氯乙烯作业工人遗传损伤及其易感性研究
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摘要
氯乙烯(CH_2=CHCl,VCM)在常温、常压下是一种无色、易燃、易爆而略带芳香味的气体,它是人工合成的化学物,在自然界中不能自发产生。VCM作为一种重要的化工原料在全世界得到了广泛的应用,其中约95%的VCM用于生产聚氯乙烯(PVC)。随着石油工业的迅速发展,VCM的产量在全球呈直线上升趋势。我国生产PVC始于1957年,至2007年PVC年产量已达971.7万吨,跃居世界第一位。我国作为PVC生产大国,VCM职业暴露人数众多,庞大的VCM职业接触人群的健康问题值得关注。
由于VCM与肝血管肉瘤(ASL)和肝细胞瘤等肝脏肿瘤的发生有关,国际癌症研究机构(IARC)于1987年将VCM划分为确定的人类致癌物。流行病学调查提示VCM可能是一种多系统、多器官的致癌剂,可诱发人类除ASL外的其他肿瘤如脑肿瘤和肺癌等。VCM作为确定的人类致癌物,其职业危害引起了更为广泛的重视。为了减少VCM对作业工人的职业危害,许多国家采用先进的生产工艺改善了工业卫生条件并加强了对VCM的管理。目前西方绝大多数国家的VCM职业接触限值低于1ppm(约2.79mg/m~3,PEL)。我国的工业场所VCM的时间加权平均容许浓度(PC-TWA)订为10 mg/m~3(GBZ 2.1-2007),高于西方国家卫生标准数倍。探讨在我国现行卫生标准接触浓度下,VCM对作业工人产生的健康损害特别是遗传损伤是十分必要的。研究发现同样的作业环境,同样VCM接触水平的工人中,仅有部分人发生遗传损伤,提示个体对VCM致遗传损伤存在易感性差异。产生遗传损伤易感性差异的原因除了个体年龄、性别、健康和营养状况以及职业和生活环境毒物暴露(如吸烟、饮酒等)等因素外,还包括代谢酶表达差异和DNA修复能力不同。研究表明,在人群中代谢能力和修复能力具有明显的个体差异,这种差异归因于它们的基因多态性差异,可能也是造成个体对环境中VCM遗传毒性易感性不同的主要原因。目前有关VCM代谢酶基因多态与毒性的关系已经研究的比较清楚,但DNA损伤修复基因多态与毒性关系的研究报道尚少,开展这方面的研究将有助于阐明VCM毒作用机制和进行作业工人健康风险评估。
本次研究通过对VCM作业工人累积接触剂量的估算,评估累积接触剂量与职业危害间的关系;通过健康体检、氧化损伤、肝损伤、遗传损伤和血清p53指标的检测来探讨这些指标作为低浓度VCM接触下效应生物标志物的可能性;通过探讨VCM代谢酶和DNA修复酶基因多态性与VCM致遗传损伤的关系,寻找VCM致遗传损伤的易感性生物标志物。
首先,探讨了VCM接触浓度在我国现行卫生标准浓度情况下,作业工人的职业危害。(1)对VCM作业工人的肝功能(血清丙氨酸氨基转移酶,ALT)和肝B超情况进行检测,结果显示VCM接触组和对照组肝功能和肝B超结果差异无统计学意义,认为肝功能和肝B超检查不能作为VCM暴露的敏感指标;(2)以超氧化物歧化酶(SOD)、丙二醛(MDA)和谷胱甘肽硫转移酶(GST)作为VCM致机体损伤的效应生物标志物。多元线性回归分析结果显示,各VCM累积接触剂量组与正常对照组相比,SOD活性显著降低而MDA活性显著增高。低剂量组和高剂量组与对照组相比GST水平显著增高(P＜0.05)。趋势卡方检验结果显示,VCM累积接触剂量与SOD和GST活性间存在明显的剂量-反应关系。此外,高龄是SOD活性降低、MDA活性增高的危险因素,男性也是MDA活性增高的危险因素。认为以血清SOD、MDA和GST作为VCM的效应生物标志物具有一定的科学价值;(3)通过对VCM作业工人淋巴细胞DNA损伤和染色体损伤的检测,评价VCM致遗传损伤情况。采用百分位数法以对照组95%的上限值作为界限值,认为双核微核细胞发生率正常界限值应≤3‰,而彗星细胞率应≤4%,以该界限值作为判断VCM作业工人是否发生遗传损伤的划分标准,超过该界限则认为个体发生了染色体或DNA损伤。DNA损伤和染色体损伤情况与累积接触剂量间存在明显的剂量-反应关系。此外,高龄和女性也成为微核升高的危险因素。本研究认为彗星率和微核率能反映VCM在体内的蓄积情况,淋巴细胞彗星实验和双核微核试验可以作为低浓度VCM接触早期健康损害的敏感指标用于职业人群的生物监测;(4)采用酶联免疫吸附法(ELISA)对研究对象血清中p53蛋白和抗体进行同时检测,分析VCM接触与血清p53指标异常率之间的关系。结果表明,VCM接触组血清p53联合阳性率显著高于对照组,各剂量接触组与对照组相比,高剂量组p53联合阳性率显著高于对照组,认为在高剂量接触时以血清p53阳性指标作为效应生物标志物有一定的意义。
