氯乙烯作业工人接触评估与遗传损伤风险
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摘要
氯乙烯单体(vinyl chloride monomer, VCM)是一种重要的化工原料,主要用于合成聚氯乙烯。随着石油工业的迅速发展,氯乙烯的产量在全球直线上升。我国目前年产量约占全球产量的1/10,已成为世界聚氯乙烯生产大国。因此,庞大的职业接触氯乙烯人群的健康问题值得关注。
VCM是确定的人类致癌剂,可导致多系统、多器官肿瘤的发生。对其致癌机制的研究认为主要是VCM活性代谢产物导致遗传物质损伤而启动致癌过程。目前,发达国家VCM职业接触限值多为1ppm (2.79mg/m3, PEL),而我国VCM时间加权平均容许浓度(PC-TWA)为10mg/m3,短时间接触容许浓度为(PC-STEL)20mg/m3,高于西方国家卫生标准数倍。在我国现行卫生标准接触浓度情况下,能否对接触工人的遗传物质产生损害作用需进一步探讨。而且在同样接触条件下,并不是所有个体都会发生遗传损伤乃至肿瘤,提示接触VCM个体肿瘤的遗传易感性不同。外来化学物对机体的效应具有个体差异,目前研究较多的是有关氯乙烯代谢酶类的多态性。已有部分DNA修复基因多态性与氯乙烯所致损伤关系的报道。有关研究多是基因单个位点的报道,同一基因多个位点及其单体型以及不同基因之间及环境交互作用的分析较少。每个人DNA损伤修复能力的差异是决定该个体遗传损伤易感性的一个因素,通过对氯乙烯作业工人DNA损伤修复能力的检测,就能早期发现易感个体,保护易感工人的健康。
本研究通过对接触VCM工人累积接触剂量的较准确计算,来评估累积接触剂量和VCM作业工人肝损伤及染色体损伤之间的关系,探讨接触较低浓度VCM时的主要效应标志物；通过人群研究探讨DNA损伤修复基因与VCM致遗传物质损伤之间的关系,为寻找易感性标志物,早期发现易感人群,提供基础研究资料。
本次研究对象包括山东某化工企业VCM接触工人人数335例(男272例,女63例),该企业对照人数165例(男119例,女46例)以及健康对照人群41例(男20例,女21例)；通过参与健康监护体检对VCM接触工人的肝功能(血清丙氨酸氨基转移酶,ALT)和肝B超情况进行分析,结果显示VCM接触组和对照组肝功能检测结果差异无统计学意义,肝B超结果虽然有统计学差异(P<0.05),但是缺乏特异性,且对化学致癌物引起遗传损伤的针对性差。在目前职业性VCM接触水平较低的情况下,肝功能和肝B超检测结果不能作为VCM接触的特异指标,但这两项指标在VCM职业工人健康监护中仍有一定意义。
本次研究对143例VCM接触工人(男129例,女14例)血清中氧化损伤标志物8-OHdG进行了检测,结果显示该指标在男女间有统计学差异(P<0.05),但是不同接触组间没有显著统计学差异,本结果显示血清8-OHdG不能作为氯乙烯敏感的损伤指标,须在以后的调查研究中仔细考虑吸烟,饮酒,性别,年龄等多个影响因素,才可以判断是否能够将8-OHdG作为有效的生物标志。
利用胞质分裂阻滞微核试验方法(简称CB微核试验)对VCM接触工人和对照人群染色体损伤进行检测,共成功获得494例(接触组317例,对照组177例)微核结果,分析显示VCM接触组外周血淋巴细胞微核细胞率(简称微核率),显著高于对照组FR=2.31(95%CI 1.81-3.01),P<0.01,提示外周血淋巴细胞微核率可以作为评价低浓度VCM接触的效应指标。
基准剂量(BMD)分析微核发生率与氯乙烯累积接触剂量关系,分析表明男性氯乙烯接触总剂量基准剂量95%可信区间下限(BMDL)为6.37g,女性为5.29g,表明在总接触剂量达到BMDL值时将引起微核损伤。为制定氯乙烯接触限值提供了参考。该结果还显示出女性相对男性为微核损伤的易感人群。
继而以外周血淋巴细胞微核率作为染色体损伤的效应指标,应用PCR-RFLP和CRS-RFLP法对335名VCM接触工人的DNA损伤修复基因的多态位点进行检测,应用Poisson回归分析和PHASE 2.0.2软件分析各基因多态位点及其双倍型与染色体损伤之间的关系。选择参与碱基切除修复(简称BER)和核苷切除修复(简称NER)过程的8个关键的DNA损伤修复基因：XRCC1、APE1、XPC、XPG、XPA、ERCC1、XPF、XPD,对其15个常见多态位点(BER途径：XRCC1-77C／T, XRCC1Arg194Trp,XRCC1Arg280His,XRCC1Arg399Gln,APE1 Asp148Glu。NER途径：XPA A23G,XPC.PAT,XPC Ala499Val,XPC Lys939Gln,XPD Met199Ile, XPD Asp312Asn,XPD Lys751Gln,XPF 5'-UTR T2063A,XPGExonl5 G-C, ERCC13'-UTR C8092A)进行检测和分析。
