应标志物(彗星Olive尾矩和基因组不稳定指标)和易感性生物标志物(外源性化学物代谢酶基因多态性)之间的关系。结果如下：
一、羟基萘和3-羟基菲检测方法与暴露标志物研究
建立了以氘代1-羟基萘为内标,用液相色谱质谱法同时测定尿中2-羟基萘、1-羟基萘和3-羟基菲的方法。本方法的检出限分别是0 .2μg/L、0.2μg/L和0.1μg／L；各指标的回收率在97.4%-103.0%范围内,批内精密度和批间精密度分别在1.4%-3.9%和1.8%-5.8%的范围内,该方法具有较高的准确度和精密度。
用该方法检测147名PAHs暴露人群和58名非PAHs暴露人群尿中羟基萘和3-羟基菲,分析用肌酐水平校正后的尿中羟基萘和3-羟基菲等代谢产物浓度与作业环境中萘和菲的暴露等级关系。结果显示PAHs暴露人群尿中羟基萘和3-羟基菲浓度显著高于对照人群,并且与外暴露等级间存在一定的剂量反应关系,其浓度存在非焦炉工<炉底工<炉侧工<炉顶工的变化趋势。羟基萘和3-羟基菲与常用暴露标志物1-羟基芘之间具有很好的相关性,相关系数分别是0.593,P<0.01和0.772,P<0.01。对影响因素的分析发现吸烟不影响尿中3-羟基菲的浓度。
本研究表明尿中羟基萘和3-羟基菲可较好的反映多环芳烃暴露的内剂量水平,可以作为常用暴露标志物1-羟基芘的有效补充。
二、羟基萘和3-羟基菲与遗传损伤效应标志物的关联研究
分析了羟基萘和3-羟基菲与反映染色体损伤的双核细胞中微核、核芽和核质桥总数以及反映DNA损伤的Olive尾距等遗传损伤效应标志物之间的相关性。
将尿3-羟基菲浓度按照四分位法分为四个内暴露等级,基因组不稳定指标双核细胞中微核、核芽和核质桥总数有随内剂量水平增加而升高的趋势；Olive尾距也有随3-羟基菲水平增加而升高的趋势,但趋势不明显。在所有研究对象中,尿中3-羟基菲与基因组不稳定指标具有良好相关性(r=0.644,P<0.01),与Olive尾距有一定的相关性(r=0.253,P<0.01)；但进一步分层分析仅在PAHs接触人群中发现3-羟基菲与基因组不稳定指标具有明显的相关性(r=0.295,P<0.01)。
将尿羟基萘浓度按照四分位法分为四个内暴露等级,基因组不稳定指标双核细胞中微核、核芽和核质桥总数有随内剂量水平增加而升高的趋势；未发现Olive尾距随羟基萘水平增加而升高的趋势。在全体研究对象中,尿中羟基萘与基因组不稳定指标具有良好相关性(r=0.450,P<0.01),与Olive尾距具有一定的相关性(r=0.207,P=0.005)。
三、羟基萘和3-羟基菲与外源性化学物代谢酶基因多态性的关系
外源性化学物代谢酶中存在大量的单核苷酸多态性(SNPs),部分外源性化学物代谢酶的基因多态性可影响个体对PAHs的代谢能力。本研究分析了参与萘和菲代谢过程的CYP1A1、CYP2E1、mEH和GST、NQO1等Ⅰ相和Ⅱ相代谢酶常见基因多态性位点与PAHs暴露人群尿中3-羟基菲和羟基萘水平的关系。
在PAHs暴露人群中具有细胞色素P450 1A1 (CYP1A1)基因Val462突变型的尿中3-羟基菲浓度显著高于野生型个体(P=0.035)；未发现Ⅱ相代谢酶与尿中3-羟基菲浓度的相关性。环氧化物水化酶(mEH)外显子3基因His113突变型的尿中羟基萘浓度显著高于野生型个体(P=0.015),而在非PAHs暴露人群中mEH外显子3基因His113突变型的尿中羟基萘浓度低于杂合子型个体(P=0.049),可能mEH外显子3基因His113多态性在影响萘的代谢方面存在环境-基因交互作用；未发现Ⅱ相代谢酶与尿中3-羟基菲浓度的相关性。
总之,本研究建立了液相色谱质谱法同时测定尿中2-羟基萘、1-羟基萘和3-羟基菲的方法,发展了新的生物标志物并进行了现场验证。分析了尿中羟基萘和3-羟基菲与外暴露环境中萘和菲的暴露等级关系,并探讨了影响其浓度的因素,表明羟基萘和3-羟基菲能够很好的反映萘和菲的暴露剂量,可作为新的多环芳烃暴露标志物应用。本研究还分析了新发现的暴露标志物与遗传损伤效应标志物的关系,进一步验证了其作为内暴露标志物的有效性。
There has been sufficient epidemiological evidence suggesting an etiological link between carcinogenic polycyclic aromatic hydrocarbons (PAHs) exposure and lung cancer risk in exposed workers.Chemicals produced in the coal-coking process has been classified as class 1 carcinogens by International Agency for Research on Cancer (IARC). Exposure biomarkers play an important roles in risk assessment process, such as dose-responds assessment and exposure assessment. Therefore, study on new biomarker of PAHs exposure will be beneficial for understanding of PAH carcinogenesis and improvement of risk assessment.