继而应用PCR-RFLP、CRS-RFLP和多重PCR技术对VCM作业工人的代谢酶基因和DNA修复基因多态性进行检测,包括VCM代谢相关的酶类GSTT1、GSTM1、GSTP1、CYP2E1、ADH2和ALDH2等基因,DNA修复类基因OGG1、MGMT,XRCC1、p53和TDG等11个基因共15个多态。通过人群流行病学调查,探讨VCM致DNA损伤与机体代谢酶基因和DNA损伤修复基因多态的关系。用多元Logistic回归筛选DNA损伤的危险因素,分析变量包括代谢酶基因和修复酶基因,及VCM累积接触剂量、年龄、性别、吸烟、饮酒等一般情况等。结果表明,VCM作业工人中GSTP1 GA/GG、CYP2E1 clc2/c2c2、ADH2 AG/GG和MGMT 84 CC基因型携带者与其他相应基因型携带者相比DNA损伤风险显著增加,认为这些基因型可能是VCM致DNA损伤的危险因素。未发现DNA损伤与其他基因型以及年龄、性别、吸烟和饮酒等因素之间的关系。采用PHASE2.0.2软件分析各基因多态位点及其单倍型和双体型与DNA损伤之间的关系。双体型分析结果表明,p53基因WGG/WCG双体型的携带者DNA损伤风险是WGG/WGG双体型携带者2.33倍(OR=2.33,95%CI:1.88-2.89,P＜0.001),而携带WCG/WGG双体型个体DNA损伤风险降低0.42倍(OR=0.42,95%CI:0.35-0.50,P＜0.001)。研究认为p53 WGG/WCG双体型是导致VCM作业工人DNA损伤的危险因素,而WCG/WGG对VCM导致的DNA损伤具有保护作用。
然后以外周血淋巴细胞微核率作为染色体损伤的效应指标,分析VCM代谢酶基因和DNA损伤修复基因多态及相关因素对微核率的影响。多元Poisson逐步回归分析微核危险因素,结果表明年龄和GSTP1、CYP2E1、ALDH2、XRCC1Arg280His等基因多态为染色体损伤的影响因素。在平衡可能混杂因素后,微核率与年龄有关,高龄组(＞35岁)染色体损伤的风险显著高于低龄组(≤35岁)(P＜0.001),调整后的FR值为1.19(1.08—1.30);CYP2E1和XRCC1 Arg280His基因突变型携带者微核的发生危险显著高于野生型个体(P＜0.05),调整后的FR值分别为1.12(1.02—1.24)和1.11(1.01-1.24);GSTP1 GA/AA和ALDH2 GA/AA基因型携带者微核率显著低于其他基因型个体(P＜0.01),调整后的FR值分别为0.74(0.59-0.94)和0.87(0.79-0.95)。本研究认为高龄及GSTP1 GG、CYP2E1clc2/c2c2、ALDH2 GG和XRCC1 280 GA/AA基因型可能是致染色体损伤的危险因素。对XRCC1基因194、280、399三个位点的双体型分析结果显示,以CGG/CGG双体型为参比,CGA/CAG双体型携带者微核率显著增高,说明CGA/CAG双体型携带者可能是VCM作业人群中染色体损伤的易感者。
综上所述,在我国现行职业卫生标准下,VCM仍可产生一定的健康危害。SOD、MDA、GST和血清p53指标可作为接触VCM致机体损伤的效应生物标志物。外周血淋巴细胞彗星细胞率和微核率可作为职业性接触氯乙烯工人健康监护的一种早期检测指标。VCM作业工人遗传损伤的发生是遗传因素、生活习惯、氯乙烯作业综合影响的结果,对VCM作业工人的健康监护应全面考虑这些因素。毒物代谢酶和DNA损伤修复基因多态与VCM致遗传损伤有关,开展这方面的研究有助于VCM致癌机制的阐明,而研究中易感性多态位点的发现也可以为识别易感人群提供理论依据。
Vinyl chloride monomer(CH_2=CHCl,VCM) is a colorless gas and a synthetic chemical that does not naturally occur.At room temperature,it has a mild sweet odor, it burns easily,and it is not stable at high temperatures.VCM is one of the highest production volume chemicals is wildly used in the world.Approximately 95%of all VCM produced is used to manufacture polyvinyl chloride(PVC).With the fast development of petroleum industry,the total output of VCM in the world increased rapidly.In 1957,China began to produce PVC,and the annual output of PVC in China has jumped to the first place in the world with a total annual production of 9.72 millions ton in 2007.China as a leading producer of PVC in the world,thousands of workers could be exposed to VCM.It is necessary to pay more attention to the health of VCM-exposed workers in our country.
