Genetic polymorphisms and chromosome damage.

Genetic polymorphisms that affect xenobiotic metabolism or cellular response to DNA damage can modulate individual sensitivity to genotoxins. Information on the effects of such polymorphisms on the level of chromosome damage may facilitate the identification of risk groups and increase the sensitivity of cytogenetic endpoints as biomarkers of genotoxic exposure and effect. Glutathione S-transferase M1 (GSTM1) is an important detoxification enzyme which, due to a homozygous gene deletion (null genotype), is lacking from about 50% of Caucasians. A higher level of DNA adducts and chromosome damage has been detected in lymphocytes of tobacco smokers and bus drivers who lack the GSTM1 gene. Other polymorphic glutathione S-transferases include GSTM3, GSTP1, and GSTT1. The GSTT1 null genotype (10-20% of Caucasians) has been associated with an increased "baseline" level of sister chromatid exchanges (SCEs) in lymphocytes. N-acetyltransferase 2 (NAT2), metabolizing xenobiotics with primary aromatic amine and hydrazine structures, is another important polymorphic phase II enzyme. Subjects having the NAT2 slow acetylator genotype appear to show an increased baseline frequency of lymphocyte CAs in the absence of identified environmental exposure. Besides human biomonitoring studies, genetic polymorphisms may be important in explaining individual variation in genotoxic response observed in genetic toxicology tests with human cells. Several studies have suggested that blood cultures from GSTT1 null and GSTM1 null individuals have increased in vitro sensitivity to various genotoxins. The best-known example is probably the diepoxybutane sensitivity of GSTT1 null donors. Recently discovered polymorphisms affecting DNA repair may be expected to be of special importance in modulating genotoxic effects; the first available studies have suggested that the exon 10 Arg399Gln polymorphism of XRCC1 gene (X-ray repair cross-complementing group 1) could affect individual genotoxic response. In conclusion, the genetic polymorphism of GSTM1 influences the frequency of chromosome damage in exposed humans, while that of GSTT1 and NAT2 affect the "baseline" level of such damage. Both GSTM1 and GSTT1 genotypes may shape the in vitro genotoxic response of human lymphocytes. The significance of DNA repair polymorphisms is presently unclear.     

Biological monitoring the exposure to polycyclic aromatic hydrocarbons of coke oven workers in relation to smoking and genetic polymorphisms for GSTM1 and GSTT1.

Occupational exposure to polycyclic aromatic hydrocarbons (PAH) increases the risk of developing lung cancer. Human exposure is often demonstrated by increased internal levels of PAH metabolites and of markers for early biological effects, like DNA adducts and cytogenetic aberrations.Objective: This study aimed to assess whether the current exposure to PAH of coke oven workers in a Dutch plant induced biological effects, and to determine if these effects are influenced by tobacco smoking and by genetic polymorphisms for the glutathione S-transferase genes GSTM1 and GSTT1.Methods: Urinary 1-hydroxypyrene (1-OHpyr) levels were used to monitor the internal dose, while the internal effective dose was assessed by monitoring PAH-DNA adducts, DNA strand breaks (Comet assay), sister-chromatid exchanges (SCE) and cells with a high frequency of SCE (HFC) in lymphocytes together with micronuclei (MN) in exfoliated urothelial cells.Results: Occupational exposure to PAH resulted in statistically significant increased 1-OHpyr levels (P<0.001), but it did not cause a significant induction of SCE, HFC, MN, DNA strand breaks or DNA adducts. Smoking caused a significant increase of 1-OHpyr (P<0.05), SCE (P<0.001), HFC (P<0.001) and DNA adducts (P<0.05), but not of MN or DNA strand breaks. Following correction for the smoking-related effects, no occupational induction of the effect biomarkers could be discerned. Multi-variate analysis did not show a significant influence of GSTM1 and GSTT1 polymorphisms on any biomarker. Also no significant interactions were observed between the various biomarkers.Conclusion: This study shows that in the examined plant, the occupational exposure to PAH does not result in measurable early biological effects     