结果发现XRCC1 T-77C, XRCC1Arg194Trp, XRCC1Arg280His, XRCC1Arg399Gln基因突变位点为VCM致染色体损伤的危险因素。与XRCC1-77TT基因型携带者相比,XRCC1-77CT和XRCC-77CC基因型携带者的微核率明显增加,FR=1.29(95%CI 1.14-1.47)P<0.01；与XRCC1 194 Arg/Arg基因型携带者相比,XRCC1 194 Arg/Trp和XRCC1 194 Trp/Trp基因型携带者的微核率明显增加,FR=1.17(95%CI 1.04-1.32)P<0.01；与XRCC1 280 Arg/Arg基因型携带者相比,XRCC1 280 Arg/His和XRCC1 280 His/His基因型携带者的微核率明显增加,FR=1.28(95%CI 1.13-1.44)P<0.01；与XRCC1 399 Arg/Arg基因型携带者相比,XRCC1 399 Arg/Gln和XRCC1 399 Gln/Gln基因型携带者的微核率明显增加,FR=1.23(95%CI 1.09-1.38)P<0.01。XRCC1各位点杂合基因型和突变基因型可以显著增加个体染色体损伤风险,与氯乙烯累积接触剂量存在交互作用(P<0.01)。个体携带的突变位点数越多,接触剂量越大,微核发生率越高。以XRCC1 T-77C为例,与携带XRCC1 -77TT基因型的低剂量接触组工人相比,携带XRCC1 -77TC或CC基因型的低剂量接触组工人,携带XRCC1 -77TT基因型的高剂量接触组工人以及携带XRCC1 -77TC或CC基因型的高剂量接触组工人微核率依次增加,FR分别为1.16,95%CI=0.94-1.43；FR=1.31,95%CI=1.13-1.52 P<0.01；FR=1.72,95%CI=1.45-2.02 P<0.01.
XRCC1 T-77C, XRCC1Arg194Trp, XRCC1Arg280His, XRCC1Arg399Gln四个多态位点两两之间D'均大于0.7,相互之间紧密连锁。XRCC1 T-77C, XRCC1Arg194Trp, XRCC1Arg280His, XRCC1Arg399Gln四个等位基因双倍型分析结果显示,调整吸烟、饮酒、性别因素后,以TGGG/TGGG作为参比,CAAA/CAAA, TAAA/TAAA, CGAA/CAAA的微核率要明显升高：FR=1.25,95%CI=1.05-1.48 P<0.05；FR=1.31,95%CI=1.04-1.65 P<0.05；FR=1.56,95%CI=1.07-2.19 P<0.05。说明这些双倍型人群为VCM致染色体损伤的易感人群,应加强监护。
调整混杂因素如年龄、性别、累计接触剂量以及吸烟、饮酒等因素后,而XPCPAT, XPF 5'-UTR T2063A两个基因的突变位点是遗传损伤的保护因素,与野生纯合型比较,FR=0.82,95%CI=0.69-0.98和FR=0.80,95%CI=0.67-0.95(P<0.05),而XPA A23G和XPC Lys939Gln两个基因的突变位点为VCM致染色体损伤的危险因素,与野生纯合型比较FR=1.20,95%CI=1.03-1.40和FR=1.30,95%CI=1.05-1.62(P<0.05)。
各位点基因型与累积接触量对微核率联合效应分析表明,与携带各多态位点野生基因型的低接触组工人相比,携带XPA A23G,XPC Ala499Val,,XPC Lys939Gln,XPD Met199Ile,XPD Lys751Gln,XPGExon15G-C,ERCC13'-UTRC8092A杂合基因型或突变基因型的低接触组工人,以及携带杂合基因型或突变基因型的高接触组工人微核率增加显著。接触剂量越高,携带的突变位点数越多,遗传损伤发生的风险越大(P<0.05),与BER途径XRCC1各位点情况类似；而携带XPF 5'-UTRT2063A杂合基因型或突变基因型的低接触组工人微核发生率,与携带野生基因型的低接触组工人相比显著降低FR=0.71,95%CI=0.55-0.91P<0.01；携带XPCPAT,XPF 5'-UTRT2063A杂合基因型或突变基因型的高剂量接触组工人微核发生率,与携带野生基因型的高剂量接触组工人相比显著降低(P<0.05)。
XPCPAT、XPC499和XPC939三个多态位点两两之间D'均大于0.7,相互之间紧密连锁。XPCPAT、XPC499和XPC939三个等位基因双倍型分析结果显示,以PAT-CA/PAT-CA作为参比,结果显示稀有类型,PAT+CA/PAT-CA, PAT-AC/PAT-TC,PAT+TC/PAT+TA微核率显著高于PAT-CA/PAT-CA,FR=1.47,95%CI=1.20-1.79 P<0.01；FR=2.73,95%CI=1.95-3.72 P<0.01;FR=1.20,95%CI=1.03-1.40 P<0.05；FR=1.48,95%CI=1.19-1.82 P<0.01,PAT-TC/PAT+TC的微核率显著低于PAT-CA/PAT-CA,FR=0.33,95%CI=0.15-0.62 P<0.01。XPD199、XPD312和XPD751三个等位基因双倍型分析结果显示平衡可能的混杂因素如年龄、性别、累计接触剂量以及吸烟饮酒等因素后,以CCA／CCA作为参比,结果显示CCC／CCC,ATA／CTA微核率显著高于CCA／CCA,FR=1.34,95%CI=1.10-1.63 P<0.01;FR=1.55,95%CI=1.06-2.18 P<0.05。
综上所述,在我国现行职业卫生标准下,VCM仍可对遗传物质产生损伤；DNA损伤修复基因多态与VCM致染色体损伤有关。
Vinyl chloride monomer (CH2=CHC1, VCM) is widely used in industry,95% of vinyl chloride was polymerized to polyvinyl chloride (PVC). China is one of the important PVC production countries, and its annual production accounts for about 10% of the global production. So the health of VCM exposed workers should be paid more attention.