VCM exposure has been associated with hepatic angiosarcoma(ASL) and hepatocellular cancer,and was classified as a group 1 carcinogen by IARC in 1987. Recent epidemiological studies have shown VCM is a multi-organ and multi-system carcinogen that induces a wide spectrum of tumors,including ASL and other tumors, brain tumors,and lung cancer.Since VCM is a known carcinogen,it has caused great concern to people who may be exposed to it.To avoid the potential health hazard, many countries have developed some techniques to make a great progress in reducing exposure concentration of VCM.At present,the permissible exposure limit(PEL) of VCM in developed countries is 1 ppm(2.79mg/m~3),and the permissible concentration-time weighted average(PC-TWA) in China is 10mg/m~3.So it is necessary to analyze occupational health effects in VCM-exposed workers whose exposure level was several times higher than the occupational health standard in developed countries.Under the same working environment and VCM-exposed level, only some VCM-exposed workers had got genetic damage,which indicated that there were genetic susceptible differences among the workers.A susceptible population will exhibit a different or enhanced response to VCM than will most persons exposed to the same level of VCM in the environment.Reasons may include age,gender,health and nutritional status,occupational and personal exposures(e.g.,alcohol drinking and cigarette smoking);moreover inherited metabolic and repaired traits may also explain the elevated risk in selected individuals.As we know,genetic polymorphisms related to VCM metabolism and DNA repair may increase the susceptibility of individuals to genotoxicity.Presently,many studies have been conducted to investigate the genotoxicity of VCM and the effect of genetic polymorphisms in genes coding for metabolic enzymes,but only a few studies paid attention to the DNA repair genes. Studies on relationship between genetic damage in VCM-exposed workers and susceptible genotypes of metabolic and/or DNA repair genes have been useful for revealing mechanism of toxicology and evaluation to health risk.
This study evaluated the relationship between VCM exposure and occupational hazards based on calculated cumulative exposure dose of the VCM-exposed workers. In order to explore effect biomarkers under low level VCM exposure,this study investigated the health condition,potential oxidative injury,liver lesion,serum p53 protein and p53-Abs level,as well as genetic damage induced by VCM.Moreover, occupational epidemiological study were performed to study common variants in genes involved in metabolism pathways and DNA repair pathways,to elucidate the relationship between susceptible genotypes of metabolic and/or DNA repair genes and genetic damage in VCM-exposed workers,and to find biomarkers of susceptibility of genetic damage induced by VCM-exposure.
This study investigated occupational health hazards among VCM-exposed workers whose exposure level was lower than the national occupational health standard.(1)Used 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 and liver morphological changes,so they could not be used as an sensitive index of VCM exposure;(2)The levels of superoxide dismutase(SOD), malondialchehyche(MDA) and glutathione S-transferases(GST) in serum were used as the effect biomarkers of VCM exposure.The findings of multiple-linear regression showed that the serum SOD activity of the VCM-exposed groups decreased significantly compared with the control group(P＜0.001),and the amount of MDA increased(P＜0.001).GST activity in the low and high exposure group was significantly higher than that of the control group(P＜0.05).Chi square-test showed that there was a dose-response relationship between serum levels of SOD/GST and the cumulative exposure dose of VCM.Furthermore,advanced age was the risk factor of the lower SOD activity and higher MDA level,and the males'MDA level was significantly elevated compared with females'.The activity of serum SOD,MDA and GST could be used as effect biomarkers when the exposure level is lower than the national occupational health standard of China;(3)Genetic damages of VCM-exposed workers were measured by the single cell gel electrophoresis(SCGE) and cytokinesis-block micronucleus(CBMN).In order to develop a normal reference value of CBMN and comet cells frequencies in cultured peripheral lymphocytes,a threshold of CBMN and comet cell frequency,such as the 95-percentile of the controls CBMN(i.e.3‰) and comet cell(i.e.4%) distribution,maybe used to define chromosomal damage and DNA damage caused by VCM-exposure,above which the CBMN or comet cell frequency may indicate an aberration from being normal,hence indicating chromosomal or DNA damage.Statistics results indicate that mean CBMN frequencies and levels of DNA damage were significantly elevated for the low, intermediate and high VCM-exposure groups compared with that of the controls(P＜0.001).Moreover,multiple Poisson regression analysis showed that a significant increase of micronuclei occurred with age and in females,when occupationally exposed.So the results of CBMN and comet assay of peripheral blood lymphocyte can be used as an early and sensitive biomarker under low level VCM exposure;(4)To determine the relation between VCM exposure and serum p53 biomarkers,this study examined serum samples for the levels of p53 protein and p53 antibodies,using an enzyme-linked immunosorbent assay(ELISA).These biomarkers results suggest that workers with VCM exposure below the current permissible exposure limit have a risk for the occurrence of seropositive for both of the p53 biomarkers is significantly greater than unexposed controls,the presence of both serum p53 biomarkers were greatly elevated in high exposure group compared with that of the normal controls. Serum p53 protein and antibodies may represent suitable biomarkers in assessing the level of occupationally exposure.