Assessment of occupational genotoxic risk in the production of rubber tyres

A broad spectrum of substances is used in the rubber industry, many of them being genotoxic and/or carcinogenic. Convincing evidence of an excess of certain forms of cancer among rubber workers has been provided. The objective of this study was to determine the genotoxic effects in a group of individuals engaged in the production of rubber tyres from a Portuguese factory. Peripheral blood samples were collected from 32 exposed workers and 32 controls, and micronucleus (MN) test, sister chromatid exchanges (SCE) and comet assay were performed. Urinary thioethers were measured as a general biomarker of exposure to electrophilic compounds, and genetic polymorphisms in metabolizing enzymes (CYP2E1 Dra I, EPHX1 codons 113 and 139, GSTP1 codon 105, and GSTM1 and GSTT1 deletion polymorphisms) were analysed as susceptibility biomarkers. Excretion of thioethers was found significantly higher in rubber workers. Also, a non-significant increase in MN frequency related to time of exposure and no effect in SCE were observed in the exposed. Comet assay data showed decreased TL values in the exposed population with respect to the control group, this might indicate the induction of crosslinks by the substances present in the workplace environment. Significant increase in MN frequency was obtained for GSTT1 null exposed individuals with respect to positive ones, and interaction with GSTP1 polymorphism was found. Higher levels of cytogenetic test frequencies were observed in epoxide hydrolase expected low activity donors with respect to medium and high activity individuals. No effect of CYP2E1 or GSTM1 variants was obtained in the biomarkers analysed.     

Benzene exposure,glutathione S-transferase theta homozygous deletion,and sister chromatid exchanges

Recent studies have shown a strong positive correlation between chromosomal aberrations and future cancer risk. Sister chromatid exchange (SCE) has been widely applied in monitoring early biological effects to assess human genetic risk of cancer at the population level. We studied 45 Chinese workers (23 in the painting workshop of a glass factory with occupational exposure to benzene, and 22 fitters and planers in the punching and planing machine workshops of a nearby shipyard without such an exposure) to examine the association between occupational exposure to benzene and SCE frequency in peripheral blood lymphocytes. We also sought to investigate whether the glutathione S-transferase class θ gene (GSTT1) affects individual susceptibility to cytogenetic damage induced by in vivo exposure to benzene or in vitro exposure to diepoxybutane. The time-weighted average concentrations of benzene were 0.71 ppm in the exposed group and 0.03 ppm in the non-exposed group. Controlling for age, gender and educational level, cigarette smoking was significantly associated with increased SCE frequencies (P < 0.05), while GSTT1 genotype was significantly associated with DEB-induced SCEs (P < 0.01). There was no relationship between benzene exposure and baseline or DEB-induced SCEs. After stratification by smoking status, the GSTT1 deletion was a significant predictor of DEB-induced SCEs for both smokers (P < 0.05) and nonsmokers (P < 0.01). A significant benzene-GSTT1 interaction was found in nonsmokers (P < 0.05). Our study suggests that GSTT1 is an important determinant of heterogeneity in individual susceptibility to chromosomal damage associated with exposure to benzene. Am. J. Ind. Med. 33:157–163, 1998. © 1998 Wiley-Liss, Inc.     

Influence of GSTT1 null genotype on the offspring sex ratio of gasoline filling station workers

The aim of this study was to investigate whether the occupational exposure to gasoline of men employed at filling stations affects the sex of their children. Altogether 115 offspring (47 males, 68 females) were identified within families of 49 men working in filling stations in Shiraz (Fars province, south of Iran) and 345 offspring (178 males, 167 females) from 147 families of unexposed persons from the general population of Shiraz, which were matched by age of fathers (+/-2 years) and number of children as a control group. The offspring sex ratio at birth (male proportion) in the filling station workers was significantly lower than the ratio in control group (OR = 0.65; 95% confidence intervals (CI) 0.42 to 0.99). Genotypes of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) were investigated on extracted genomic DNA of 37 exposed workers using the polymerase chain reaction based method. In exposed group with active GSTM1 and GSTT1 genes, offspring sex ratio was the same as the ratio in the control group (OR = 0.66; 95% CI 0.34 to 1.28). However, in the exposed group with active GSTM1 and null genotype of GSTT1, the offspring sex ratio statistically decreased (OR = 0.45; 95% CI = 0.21 to 0.96). It seems that the GSTT1 null genotype has an effect on offspring sex ratio in the filling station workers.     

GSTT1及GSTM1和CYP2E1基因多态性与二甲基甲酰胺所致肝脏损害的关系

目的 探讨GSTT1、GSTM1和CYP2E1基因多态性与二甲基甲酰胺(DMF)作业人员肝脏损害的关系.方法 以某皮革厂69名肝功能异常的DMF作业人员为病例组,选取与病例组相似岗位、DMF接触水平相近而肝功能正常的125名工人为对照组,应用聚合酶链反应(PCR)、PCR-RFLP方法分别对GSIT1、GSTM1和CYP2E1 PstI位点基因进行分型.结果 病例组和对照组中GSTM1阳性和GSTM1阴性的分布频率分别为59.42%、38.40%和40.58%、61.60%,两组间分布的差异有统计学意义(P=0.005),携带GSTM1阳性基因型个体发生肝功能异常的风险是GSTM1阴性基因型个体的2.34倍(OR=2.34,95%CI:1.29～4.29).而GSTT1和CYP2E1 PstI位点不同基因型在病例组和对照组中没有明显差异.结论 携带GSTM1阳性基因型个体的DMF作业人员发生肝功能异常的风险性可能增加.     