VCM is a certain human carcinogen and it has been proved to be a multi-organ and multi-system carcinogen. The mechanism of carcinogenesis was presumed to be related to the genetic material damage induced by electrophilic metabolites of VCM. At present, the permissible exposure limit (PEL)of VCM in developed countries is 1 ppm (2.79mg/m3), while the STEL and TWA in China are 20mg/m3 and 10mg/m3 respectively. This study analyzed occupational health effects in VCM-exposed workers whose exposure level was lower than the national occupational health standard. Since VCM is a human carcinogen, the majority of VCM-exposed workers do not develop neoplasm, suggesting the susceptibility is modulated, at least in part, by polymorphisms in genes encoding metabolic enzymes, DNA repair proteins. Many studies have been done to investigate the effect of genetic polymorphisms of genes involved in VCM metabolism. But only a few studies paid attention to the DNA repair genes, and to our knowledge, there was limited reports concerning the interaction effect of genetic polymorphisms and exposure dose.
In order to explore effect biomarkers under low level VCM exposure, this study evaluated the relationship between the cumulative exposure dose and VCM-induced liver lesion, chromosome damage in exposure groups (335 individuals:male 272 and female 63) and control groups (165 indivuals:male 119 and female 46) of this company as well as health groups (41indivuals:male 20 and female 21). Occupational epidemiological study was performed to investigate the relationship between chromosome damage induced by VCM and polymorphisms of DNA damage repair genes, in order to provide scientific evidence to screen the susceptible workers.
Using ALT as an indicator of liver function and liver ultrasonography to detect liver morphological changes, we found VCM exposure was not associated with ALT level. Although liver morphological changes had statistical difference between the exposure and control groups (P<0.05), this result lacked of specificity.
Concentration of 8-OHdG, which is a well-known biomarker of oxidative damage in serum, was also detected in parts of workers (143 indivuals:male 129 and female 14). No difference was observed among different cumulative exposure individuals (P>0.05), even there was a statistical difference in gender (P<0.05). This substance in serum was not available to be a sensitive biomarker for VCM exposed in this study.
Cytokinesis-block micronucleus (CB-MN) assay were used to detect chromosome damage and DNA damage of the peripheral blood lymphocyte in VCM-exposed workers. The results showed that the frequency of CB-MN in VCM-exposed group were significantly higher than the control groups FR=2.31 (95%CI 1.81-3.01), P<0.01. So the frequency of CB-MN of peripheral blood lymphocyte can be used as an effect biomarker under low level VCM exposure.
Moreover, the dose-response relationship between cumulative exposure dose and CBMN frequency in all individuals was analyzed with benchmark dose (BMD) methods. Results showed cumulative exposure dose and MN frequency had dose-response relationship, also the benchmark dose low (BMDL) for male and female was 6.37g and 5.29g respectively. Female had more susceptibility for CBMN damage than male workers. The BMDL dose in this study provided possible reference for further national standard.
Next, PCR-RFLP and CRS-RFLP were used to detect polymorphisms of DNA repair genes related to VCM-induced DNA damage. Using Poisson regression analysis, we analyzed the relationship between polymorphism of DNA repair genes and the frequency of CB-MN. The PHASE 2.0.2 software was used to obtain maximum-likelihood estimates of the haplotype frequencies.
In this study, we detected the polymorphism of eight DNA repair genes:XRCC1、APE1、XPC、XPG、XPA、ERCC1、XPF、XPD, which play important role in the pathways of base excision repair (BER) and nucleus excision repair (NER).