Then,PCR-RFLP,CRS-RFLP and multiplex PCR was used to detect polymorphisms of metabolizing enzymes and DNA repair genes.In this study,we detected the 15 polymorphisms in 11 genes:GSTT1、GSTM1、GSTP1、CYP2E1、ADH2 and ALDH2,which participate in the metabolism of VCM;OGG1、MGMT、XRCC1,p53 and TDG,which participate in the process of DNA repair.Occupational epidemiological study was performed to investigate the relationship between DNA damage induced by VCM and polymorphisms of metabolizing enzymes and DNA damage repair genes.Logistic regression analysis was employed to model the relationship between DNA damages and genotypes of xenobiotic metabolizing and DNA repair genes and related indicator among VCM-exposed workers.A prominent risk increasing of DNA damage was observed for those individuals possessing the GSTP1 GA/GG,CYP2E1 clc2/c2c2,ADH2 AG/ GG and MGMT 84 CC genotypes when compared with other genotypes,these genotypes may jointly contribute to the susceptibility of DNA damage.There was no association between DNA damage and other genotypes and gender,age,drinking,smoking.PHASE software(version 2.0.2) was used to obtain maximum-likelihood estimates of the XRCC1 and p53 haplotype frequencies.Diplotype analysis showed that risk of DNA damage increased in the subjects carrying the WGG/WCG diplotype compared with those with the WGG/WGG diplotype of p53 intron 3,exon 4,and intron 6 genes(OR=2.33,95%CI: 1.88-2.89,P＜0.001),the risk of DNA damage for individuals with the WCG/WGG diplotype was 0.42-fold(OR=0.42,95%CI:0.35-0.50,P＜0.001) compared with those with the WGG/WGG diplotype.These implied that WGG/WCG diplotype of p53 is potentially one of the risk factors for DNA damage,and WCG/WGG diplotype of p53 may contribute to resist against DNA damage in VCM-exposed workers.
Moreover,we studied common variants in genes involved in metabolism pathways(phaseⅠand phaseⅡenzymes) and DNA repair pathways,in order to elucidate the relationship between genetic polymorphisms and chromosomal damage in workers exposure to VCM.Poisson analyze showed that five factors that significantly altered CBMN frequencies:GSTP1,CYP2E1,ALDH2,XRCC1 Arg280His genotypes and age.This analysis confirmed the increase in CBMN frequency with age,mean CBMN frequencies were significantly elevated for the older workers compared with yonger workers(P＜0.001).Specifically,subjects with CYP2E1 and XRCC1 Arg280His variance showed higher mean CBMN frequencies compared with their wild-type homozygous counterparts(P＜0.05);those with GSTP1 GG genotype and ALDH2 GG genotype showed higher mean CBMN frequencies than those with other genotypes(P＜0.01).Our findings consider that age and GSTP1,CYP2E1, ALDH2 andXRCC1 Arg280His genotypes are the major factors that modulate CBMN induction in VCM-exposed workers.Diplotype analysis of XRCC1 194,280 and 399 demonstrated that the CBMN frequency in subjects with CGA/CAG diplotype was significantly higher than that in subjects with CGG/CGG(P＜0.001),and CGA/CAG diplotype is potentially one of the risk factors for chromosomal damage in VCM-exposed workers.
In conclusion,VCM can induce some occupational health hazards of workers whose exposure level was lower than the national occupational health standard.The activity of serum SOD,MDA,GST and occurrence of seropositive p53 could be used as effect biomarkers for estimation of in vivo dose of VCM exposure.The CBMN and comet assay seems to be a valuable indicator in the regular health surveillance of VCM-exposed workers.We should pay attention to the genotoxic effect from the aspects such as hereditary factors,lifestyles and VCM performance.The health care of VCM-exposed workers should be given full consideration.Further study to investigate the relationship of individual characteristics and genetic susceptibility with VCM-caused DNA and chromosome damage is warranted,it could help us to understand the mechanism of VCM metabolism and find the biomarkers of susceptibility,which is useful for us to recognize the susceptible individuals in the primary prevention of VCM-caused damage.