In this cross-sectional molecular epidemiologically designed study, We establish an HPLC-MS/MS analysis method for simultaneous determination of urinary monohydroxy metabolites of PAHs. Base on this method, urinary monohydroxy metabolites were quantified among 147 PAHs exposed workers and 58 unexposed controls. We investigated the relationship between naphthol and 3-phenanthrol with exposure level, correlation with 1-hydroxypyrene. The relationship between naphthol and 3-phenanthrol with biomarkers of effect (Olive tail moment and genomic instability parameter) and biomarkers of susceptibility (genetic polymorphisms of metabolic enzymes) were investigated. The main results are as follows:
Part 1. Naphthol and 3-phenanthrol determination method and study of exposure biomarker
Use naphthol-d8 as the internal standard, establish an HPLC-MS/MS method for the simultaneous determination of urinary monohydroxy metabolites of PAHs, namely 1-naphthol,2-naphthol and 3-phenanthrol, the limits of quantification(LOQ) was 0.2μg/L for 1-naphthol,2-naphthol and 1-pyrenol, LOQ for 3-phenanthrol was O.1μg/L. Internal standard calibration help the method has good reproducibility and precision, recovery of target compounds range from 97.4%to 103.0%, intra-and inter-batch precision was 1.4%-3.9% and 1.8%-5.8% respectively.
Urinary monohydroxy metabolites quantified among 147 PAHs-exposed workers and 58 unexposed controls was corrected by urinary creatinine.The geometric mean of urinary naphthol and 3-phenanthrol was significant higher in PAHs-exposed workers than in unexposed workers. It was found that Urinary monohydroxy metabolites were well correlated with extra PAHs exposure level. Naphthol (Pearson's r=0.593, P<0.01) and 3-phenanthrol (Pearson's r=0.772, P<0.01) have an significant correlation with 1-hydroxypyrene. Cigarettes smoking was not a confounding factor to affect the concentration of 3-phenanthrol in urine.
The results showed that urinary naphthol and 3-phenanthrol were valid exposure biomarker of PAHs, can serve as an useful complement of the common exposure biomarker 1-hydroxypyrene.
Part 2. Association between naphthol 3-phenanthrol and effective biomarkers of genetic damage induced by PAHs
Urinary 3-phenanthrol were divided into four group according to quartile. Chromosomal damage or instability status (present as the total number of micronuleus, nucleoplasmic bridge and nuclear bud in one thousand binucleated cells) was significiantly increased with the increased concentration of 3-phenanthrol. Olive tail moment was also increased with the increased concentration of 3-phenanthrol but not significiant as instability status. Significiant correlation was found in total population between 3-phenanthrol with instability status(r=0.644, P<0.01) and in PAHs-exposed worker(r=0.295, P<0.01). Correlation between 3-phenanthrol and Olive tail moment was found in total studied population (r=0.295, P<0.01).
Urinary naphthol were divided into four group according to quartile. Chromosomal damage or instability status was significiantly increased with the increased concentration of naphthol, while Olive tail moment was not found this trend. Significiant correlation was found in total population between naphthol with instability status(r=0.450, P<0.01), ther is a certain correlation between naphthol with Olive tail moment in total population (r=0.207, P=0.005).