When the confounding factors such as age, gender, VCM exposure, drinking and smoking habits were adjusted, the MN frequency in subjects with XRCC1 T-77C, XRCC1Arg194Trp, XRCC1Arg280His, XRCC1Arg399Gln mutant homozygous and heterozygous is higher than their homozygous counterparts (P<0.05). XRCC1-77CT and CC, FR=1.29 (95%CI 1.14-1.47) P<0.01; XRCC1 194 Arg/Trp and Trp/Trp, FR=1.17 (95%CI 1.04-1.32) P<0.01; XRCC1 280 Arg/His and His/His, FR=1.28 (95%CI 1.13-1.44) P<0.01; XRCC1 399 Arg/Gln and XRCC1 399 Gln/Gln, FR=1.23(95%CI 1.09-1.38) P<0.01.
Similar result was showed in the interaction effect of these mutant genotype and exposure dose. Take XRCC1 T-77C for example, compared with XRCC1-77TT genotyope carriers in low exposure dose groups, The MN frequency of XRCC1-77TC or CC genotyope carriers in low exposure dose groups, XRCC1-77TT genotyope carriers in high exposure dose groups, XRCC1-77TC or CC genotyope carriers in high exposure dose groups, were increased. FR=1.16,95%CI 0.94-1.43; FR=1.31, 95%CI 1.13-1.52 P<0.01; FR=1.72,95%CI 1.45-2.02 P<0.01, respectively.
To further elucidate the relevance of XRCC1 variants with MN frequency, linkage disequilibrium (LD) among the four XRCC1 polymorphisms (XRCC1-77 C/T, Arg194Trp, Arg280His, and Arg399Gln) was analyzed and haplotypes were reconstructed. The D'value of the four loci of XRCC1 were 0.716(XRCC1-77 with 194), 0.776(XRCC1-77 with 280), 0.752(XRCC1-77 with 399),0.833 (XRCC1 194 with 280),0.849 (XRCC1 194 with 399), and 0.899(XRCC1 280 with 399). Haplotype analysis demonstrated the MN frequency in subjects with CAAA/CAAA, TAAA/TAAA, CGAA/CAAA was significantly higher than that in subjects with TGGG. FR=1.25, 95%CI 1.05-1.48 P<0.05; FR=1.31,95%CI 1.04-1.65 P<0.05; FR=1.56,95%CI 1.07-2.19 P<0.05, respectively.
The MN frequency in subjects with XPC PAT and XPF T2063A mutant homozygous and heterozygous is lower than their wild-type homozygous counterparts, the frequency ratio (FR) and its 95% confidence interval (95% CI) were 0.82 (0.69-0.98),0.80 (0.67-0.95) respectively(P<0.05). However, MN frequency in subjects with XPA A23G and XPC Lys939Gln mutant homozygous and heterozygous is higher than their wild-type homozygous counterparts, FR and 95%CI were 1.20 (1.03-1.40) and 1.31 (1.05-1.62) respectively (P<0.05). These results suggest XPC PAT and XPF T2063A variant may be protective factors while XPA A23G and XPC Lys939Gln variant may be risk factors for the chromosome damage induced by VCM.
The interaction effect of these mutant genotype and exposure dose showed XPA A23G, XPC Ala499Val,XPC Lys939Gln, XPD Metl99Ile, XPD Lys751Gln, XPGExon15G-C, ERCC13'-UTR C8092A mutant homozygous and heterozygous in low exposure groups and high exposure groups had higher MN frequency than their wild-type homozygous in low exposure groups (P<0.05). While, XPCPAT, XPF 5'-UTRT2063A mutant homozygous and heterozygous in low exposure groups and high exposure groups had lower MN frequency than their wild-type homozygous (P<0.05).
Linkage disequilibrium (LD) analysis among the four XPC polymorphisms (XPC PAT+/-, Ala499Val, Lys939Gln) showed strongly LD between these sites. Haplotype analysis demonstrated the MN frequency in subjects with PAT+CA/PAT-CA, PAT-AC/PAT-TC, and PAT+TC/PAT+TA was significantly higher, FR=2.73,95%CI 1.95-3.72 P<0.01; FR=1.20,95%CI 1.03-1.40 P<0.05; FR=1.48,95%CI 1.19-1.82 P<0.01, while PAT-TC/PAT+TC lower than that in subjects with PAT-CA/PAT-CA, FR=0.33,95%CI 0.15-0.62 P<0.01.
No association of Linkage disequilibrium occurred in XPD(XPD Met199Ile, Asp312Asn, Lys751Gln). Haplotype analysis of showed the MN frequency in subjects with CCC/CCC, ATA/CTA was significantly higher than that in subjects with CCA/CCA, FR=1.34,95%CI 1.10-1.63 P<0.01; FR=1.55,95%CI 1.06-2.18 P<0.05.