由于VCM与肝血管肉瘤(ASL)和肝细胞瘤等肝脏肿瘤的发生有关,国际癌症研究机构(IARC)于1987年将VCM划分为确定的人类致癌物。流行病学调查提示VCM可能是一种多系统、多器官的致癌剂,可诱发人类除ASL外的其他肿瘤如脑肿瘤和肺癌等。VCM作为确定的人类致癌物,其职业危害引起了更为广泛的重视。为了减少VCM对作业工人的职业危害,许多国家采用先进的生产工艺改善了工业卫生条件并加强了对VCM的管理。目前西方绝大多数国家的VCM职业接触限值低于1ppm(约2.79mg/m~3,PEL)。我国的工业场所VCM的时间加权平均容许浓度(PC-TWA)订为10 mg/m~3(GBZ 2.1-2007),高于西方国家卫生标准数倍。探讨在我国现行卫生标准接触浓度下,VCM对作业工人产生的健康损害特别是遗传损伤是十分必要的。研究发现同样的作业环境,同样VCM接触水平的工人中,仅有部分人发生遗传损伤,提示个体对VCM致遗传损伤存在易感性差异。产生遗传损伤易感性差异的原因除了个体年龄、性别、健康和营养状况以及职业和生活环境毒物暴露(如吸烟、饮酒等)等因素外,还包括代谢酶表达差异和DNA修复能力不同。研究表明,在人群中代谢能力和修复能力具有明显的个体差异,这种差异归因于它们的基因多态性差异,可能也是造成个体对环境中VCM遗传毒性易感性不同的主要原因。目前有关VCM代谢酶基因多态与毒性的关系已经研究的比较清楚,但DNA损伤修复基因多态与毒性关系的研究报道尚少,开展这方面的研究将有助于阐明VCM毒作用机制和进行作业工人健康风险评估。
本次研究通过对VCM作业工人累积接触剂量的估算,评估累积接触剂量与职业危害间的关系;通过健康体检、氧化损伤、肝损伤、遗传损伤和血清p53指标的检测来探讨这些指标作为低浓度VCM接触下效应生物标志物的可能性;通过探讨VCM代谢酶和DNA修复酶基因多态性与VCM致遗传损伤的关系,寻找VCM致遗传损伤的易感性生物标志物。
首先,探讨了VCM接触浓度在我国现行卫生标准浓度情况下,作业工人的职业危害。(1)对VCM作业工人的肝功能(血清丙氨酸氨基转移酶,ALT)和肝B超情况进行检测,结果显示VCM接触组和对照组肝功能和肝B超结果差异无统计学意义,认为肝功能和肝B超检查不能作为VCM暴露的敏感指标;(2)以超氧化物歧化酶(SOD)、丙二醛(MDA)和谷胱甘肽硫转移酶(GST)作为VCM致机体损伤的效应生物标志物。多元线性回归分析结果显示,各VCM累积接触剂量组与正常对照组相比,SOD活性显著降低而MDA活性显著增高。低剂量组和高剂量组与对照组相比GST水平显著增高(P＜0.05)。趋势卡方检验结果显示,VCM累积接触剂量与SOD和GST活性间存在明显的剂量-反应关系。此外,高龄是SOD活性降低、MDA活性增高的危险因素,男性也是MDA活性增高的危险因素。认为以血清SOD、MDA和GST作为VCM的效应生物标志物具有一定的科学价值;(3)通过对VCM作业工人淋巴细胞DNA损伤和染色体损伤的检测,评价VCM致遗传损伤情况。采用百分位数法以对照组95%的上限值作为界限值,认为双核微核细胞发生率正常界限值应≤3‰,而彗星细胞率应≤4%,以该界限值作为判断VCM作业工人是否发生遗传损伤的划分标准,超过该界限则认为个体发生了染色体或DNA损伤。DNA损伤和染色体损伤情况与累积接触剂量间存在明显的剂量-反应关系。此外,高龄和女性也成为微核升高的危险因素。本研究认为彗星率和微核率能反映VCM在体内的蓄积情况,淋巴细胞彗星实验和双核微核试验可以作为低浓度VCM接触早期健康损害的敏感指标用于职业人群的生物监测;(4)采用酶联免疫吸附法(ELISA)对研究对象血清中p53蛋白和抗体进行同时检测,分析VCM接触与血清p53指标异常率之间的关系。结果表明,VCM接触组血清p53联合阳性率显著高于对照组,各剂量接触组与对照组相比,高剂量组p53联合阳性率显著高于对照组,认为在高剂量接触时以血清p53阳性指标作为效应生物标志物有一定的意义。
继而应用PCR-RFLP、CRS-RFLP和多重PCR技术对VCM作业工人的代谢酶基因和DNA修复基因多态性进行检测,包括VCM代谢相关的酶类GSTT1、GSTM1、GSTP1、CYP2E1、ADH2和ALDH2等基因,DNA修复类基因OGG1、MGMT,XRCC1、p53和TDG等11个基因共15个多态。通过人群流行病学调查,探讨VCM致DNA损伤与机体代谢酶基因和DNA损伤修复基因多态的关系。用多元Logistic回归筛选DNA损伤的危险因素,分析变量包括代谢酶基因和修复酶基因,及VCM累积接触剂量、年龄、性别、吸烟、饮酒等一般情况等。结果表明,VCM作业工人中GSTP1 GA/GG、CYP2E1 clc2/c2c2、ADH2 AG/GG和MGMT 84 CC基因型携带者与其他相应基因型携带者相比DNA损伤风险显著增加,认为这些基因型可能是VCM致DNA损伤的危险因素。