Decreased lung function associated with occupational exposure to epichlorohydrin and the modification effects of glutathione s-transferase polymorphisms

Epichlorohydrin (1-chloro-2,3,-epoxypropane; ECH) is a strong irritant of the eyes, respiratory tract, and skin. Because the toxic effect of various chemicals can be modified by metabolic traits, in this study, we also investigated the influence of the glutathione S-transferase (GSTM1) and (GSTT1) genes on the toxic effect of ECH. In the GSTM1 null genotype workers, there is a dose-response of lung function tests (FEV1, FEV1/FVC, MMEF) for ECH exposure, but not in the GSTM1 non-null genotype workers. The ECH exposure was found to be significantly associated with a decreased FEV1 value (P = 0.09) and a decreased MMEF value (P = 0.053) after adjusting for other factors. The GSTM1 null genotype was found to be significantly associated with a decreased FEV1 value (P = 0.038), decreased FEV1/FVC value (P = 0.056), and decreased MMEF value (P = 0.012) after adjusting for other factors. This study indicates that obstructive lung abnormalities and small airway lung damage are associated with ECH exposure, and ECH workers with GSTM1 null-type are also associated with increased respiratory damage.     

氯乙烯作业工人染色体损伤及其遗传易感性

目的 探讨氯乙烯(VCM)致染色体损伤与DNA修复基因和代谢酶基因多态间的关系.方法 收集上海某化工厂402名VCM接触工人健康体检资料、人口学资料(年龄和性别)、生活方式(吸烟、饮酒)和职业接触等因素,评估个人VCM累积接触剂量并分组.采集静脉血3 ml,采用外周血淋巴细胞胞质分裂阻滞微核试验(CBMN)检测染色体损伤,采用聚合酶链式反应(PCR)检测GSTT1、GSTM1基因缺失情况,采用PCR-限制性片段长度多态性技术(RFLP)检测其他基因多态.结果 多元Poisson回归分析结果表明,中(4000～40000 mg)、高(＞40000 mg)VCM接触剂量组染色体损伤的风险明显高于低剂量组,调整后的FR值分别为1.19(1.06～1.34)和1.20(1.06～1.38),差异有统计学意义(P值分别为0.003和0.01);携带CYP2E1和XRCC1 Arg280His突变型基因的个体微核率明显高于野生型个体,调整后的FR值分别为1.12(1.02～1.23)和1.13(1.02～1.25),差异有统计学意义(P值均为0.02);携带GSTP1Val/Val和ALDH2 Glu/Glu基因型个体微核率明显高于其他基因型个体,调整后的FR值分别为0.74(0.59～0.94)和0.87(0.79～0.95),差异有统计学意义(P值分别为0.01和0.003).结论 VCM致染色体损伤与VCM累积接触剂量增高及GSTP1 Val/Val、CYP21E1 c1c2/c2c2、ALDH2 Glu/Glu、XRCC1 280His/His 或Arg/His基因型多态性等因素有关.开展VCM致染色体损伤与遗传易感性方面的研究,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.     

谷胱甘肽硫转移酶M1和T1基因多态性与噪声性听力损失易感性的关系研究

目的探讨谷胱甘肽硫转移酶M1和T1(GSTM1和GSTT1)的基因多态性与噪声性听力损失易感性之间的关系。方法采用横断面流行病学研究方法,对194名噪声暴露作业工人进行调查和听力测试,按听力学评价的结果将其分为听力损失组和听力正常组。用多重PCR方法检测其GSTM1和GSTT1的存在空白基因多态性。结果GSTM1和GSTT1的存在空白基因型分布在93名噪声性听力损失与101名听力正常工人之间差异无显著性(P>0.05)。采用多元Logistic回归分析对两组间年龄、性别、吸烟状况、爆震史和累积噪声暴露量等因素进行校正后,发现GSTT1空白基因型组与GSTT1存在基因型组相比噪声性听力损失的危险度显著性升高(P<0.05),调整OR值为1.952(95%可信区间为1.017～3.746);GSTM1存在与空白基因型之间发生噪声性听力损失的相对危险度差异无显著性(P>0.05)。结论谷胱甘肽硫转移酶T1基因多态性可能在噪声性听力损失的发病过程中起一定作用,携带GSTT1空白基因型的个体对噪声性听力损失的易感性升高。     