In conclusion, VCM can induce chromosome damage even when the exposure level is lower than the national occupational health standard of China; the polymorphism of DNA damage repair genes may be associated with chromosome damage induced by VCM.
VCM是确定的人类致癌剂,可导致多系统、多器官肿瘤的发生。对其致癌机制的研究认为主要是VCM活性代谢产物导致遗传物质损伤而启动致癌过程。目前,发达国家VCM职业接触限值多为1ppm (2.79mg/m3, PEL),而我国VCM时间加权平均容许浓度(PC-TWA)为10mg/m3,短时间接触容许浓度为(PC-STEL)20mg/m3,高于西方国家卫生标准数倍。在我国现行卫生标准接触浓度情况下,能否对接触工人的遗传物质产生损害作用需进一步探讨。而且在同样接触条件下,并不是所有个体都会发生遗传损伤乃至肿瘤,提示接触VCM个体肿瘤的遗传易感性不同。外来化学物对机体的效应具有个体差异,目前研究较多的是有关氯乙烯代谢酶类的多态性。已有部分DNA修复基因多态性与氯乙烯所致损伤关系的报道。有关研究多是基因单个位点的报道,同一基因多个位点及其单体型以及不同基因之间及环境交互作用的分析较少。每个人DNA损伤修复能力的差异是决定该个体遗传损伤易感性的一个因素,通过对氯乙烯作业工人DNA损伤修复能力的检测,就能早期发现易感个体,保护易感工人的健康。
本研究通过对接触VCM工人累积接触剂量的较准确计算,来评估累积接触剂量和VCM作业工人肝损伤及染色体损伤之间的关系,探讨接触较低浓度VCM时的主要效应标志物；通过人群研究探讨DNA损伤修复基因与VCM致遗传物质损伤之间的关系,为寻找易感性标志物,早期发现易感人群,提供基础研究资料。
本次研究对象包括山东某化工企业VCM接触工人人数335例(男272例,女63例),该企业对照人数165例(男119例,女46例)以及健康对照人群41例(男20例,女21例)；通过参与健康监护体检对VCM接触工人的肝功能(血清丙氨酸氨基转移酶,ALT)和肝B超情况进行分析,结果显示VCM接触组和对照组肝功能检测结果差异无统计学意义,肝B超结果虽然有统计学差异(P<0.05),但是缺乏特异性,且对化学致癌物引起遗传损伤的针对性差。在目前职业性VCM接触水平较低的情况下,肝功能和肝B超检测结果不能作为VCM接触的特异指标,但这两项指标在VCM职业工人健康监护中仍有一定意义。
本次研究对143例VCM接触工人(男129例,女14例)血清中氧化损伤标志物8-OHdG进行了检测,结果显示该指标在男女间有统计学差异(P<0.05),但是不同接触组间没有显著统计学差异,本结果显示血清8-OHdG不能作为氯乙烯敏感的损伤指标,须在以后的调查研究中仔细考虑吸烟,饮酒,性别,年龄等多个影响因素,才可以判断是否能够将8-OHdG作为有效的生物标志。
利用胞质分裂阻滞微核试验方法(简称CB微核试验)对VCM接触工人和对照人群染色体损伤进行检测,共成功获得494例(接触组317例,对照组177例)微核结果,分析显示VCM接触组外周血淋巴细胞微核细胞率(简称微核率),显著高于对照组FR=2.31(95%CI 1.81-3.01),P<0.01,提示外周血淋巴细胞微核率可以作为评价低浓度VCM接触的效应指标。
基准剂量(BMD)分析微核发生率与氯乙烯累积接触剂量关系,分析表明男性氯乙烯接触总剂量基准剂量95%可信区间下限(BMDL)为6.37g,女性为5.29g,表明在总接触剂量达到BMDL值时将引起微核损伤。为制定氯乙烯接触限值提供了参考。该结果还显示出女性相对男性为微核损伤的易感人群。
继而以外周血淋巴细胞微核率作为染色体损伤的效应指标,应用PCR-RFLP和CRS-RFLP法对335名VCM接触工人的DNA损伤修复基因的多态位点进行检测,应用Poisson回归分析和PHASE 2.0.2软件分析各基因多态位点及其双倍型与染色体损伤之间的关系。选择参与碱基切除修复(简称BER)和核苷切除修复(简称NER)过程的8个关键的DNA损伤修复基因：XRCC1、APE1、XPC、XPG、XPA、ERCC1、XPF、XPD,对其15个常见多态位点(BER途径：XRCC1-77C／T, XRCC1Arg194Trp,XRCC1Arg280His,XRCC1Arg399Gln,APE1 Asp148Glu。NER途径：XPA A23G,XPC.PAT,XPC Ala499Val,XPC Lys939Gln,XPD Met199Ile, XPD Asp312Asn,XPD Lys751Gln,XPF 5'-UTR T2063A,XPGExonl5 G-C, ERCC13'-UTR C8092A)进行检测和分析。