Part 3. Association between genetic polymorphisms of metabolic enzymes and levels of naphthol and 3-phenanthrol
The gene encoding metabolic enzymes are highly polymorphic and can affect the metabolism of PAHs.We analysis the association between naphthol and 3-phenanthrol with common genetic polymorphisms of metabolic enzymes phaseⅠandⅡincluding cytochrome P450 1A1, cytochrome P450 2E1, microsomal epoxide hydrolase, glutathione S-transferase and NADP quinone oxidoreductasel.The enzymes are involving in the metabolic process of nathlene and phenanthrene.
Among PAHs-exposed workers, there was a significant association between Val462 allele of CYP1A1 gene and increased urinary 3-phenanthrol level (P=0.035). We have not found significant association between 3-phenanthrol with polymorphism of phaseⅡenzymes.
Among PAHs-exposed workers, the significant association was found between His113 allele on exon 3 of mEH gene and the level of naphthol was higher which has His/His genetype than which has Tyr/His genetype (P=0.015). However, among non PAHs-exposed workers, there was an association between His113 allele on exon 3 of mEH gene (P=0.049) and the naphthol level was lower which has His/His genetype than which has Tyr/His genetype. The different effects of genetic polymorphisms on naphthol level between PAHs-exposed workers and non-PAHs-exposed workers suggested the existence of genetic polymorphisms and gene-environment interactions. We have not found significant association between level of naphthol with polymorphism of phaseⅡenzymes.
In summary, the HPLC-MS/MS method for simultaneous detecting urinary was established, The new new biomarker was developed and validated.We investigated the relationship between naphthol and 3-phenanthrol with environmental exposure level, and explored the factors of affecting their concentration.The results indicated that naphthol and 3-phenanthrol can reflecte the environmental exposure of PAHs well, can be used as new exposure biomarker. The study also explored the relationship between new exposure biomarker with effect biomarkers and genetic polymorphisms of metabolic enzymes, which further validated the effectiveness of naphthol and 3-phenanthrol as a new exposure biomarker.
本论文建立了尿中羟基萘和3-羟基菲的液相色谱质谱检测方法,采用横断面分子流行病学设计探讨了147名PAHs暴露工人和58名非PAHs暴露工人尿中羟基萘和3-羟基菲与外暴露等级之间的关系,分析了与常用暴露标志物1-羟基芘之间的相关性；探讨了暴露标志物羟基萘和3-羟基菲与遗传损伤效应标志物(彗星Olive尾矩和基因组不稳定指标)和易感性生物标志物(外源性化学物代谢酶基因多态性)之间的关系。结果如下：
一、羟基萘和3-羟基菲检测方法与暴露标志物研究
建立了以氘代1-羟基萘为内标,用液相色谱质谱法同时测定尿中2-羟基萘、1-羟基萘和3-羟基菲的方法。本方法的检出限分别是0 .2μg/L、0.2μg/L和0.1μg／L；各指标的回收率在97.4%-103.0%范围内,批内精密度和批间精密度分别在1.4%-3.9%和1.8%-5.8%的范围内,该方法具有较高的准确度和精密度。
用该方法检测147名PAHs暴露人群和58名非PAHs暴露人群尿中羟基萘和3-羟基菲,分析用肌酐水平校正后的尿中羟基萘和3-羟基菲等代谢产物浓度与作业环境中萘和菲的暴露等级关系。结果显示PAHs暴露人群尿中羟基萘和3-羟基菲浓度显著高于对照人群,并且与外暴露等级间存在一定的剂量反应关系,其浓度存在非焦炉工<炉底工<炉侧工<炉顶工的变化趋势。羟基萘和3-羟基菲与常用暴露标志物1-羟基芘之间具有很好的相关性,相关系数分别是0.593,P<0.01和0.772,P<0.01。对影响因素的分析发现吸烟不影响尿中3-羟基菲的浓度。
本研究表明尿中羟基萘和3-羟基菲可较好的反映多环芳烃暴露的内剂量水平,可以作为常用暴露标志物1-羟基芘的有效补充。
二、羟基萘和3-羟基菲与遗传损伤效应标志物的关联研究
分析了羟基萘和3-羟基菲与反映染色体损伤的双核细胞中微核、核芽和核质桥总数以及反映DNA损伤的Olive尾距等遗传损伤效应标志物之间的相关性。