未发现DNA损伤与其他基因型以及年龄、性别、吸烟和饮酒等因素之间的关系。采用PHASE2.0.2软件分析各基因多态位点及其单倍型和双体型与DNA损伤之间的关系。双体型分析结果表明,p53基因WGG/WCG双体型的携带者DNA损伤风险是WGG/WGG双体型携带者2.33倍(OR=2.33,95%CI:1.88-2.89,P＜0.001),而携带WCG/WGG双体型个体DNA损伤风险降低0.42倍(OR=0.42,95%CI:0.35-0.50,P＜0.001)。研究认为p53 WGG/WCG双体型是导致VCM作业工人DNA损伤的危险因素,而WCG/WGG对VCM导致的DNA损伤具有保护作用。
然后以外周血淋巴细胞微核率作为染色体损伤的效应指标,分析VCM代谢酶基因和DNA损伤修复基因多态及相关因素对微核率的影响。多元Poisson逐步回归分析微核危险因素,结果表明年龄和GSTP1、CYP2E1、ALDH2、XRCC1Arg280His等基因多态为染色体损伤的影响因素。在平衡可能混杂因素后,微核率与年龄有关,高龄组(＞35岁)染色体损伤的风险显著高于低龄组(≤35岁)(P＜0.001),调整后的FR值为1.19(1.08—1.30);CYP2E1和XRCC1 Arg280His基因突变型携带者微核的发生危险显著高于野生型个体(P＜0.05),调整后的FR值分别为1.12(1.02—1.24)和1.11(1.01-1.24);GSTP1 GA/AA和ALDH2 GA/AA基因型携带者微核率显著低于其他基因型个体(P＜0.01),调整后的FR值分别为0.74(0.59-0.94)和0.87(0.79-0.95)。本研究认为高龄及GSTP1 GG、CYP2E1clc2/c2c2、ALDH2 GG和XRCC1 280 GA/AA基因型可能是致染色体损伤的危险因素。对XRCC1基因194、280、399三个位点的双体型分析结果显示,以CGG/CGG双体型为参比,CGA/CAG双体型携带者微核率显著增高,说明CGA/CAG双体型携带者可能是VCM作业人群中染色体损伤的易感者。
综上所述,在我国现行职业卫生标准下,VCM仍可产生一定的健康危害。SOD、MDA、GST和血清p53指标可作为接触VCM致机体损伤的效应生物标志物。外周血淋巴细胞彗星细胞率和微核率可作为职业性接触氯乙烯工人健康监护的一种早期检测指标。VCM作业工人遗传损伤的发生是遗传因素、生活习惯、氯乙烯作业综合影响的结果,对VCM作业工人的健康监护应全面考虑这些因素。毒物代谢酶和DNA损伤修复基因多态与VCM致遗传损伤有关,开展这方面的研究有助于VCM致癌机制的阐明,而研究中易感性多态位点的发现也可以为识别易感人群提供理论依据。
Vinyl chloride monomer(CH_2=CHCl,VCM) is a colorless gas and a synthetic chemical that does not naturally occur.At room temperature,it has a mild sweet odor, it burns easily,and it is not stable at high temperatures.VCM is one of the highest production volume chemicals is wildly used in the world.Approximately 95%of all VCM produced is used to manufacture polyvinyl chloride(PVC).With the fast development of petroleum industry,the total output of VCM in the world increased rapidly.In 1957,China began to produce PVC,and the annual output of PVC in China has jumped to the first place in the world with a total annual production of 9.72 millions ton in 2007.China as a leading producer of PVC in the world,thousands of workers could be exposed to VCM.It is necessary to pay more attention to the health of VCM-exposed workers in our country.