结果发现XRCC1 T-77C, XRCC1Arg194Trp, XRCC1Arg280His, XRCC1Arg399Gln基因突变位点为VCM致染色体损伤的危险因素。与XRCC1-77TT基因型携带者相比,XRCC1-77CT和XRCC-77CC基因型携带者的微核率明显增加,FR=1.29(95%CI 1.14-1.47)P<0.01；与XRCC1 194 Arg/Arg基因型携带者相比,XRCC1 194 Arg/Trp和XRCC1 194 Trp/Trp基因型携带者的微核率明显增加,FR=1.17(95%CI 1.04-1.32)P<0.01；与XRCC1 280 Arg/Arg基因型携带者相比,XRCC1 280 Arg/His和XRCC1 280 His/His基因型携带者的微核率明显增加,FR=1.28(95%CI 1.13-1.44)P<0.01；与XRCC1 399 Arg/Arg基因型携带者相比,XRCC1 399 Arg/Gln和XRCC1 399 Gln/Gln基因型携带者的微核率明显增加,FR=1.23(95%CI 1.09-1.38)P<0.01。XRCC1各位点杂合基因型和突变基因型可以显著增加个体染色体损伤风险,与氯乙烯累积接触剂量存在交互作用(P<0.01)。个体携带的突变位点数越多,接触剂量越大,微核发生率越高。以XRCC1 T-77C为例,与携带XRCC1 -77TT基因型的低剂量接触组工人相比,携带XRCC1 -77TC或CC基因型的低剂量接触组工人,携带XRCC1 -77TT基因型的高剂量接触组工人以及携带XRCC1 -77TC或CC基因型的高剂量接触组工人微核率依次增加,FR分别为1.16,95%CI=0.94-1.43；FR=1.31,95%CI=1.13-1.52 P<0.01；FR=1.72,95%CI=1.45-2.02 P<0.01.
XRCC1 T-77C, XRCC1Arg194Trp, XRCC1Arg280His, XRCC1Arg399Gln四个多态位点两两之间D'均大于0.7,相互之间紧密连锁。XRCC1 T-77C, XRCC1Arg194Trp, XRCC1Arg280His, XRCC1Arg399Gln四个等位基因双倍型分析结果显示,调整吸烟、饮酒、性别因素后,以TGGG/TGGG作为参比,CAAA/CAAA, TAAA/TAAA, CGAA/CAAA的微核率要明显升高：FR=1.25,95%CI=1.05-1.48 P<0.05；FR=1.31,95%CI=1.04-1.65 P<0.05；FR=1.56,95%CI=1.07-2.19 P<0.05。说明这些双倍型人群为VCM致染色体损伤的易感人群,应加强监护。
调整混杂因素如年龄、性别、累计接触剂量以及吸烟、饮酒等因素后,而XPCPAT, XPF 5'-UTR T2063A两个基因的突变位点是遗传损伤的保护因素,与野生纯合型比较,FR=0.82,95%CI=0.69-0.98和FR=0.80,95%CI=0.67-0.95(P<0.05),而XPA A23G和XPC Lys939Gln两个基因的突变位点为VCM致染色体损伤的危险因素,与野生纯合型比较FR=1.20,95%CI=1.03-1.40和FR=1.30,95%CI=1.05-1.62(P<0.05)。
各位点基因型与累积接触量对微核率联合效应分析表明,与携带各多态位点野生基因型的低接触组工人相比,携带XPA A23G,XPC Ala499Val,,XPC Lys939Gln,XPD Met199Ile,XPD Lys751Gln,XPGExon15G-C,ERCC13'-UTRC8092A杂合基因型或突变基因型的低接触组工人,以及携带杂合基因型或突变基因型的高接触组工人微核率增加显著。接触剂量越高,携带的突变位点数越多,遗传损伤发生的风险越大(P<0.05),与BER途径XRCC1各位点情况类似；而携带XPF 5'-UTRT2063A杂合基因型或突变基因型的低接触组工人微核发生率,与携带野生基因型的低接触组工人相比显著降低FR=0.71,95%CI=0.55-0.91P<0.01；携带XPCPAT,XPF 5'-UTRT2063A杂合基因型或突变基因型的高剂量接触组工人微核发生率,与携带野生基因型的高剂量接触组工人相比显著降低(P<0.05)。
XPCPAT、XPC499和XPC939三个多态位点两两之间D'均大于0.7,相互之间紧密连锁。XPCPAT、XPC499和XPC939三个等位基因双倍型分析结果显示,以PAT-CA/PAT-CA作为参比,结果显示稀有类型,PAT+CA/PAT-CA, PAT-AC/PAT-TC,PAT+TC/PAT+TA微核率显著高于PAT-CA/PAT-CA,FR=1.47,95%CI=1.20-1.79 P<0.01；FR=2.73,95%CI=1.95-3.72 P<0.01;FR=1.20,95%CI=1.03-1.40 P<0.05；FR=1.48,95%CI=1.19-1.82 P<0.01,PAT-TC/PAT+TC的微核率显著低于PAT-CA/PAT-CA,FR=0.33,95%CI=0.15-0.62 P<0.01。XPD199、XPD312和XPD751三个等位基因双倍型分析结果显示平衡可能的混杂因素如年龄、性别、累计接触剂量以及吸烟饮酒等因素后,以CCA／CCA作为参比,结果显示CCC／CCC,ATA／CTA微核率显著高于CCA／CCA,FR=1.34,95%CI=1.10-1.63 P<0.01;FR=1.55,95%CI=1.06-2.18 P<0.05。
综上所述,在我国现行职业卫生标准下,VCM仍可对遗传物质产生损伤；DNA损伤修复基因多态与VCM致染色体损伤有关。
Vinyl chloride monomer (CH2=CHC1, VCM) is widely used in industry,95% of vinyl chloride was polymerized to polyvinyl chloride (PVC). China is one of the important PVC production countries, and its annual production accounts for about 10% of the global production. So the health of VCM exposed workers should be paid more attention.