将尿3-羟基菲浓度按照四分位法分为四个内暴露等级,基因组不稳定指标双核细胞中微核、核芽和核质桥总数有随内剂量水平增加而升高的趋势；Olive尾距也有随3-羟基菲水平增加而升高的趋势,但趋势不明显。在所有研究对象中,尿中3-羟基菲与基因组不稳定指标具有良好相关性(r=0.644,P<0.01),与Olive尾距有一定的相关性(r=0.253,P<0.01)；但进一步分层分析仅在PAHs接触人群中发现3-羟基菲与基因组不稳定指标具有明显的相关性(r=0.295,P<0.01)。
将尿羟基萘浓度按照四分位法分为四个内暴露等级,基因组不稳定指标双核细胞中微核、核芽和核质桥总数有随内剂量水平增加而升高的趋势；未发现Olive尾距随羟基萘水平增加而升高的趋势。在全体研究对象中,尿中羟基萘与基因组不稳定指标具有良好相关性(r=0.450,P<0.01),与Olive尾距具有一定的相关性(r=0.207,P=0.005)。
三、羟基萘和3-羟基菲与外源性化学物代谢酶基因多态性的关系
外源性化学物代谢酶中存在大量的单核苷酸多态性(SNPs),部分外源性化学物代谢酶的基因多态性可影响个体对PAHs的代谢能力。本研究分析了参与萘和菲代谢过程的CYP1A1、CYP2E1、mEH和GST、NQO1等Ⅰ相和Ⅱ相代谢酶常见基因多态性位点与PAHs暴露人群尿中3-羟基菲和羟基萘水平的关系。
在PAHs暴露人群中具有细胞色素P450 1A1 (CYP1A1)基因Val462突变型的尿中3-羟基菲浓度显著高于野生型个体(P=0.035)；未发现Ⅱ相代谢酶与尿中3-羟基菲浓度的相关性。环氧化物水化酶(mEH)外显子3基因His113突变型的尿中羟基萘浓度显著高于野生型个体(P=0.015),而在非PAHs暴露人群中mEH外显子3基因His113突变型的尿中羟基萘浓度低于杂合子型个体(P=0.049),可能mEH外显子3基因His113多态性在影响萘的代谢方面存在环境-基因交互作用；未发现Ⅱ相代谢酶与尿中3-羟基菲浓度的相关性。
总之,本研究建立了液相色谱质谱法同时测定尿中2-羟基萘、1-羟基萘和3-羟基菲的方法,发展了新的生物标志物并进行了现场验证。分析了尿中羟基萘和3-羟基菲与外暴露环境中萘和菲的暴露等级关系,并探讨了影响其浓度的因素,表明羟基萘和3-羟基菲能够很好的反映萘和菲的暴露剂量,可作为新的多环芳烃暴露标志物应用。本研究还分析了新发现的暴露标志物与遗传损伤效应标志物的关系,进一步验证了其作为内暴露标志物的有效性。
There has been sufficient epidemiological evidence suggesting an etiological link between carcinogenic polycyclic aromatic hydrocarbons (PAHs) exposure and lung cancer risk in exposed workers.Chemicals produced in the coal-coking process has been classified as class 1 carcinogens by International Agency for Research on Cancer (IARC). Exposure biomarkers play an important roles in risk assessment process, such as dose-responds assessment and exposure assessment. Therefore, study on new biomarker of PAHs exposure will be beneficial for understanding of PAH carcinogenesis and improvement of risk assessment.
In this cross-sectional molecular epidemiologically designed study, We establish an HPLC-MS/MS analysis method for simultaneous determination of urinary monohydroxy metabolites of PAHs. Base on this method, urinary monohydroxy metabolites were quantified among 147 PAHs exposed workers and 58 unexposed controls. We investigated the relationship between naphthol and 3-phenanthrol with exposure level, correlation with 1-hydroxypyrene. The relationship between naphthol and 3-phenanthrol with biomarkers of effect (Olive tail moment and genomic instability parameter) and biomarkers of susceptibility (genetic polymorphisms of metabolic enzymes) were investigated. The main results are as follows:
Part 1. Naphthol and 3-phenanthrol determination method and study of exposure biomarker
Use naphthol-d8 as the internal standard, establish an HPLC-MS/MS method for the simultaneous determination of urinary monohydroxy metabolites of PAHs, namely 1-naphthol,2-naphthol and 3-phenanthrol, the limits of quantification(LOQ) was 0.2μg/L for 1-naphthol,2-naphthol and 1-pyrenol, LOQ for 3-phenanthrol was O.1μg/L. Internal standard calibration help the method has good reproducibility and precision, recovery of target compounds range from 97.4%to 103.0%, intra-and inter-batch precision was 1.4%-3.9% and 1.8%-5.8% respectively.