VCM exposure has been associated with hepatic angiosarcoma(ASL) and hepatocellular cancer,and was classified as a group 1 carcinogen by IARC in 1987. Recent epidemiological studies have shown VCM is a multi-organ and multi-system carcinogen that induces a wide spectrum of tumors,including ASL and other tumors, brain tumors,and lung cancer.Since VCM is a known carcinogen,it has caused great concern to people who may be exposed to it.To avoid the potential health hazard, many countries have developed some techniques to make a great progress in reducing exposure concentration of VCM.At present,the permissible exposure limit(PEL) of VCM in developed countries is 1 ppm(2.79mg/m~3),and the permissible concentration-time weighted average(PC-TWA) in China is 10mg/m~3.So it is necessary to analyze occupational health effects in VCM-exposed workers whose exposure level was several times higher than the occupational health standard in developed countries.Under the same working environment and VCM-exposed level, only some VCM-exposed workers had got genetic damage,which indicated that there were genetic susceptible differences among the workers.A susceptible population will exhibit a different or enhanced response to VCM than will most persons exposed to the same level of VCM in the environment.Reasons may include age,gender,health and nutritional status,occupational and personal exposures(e.g.,alcohol drinking and cigarette smoking);moreover inherited metabolic and repaired traits may also explain the elevated risk in selected individuals.As we know,genetic polymorphisms related to VCM metabolism and DNA repair may increase the susceptibility of individuals to genotoxicity.Presently,many studies have been conducted to investigate the genotoxicity of VCM and the effect of genetic polymorphisms in genes coding for metabolic enzymes,but only a few studies paid attention to the DNA repair genes. Studies on relationship between genetic damage in VCM-exposed workers and susceptible genotypes of metabolic and/or DNA repair genes have been useful for revealing mechanism of toxicology and evaluation to health risk.
This study evaluated the relationship between VCM exposure and occupational hazards based on calculated cumulative exposure dose of the VCM-exposed workers. In order to explore effect biomarkers under low level VCM exposure,this study investigated the health condition,potential oxidative injury,liver lesion,serum p53 protein and p53-Abs level,as well as genetic damage induced by VCM.Moreover, occupational epidemiological study were performed to study common variants in genes involved in metabolism pathways and DNA repair pathways,to elucidate the relationship between susceptible genotypes of metabolic and/or DNA repair genes and genetic damage in VCM-exposed workers,and to find biomarkers of susceptibility of genetic damage induced by VCM-exposure.
This study investigated occupational health hazards among VCM-exposed workers whose exposure level was lower than the national occupational health standard.(1)Used 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 and liver morphological changes,so they could not be used as an sensitive index of VCM exposure;(2)The levels of superoxide dismutase(SOD), malondialchehyche(MDA) and glutathione S-transferases(GST) in serum were used as the effect biomarkers of VCM exposure.The findings of multiple-linear regression showed that the serum SOD activity of the VCM-exposed groups decreased significantly compared with the control group(P＜0.001),and the amount of MDA increased(P＜0.001).GST activity in the low and high exposure group was significantly higher than that of the control group(P＜0.05).Chi square-test showed that there was a dose-response relationship between serum levels of SOD/GST and the cumulative exposure dose of VCM.Furthermore,advanced age was the risk factor of the lower SOD activity and higher MDA level,and the males'MDA level was significantly elevated compared with females'.The activity of serum SOD,MDA and GST could be used as effect biomarkers when the exposure level is lower than the national occupational health standard of China;(3)Genetic damages of VCM-exposed workers were measured by the single cell gel electrophoresis(SCGE) and cytokinesis-block micronucleus(CBMN).In order to develop a normal reference value of CBMN and comet cells frequencies in cultured peripheral lymphocytes,a threshold of CBMN and comet cell frequency,such as the 95-percentile of the controls CBMN(i.e.3‰) and comet cell(i.e.4%) distribution,maybe used to define chromosomal damage and DNA damage caused by VCM-exposure,above which the CBMN or comet cell frequency may indicate an aberration from being normal,hence indicating chromosomal or DNA damage.Statistics results indicate that mean CBMN frequencies and levels of DNA damage were significantly elevated for the low, intermediate and high VCM-exposure groups compared with that of the controls(P＜0.001).Moreover,multiple Poisson regression analysis showed that a significant increase of micronuclei occurred with age and in females,when occupationally exposed.So the results of CBMN and comet assay of peripheral blood lymphocyte can be used as an early and sensitive biomarker under low level VCM exposure;(4)To determine the relation between VCM exposure and serum p53 biomarkers,this study examined serum samples for the levels of p53 protein and p53 antibodies,using an enzyme-linked immunosorbent assay(ELISA).These biomarkers results suggest that workers with VCM exposure below the current permissible exposure limit have a risk for the occurrence of seropositive for both of the p53 biomarkers is significantly greater than unexposed controls,the presence of both serum p53 biomarkers were greatly elevated in high exposure group compared with that of the normal controls. Serum p53 protein and antibodies may represent suitable biomarkers in assessing the level of occupationally exposure.