VCM is a certain human carcinogen and it has been proved to be a multi-organ and multi-system carcinogen. The mechanism of carcinogenesis was presumed to be related to the genetic material damage induced by electrophilic metabolites of VCM. At present, the permissible exposure limit (PEL)of VCM in developed countries is 1 ppm (2.79mg/m3), while the STEL and TWA in China are 20mg/m3 and 10mg/m3 respectively. This study analyzed occupational health effects in VCM-exposed workers whose exposure level was lower than the national occupational health standard. Since VCM is a human carcinogen, the majority of VCM-exposed workers do not develop neoplasm, suggesting the susceptibility is modulated, at least in part, by polymorphisms in genes encoding metabolic enzymes, DNA repair proteins. Many studies have been done to investigate the effect of genetic polymorphisms of genes involved in VCM metabolism. But only a few studies paid attention to the DNA repair genes, and to our knowledge, there was limited reports concerning the interaction effect of genetic polymorphisms and exposure dose.
In order to explore effect biomarkers under low level VCM exposure, this study evaluated the relationship between the cumulative exposure dose and VCM-induced liver lesion, chromosome damage in exposure groups (335 individuals:male 272 and female 63) and control groups (165 indivuals:male 119 and female 46) of this company as well as health groups (41indivuals:male 20 and female 21). Occupational epidemiological study was performed to investigate the relationship between chromosome damage induced by VCM and polymorphisms of DNA damage repair genes, in order to provide scientific evidence to screen the susceptible workers.
Using ALT as an indicator of liver function and liver ultrasonography to detect liver morphological changes, we found VCM exposure was not associated with ALT level. Although liver morphological changes had statistical difference between the exposure and control groups (P<0.05), this result lacked of specificity.
Concentration of 8-OHdG, which is a well-known biomarker of oxidative damage in serum, was also detected in parts of workers (143 indivuals:male 129 and female 14). No difference was observed among different cumulative exposure individuals (P>0.05), even there was a statistical difference in gender (P<0.05). This substance in serum was not available to be a sensitive biomarker for VCM exposed in this study.
Cytokinesis-block micronucleus (CB-MN) assay were used to detect chromosome damage and DNA damage of the peripheral blood lymphocyte in VCM-exposed workers. The results showed that the frequency of CB-MN in VCM-exposed group were significantly higher than the control groups FR=2.31 (95%CI 1.81-3.01), P<0.01. So the frequency of CB-MN of peripheral blood lymphocyte can be used as an effect biomarker under low level VCM exposure.
Moreover, the dose-response relationship between cumulative exposure dose and CBMN frequency in all individuals was analyzed with benchmark dose (BMD) methods. Results showed cumulative exposure dose and MN frequency had dose-response relationship, also the benchmark dose low (BMDL) for male and female was 6.37g and 5.29g respectively. Female had more susceptibility for CBMN damage than male workers. The BMDL dose in this study provided possible reference for further national standard.
Next, PCR-RFLP and CRS-RFLP were used to detect polymorphisms of DNA repair genes related to VCM-induced DNA damage. Using Poisson regression analysis, we analyzed the relationship between polymorphism of DNA repair genes and the frequency of CB-MN. The PHASE 2.0.2 software was used to obtain maximum-likelihood estimates of the haplotype frequencies.
In this study, we detected the polymorphism of eight DNA repair genes:XRCC1、APE1、XPC、XPG、XPA、ERCC1、XPF、XPD, which play important role in the pathways of base excision repair (BER) and nucleus excision repair (NER).