Urinary monohydroxy metabolites quantified among 147 PAHs-exposed workers and 58 unexposed controls was corrected by urinary creatinine.The geometric mean of urinary naphthol and 3-phenanthrol was significant higher in PAHs-exposed workers than in unexposed workers. It was found that Urinary monohydroxy metabolites were well correlated with extra PAHs exposure level. Naphthol (Pearson's r=0.593, P<0.01) and 3-phenanthrol (Pearson's r=0.772, P<0.01) have an significant correlation with 1-hydroxypyrene. Cigarettes smoking was not a confounding factor to affect the concentration of 3-phenanthrol in urine.
The results showed that urinary naphthol and 3-phenanthrol were valid exposure biomarker of PAHs, can serve as an useful complement of the common exposure biomarker 1-hydroxypyrene.
Part 2. Association between naphthol 3-phenanthrol and effective biomarkers of genetic damage induced by PAHs
Urinary 3-phenanthrol were divided into four group according to quartile. Chromosomal damage or instability status (present as the total number of micronuleus, nucleoplasmic bridge and nuclear bud in one thousand binucleated cells) was significiantly increased with the increased concentration of 3-phenanthrol. Olive tail moment was also increased with the increased concentration of 3-phenanthrol but not significiant as instability status. Significiant correlation was found in total population between 3-phenanthrol with instability status(r=0.644, P<0.01) and in PAHs-exposed worker(r=0.295, P<0.01). Correlation between 3-phenanthrol and Olive tail moment was found in total studied population (r=0.295, P<0.01).
Urinary naphthol were divided into four group according to quartile. Chromosomal damage or instability status was significiantly increased with the increased concentration of naphthol, while Olive tail moment was not found this trend. Significiant correlation was found in total population between naphthol with instability status(r=0.450, P<0.01), ther is a certain correlation between naphthol with Olive tail moment in total population (r=0.207, P=0.005).
Part 3. Association between genetic polymorphisms of metabolic enzymes and levels of naphthol and 3-phenanthrol
The gene encoding metabolic enzymes are highly polymorphic and can affect the metabolism of PAHs.We analysis the association between naphthol and 3-phenanthrol with common genetic polymorphisms of metabolic enzymes phaseⅠandⅡincluding cytochrome P450 1A1, cytochrome P450 2E1, microsomal epoxide hydrolase, glutathione S-transferase and NADP quinone oxidoreductasel.The enzymes are involving in the metabolic process of nathlene and phenanthrene.
Among PAHs-exposed workers, there was a significant association between Val462 allele of CYP1A1 gene and increased urinary 3-phenanthrol level (P=0.035). We have not found significant association between 3-phenanthrol with polymorphism of phaseⅡenzymes.
Among PAHs-exposed workers, the significant association was found between His113 allele on exon 3 of mEH gene and the level of naphthol was higher which has His/His genetype than which has Tyr/His genetype (P=0.015). However, among non PAHs-exposed workers, there was an association between His113 allele on exon 3 of mEH gene (P=0.049) and the naphthol level was lower which has His/His genetype than which has Tyr/His genetype. The different effects of genetic polymorphisms on naphthol level between PAHs-exposed workers and non-PAHs-exposed workers suggested the existence of genetic polymorphisms and gene-environment interactions. We have not found significant association between level of naphthol with polymorphism of phaseⅡenzymes.
In summary, the HPLC-MS/MS method for simultaneous detecting urinary was established, The new new biomarker was developed and validated.We investigated the relationship between naphthol and 3-phenanthrol with environmental exposure level, and explored the factors of affecting their concentration.The results indicated that naphthol and 3-phenanthrol can reflecte the environmental exposure of PAHs well, can be used as new exposure biomarker. The study also explored the relationship between new exposure biomarker with effect biomarkers and genetic polymorphisms of metabolic enzymes, which further validated the effectiveness of naphthol and 3-phenanthrol as a new exposure biomarker.
引文
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