Then,PCR-RFLP,CRS-RFLP and multiplex PCR was used to detect polymorphisms of metabolizing enzymes and DNA repair genes.In this study,we detected the 15 polymorphisms in 11 genes:GSTT1、GSTM1、GSTP1、CYP2E1、ADH2 and ALDH2,which participate in the metabolism of VCM;OGG1、MGMT、XRCC1,p53 and TDG,which participate in the process of DNA repair.Occupational epidemiological study was performed to investigate the relationship between DNA damage induced by VCM and polymorphisms of metabolizing enzymes and DNA damage repair genes.Logistic regression analysis was employed to model the relationship between DNA damages and genotypes of xenobiotic metabolizing and DNA repair genes and related indicator among VCM-exposed workers.A prominent risk increasing of DNA damage was observed for those individuals possessing the GSTP1 GA/GG,CYP2E1 clc2/c2c2,ADH2 AG/ GG and MGMT 84 CC genotypes when compared with other genotypes,these genotypes may jointly contribute to the susceptibility of DNA damage.There was no association between DNA damage and other genotypes and gender,age,drinking,smoking.PHASE software(version 2.0.2) was used to obtain maximum-likelihood estimates of the XRCC1 and p53 haplotype frequencies.Diplotype analysis showed that risk of DNA damage increased in the subjects carrying the WGG/WCG diplotype compared with those with the WGG/WGG diplotype of p53 intron 3,exon 4,and intron 6 genes(OR=2.33,95%CI: 1.88-2.89,P＜0.001),the risk of DNA damage for individuals with the WCG/WGG diplotype was 0.42-fold(OR=0.42,95%CI:0.35-0.50,P＜0.001) compared with those with the WGG/WGG diplotype.These implied that WGG/WCG diplotype of p53 is potentially one of the risk factors for DNA damage,and WCG/WGG diplotype of p53 may contribute to resist against DNA damage in VCM-exposed workers.
Moreover,we studied common variants in genes involved in metabolism pathways(phaseⅠand phaseⅡenzymes) and DNA repair pathways,in order to elucidate the relationship between genetic polymorphisms and chromosomal damage in workers exposure to VCM.Poisson analyze showed that five factors that significantly altered CBMN frequencies:GSTP1,CYP2E1,ALDH2,XRCC1 Arg280His genotypes and age.This analysis confirmed the increase in CBMN frequency with age,mean CBMN frequencies were significantly elevated for the older workers compared with yonger workers(P＜0.001).Specifically,subjects with CYP2E1 and XRCC1 Arg280His variance showed higher mean CBMN frequencies compared with their wild-type homozygous counterparts(P＜0.05);those with GSTP1 GG genotype and ALDH2 GG genotype showed higher mean CBMN frequencies than those with other genotypes(P＜0.01).Our findings consider that age and GSTP1,CYP2E1, ALDH2 andXRCC1 Arg280His genotypes are the major factors that modulate CBMN induction in VCM-exposed workers.Diplotype analysis of XRCC1 194,280 and 399 demonstrated that the CBMN frequency in subjects with CGA/CAG diplotype was significantly higher than that in subjects with CGG/CGG(P＜0.001),and CGA/CAG diplotype is potentially one of the risk factors for chromosomal damage in VCM-exposed workers.
In conclusion,VCM can induce some occupational health hazards of workers whose exposure level was lower than the national occupational health standard.The activity of serum SOD,MDA,GST and occurrence of seropositive p53 could be used as effect biomarkers for estimation of in vivo dose of VCM exposure.The CBMN and comet assay seems to be a valuable indicator in the regular health surveillance of VCM-exposed workers.We should pay attention to the genotoxic effect from the aspects such as hereditary factors,lifestyles and VCM performance.The health care of VCM-exposed workers should be given full consideration.Further study to investigate the relationship of individual characteristics and genetic susceptibility with VCM-caused DNA and chromosome damage is warranted,it could help us to understand the mechanism of VCM metabolism and find the biomarkers of susceptibility,which is useful for us to recognize the susceptible individuals in the primary prevention of VCM-caused damage.
引文
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