When the confounding factors such as age, gender, VCM exposure, drinking and smoking habits were adjusted, the MN frequency in subjects with XRCC1 T-77C, XRCC1Arg194Trp, XRCC1Arg280His, XRCC1Arg399Gln mutant homozygous and heterozygous is higher than their homozygous counterparts (P<0.05). XRCC1-77CT and CC, FR=1.29 (95%CI 1.14-1.47) P<0.01; XRCC1 194 Arg/Trp and Trp/Trp, FR=1.17 (95%CI 1.04-1.32) P<0.01; XRCC1 280 Arg/His and His/His, FR=1.28 (95%CI 1.13-1.44) P<0.01; XRCC1 399 Arg/Gln and XRCC1 399 Gln/Gln, FR=1.23(95%CI 1.09-1.38) P<0.01.
Similar result was showed in the interaction effect of these mutant genotype and exposure dose. Take XRCC1 T-77C for example, compared with XRCC1-77TT genotyope carriers in low exposure dose groups, The MN frequency of XRCC1-77TC or CC genotyope carriers in low exposure dose groups, XRCC1-77TT genotyope carriers in high exposure dose groups, XRCC1-77TC or CC genotyope carriers in high exposure dose groups, were increased. FR=1.16,95%CI 0.94-1.43; FR=1.31, 95%CI 1.13-1.52 P<0.01; FR=1.72,95%CI 1.45-2.02 P<0.01, respectively.
To further elucidate the relevance of XRCC1 variants with MN frequency, linkage disequilibrium (LD) among the four XRCC1 polymorphisms (XRCC1-77 C/T, Arg194Trp, Arg280His, and Arg399Gln) was analyzed and haplotypes were reconstructed. The D'value of the four loci of XRCC1 were 0.716(XRCC1-77 with 194), 0.776(XRCC1-77 with 280), 0.752(XRCC1-77 with 399),0.833 (XRCC1 194 with 280),0.849 (XRCC1 194 with 399), and 0.899(XRCC1 280 with 399). Haplotype analysis demonstrated the MN frequency in subjects with CAAA/CAAA, TAAA/TAAA, CGAA/CAAA was significantly higher than that in subjects with TGGG. FR=1.25, 95%CI 1.05-1.48 P<0.05; FR=1.31,95%CI 1.04-1.65 P<0.05; FR=1.56,95%CI 1.07-2.19 P<0.05, respectively.
The MN frequency in subjects with XPC PAT and XPF T2063A mutant homozygous and heterozygous is lower than their wild-type homozygous counterparts, the frequency ratio (FR) and its 95% confidence interval (95% CI) were 0.82 (0.69-0.98),0.80 (0.67-0.95) respectively(P<0.05). However, MN frequency in subjects with XPA A23G and XPC Lys939Gln mutant homozygous and heterozygous is higher than their wild-type homozygous counterparts, FR and 95%CI were 1.20 (1.03-1.40) and 1.31 (1.05-1.62) respectively (P<0.05). These results suggest XPC PAT and XPF T2063A variant may be protective factors while XPA A23G and XPC Lys939Gln variant may be risk factors for the chromosome damage induced by VCM.
The interaction effect of these mutant genotype and exposure dose showed XPA A23G, XPC Ala499Val,XPC Lys939Gln, XPD Metl99Ile, XPD Lys751Gln, XPGExon15G-C, ERCC13'-UTR C8092A mutant homozygous and heterozygous in low exposure groups and high exposure groups had higher MN frequency than their wild-type homozygous in low exposure groups (P<0.05). While, XPCPAT, XPF 5'-UTRT2063A mutant homozygous and heterozygous in low exposure groups and high exposure groups had lower MN frequency than their wild-type homozygous (P<0.05).
Linkage disequilibrium (LD) analysis among the four XPC polymorphisms (XPC PAT+/-, Ala499Val, Lys939Gln) showed strongly LD between these sites. Haplotype analysis demonstrated the MN frequency in subjects with PAT+CA/PAT-CA, PAT-AC/PAT-TC, and PAT+TC/PAT+TA was significantly higher, FR=2.73,95%CI 1.95-3.72 P<0.01; FR=1.20,95%CI 1.03-1.40 P<0.05; FR=1.48,95%CI 1.19-1.82 P<0.01, while PAT-TC/PAT+TC lower than that in subjects with PAT-CA/PAT-CA, FR=0.33,95%CI 0.15-0.62 P<0.01.
No association of Linkage disequilibrium occurred in XPD(XPD Met199Ile, Asp312Asn, Lys751Gln). Haplotype analysis of showed the MN frequency in subjects with CCC/CCC, ATA/CTA was significantly higher than that in subjects with CCA/CCA, FR=1.34,95%CI 1.10-1.63 P<0.01; FR=1.55,95%CI 1.06-2.18 P<0.05.
In conclusion, VCM can induce chromosome damage even when the exposure level is lower than the national occupational health standard of China; the polymorphism of DNA damage repair genes may be associated with chromosome damage induced by VCM.
引文
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