Glutathione S-transferase polymorphisms and colorectal cancer: a HuGE review

The genes glutathione S-transferase M1 (GSTM1) (chromosome 1p13.3) and glutathione S-transferase T1 (GSTT1) (22q11.2) code for cytosolic enzymes glutathione S-transferase (GST)-mu and GST-theta, respectively, which are involved in phase 2 metabolism. Both genes may be deleted. There is geographic and ethnic variation in genotype frequencies for both genes. In developed countries, colorectal cancer is the second most common cancer. Colorectal cancer has been inconsistently associated with polycyclic aromatic hydrocarbons in diet and tobacco. Because GST enzymes are involved in polycyclic aromatic hydrocarbon metabolism, it has been postulated that genotype may modify colorectal cancer risk associated with polycyclic aromatic hydrocarbon exposure. No consistent associations between GSTM1 or GSTT1 genotype and colorectal cancer have been observed. However, most studies have methodological limitations. Few have investigated gene-environment interactions. No interactions between GSTM1 or GSTT1 genotype and smoking and colorectal cancer risk have been reported. One polyp study suggests an interaction between GSTM1 genotype and smoking. Two studies suggest increased disease risk in subjects with high meat intake and GST nonnull genotype, contrary to the underlying hypothesis. One study suggests a strong inverse relation between colorectal adenomas and broccoli consumption, particularly in subjects who are GSTM1 null. These finding require confirmation. Methods for determining GSTM1 and GSTT1 genotype are well established. Population testing is not currently justified.     

谷胱甘肽转硫酶M1和T1基因型与高原反应的危险性

目的探讨谷胱甘肽转硫酶M1、T1基因型(GSTM1、GSTT1)与高原反应危险性的关系。方法从同一生活和工作环境中选取123名男性武警战士作为调查对象，根据是否发生急性高原反应，将其分成病例组和对照组，其中病例组43人、对照组80人。基因组DNA来自研究对象提供的外周血有核细胞，采用多重聚合酶链反应(17CR)方法对这些武警战士的谷胱甘肽转硫酶M1和T1基因进行分型。结果病例组GSTT1非缺失型基因频率为69．8％，明显高于正常对照组(42．5％)，差异有统计学意义(P=0．004，OR=3．12，95％CI为1．42—6．86)。两组GSTM1缺失型基因频率分别为72．1％和52．5％，差异有统计学意义(P=0．03，OR=2．34，95％CI为1．05—5．02)。GSTT1阴性／GSTM1阴性基因型者发生高原反应的危险性比携带GSTT1阴性／GSTM1阳性者高5倍(OR=5．04；95％CI为1．00-25．3)。结论谷胱甘肽转硫酶M1、T1基因多态性与高原反应危险性有关。     

焦炉作业工人外周血淋巴细胞染色体损伤的遗传易感性研究

目的研究外源性化学物代谢酶基因多态性与焦炉作业工人外周血淋巴细胞染色体损伤的关系。方法选取149名焦炉作业工人和24名非职业多环芳烃(PAH)暴露人员作为研究对象,测定其尿中1-羟基芘浓度来反映PAH暴露的内剂量;对照组的外周血淋巴细胞微核水平的上4分位数(6‰)作为判断个体染色体损伤阳性的界值;分析CYP1A1、GSTM1、GSTT1、GSTP1、CYP2E1、NQO1、NAT2和mEH基因的多态性;使用多元logistic回归方程校正职业暴露情况、年龄、性别、吸烟和饮酒状况因素,计算不同基因型工人发生染色体损伤阳性的OR值,并探讨基因间的交互作用。结果调整了173名研究对象的职业暴露、年龄、性别、吸烟和饮酒状况后,GSTM1缺失基因型个体染色体损伤危险度显著性增加(调整OR=2．01,95％CI=1．03—3.91);与NQO1基因P187S位点野生型纯合子个体比较,变异型纯合子个体染色体损伤危险度显著性增加(调整OR=3．18,95％CI=1．18—8．62);与mEH基因H113Y位点野生型纯合子个体比较,变异型纯合子个体染色体损伤危险度显著性降低(调整OR=0．40,95％CI=0.19～0．88);未发现其他基因的遗传变异与研究对象外周血淋巴细胞染色体损伤危险度的显著关联。此外,还发现GSTM1、NQO1基因P187S位点和mEH基因H113Y位点的遗传变异对染色体损伤危险度的影响中存在基因-基因交互作用。结论本研究发现GSTM1、NQO1和mEH基因的遗传变异可显著性影响职业PAH暴露个体外周血淋巴细胞染色体损伤危险度,并存在基因一基因交互作用。     

Lack of modulating influence of GSTM1 and GSTT1 polymorphisms on urinary biomonitoring markers in coke-oven workers

BACKGROUND: Coke-oven workers (COWs) are occupationally exposed to high concentrations of polycyclic aromatic hydrocarbons (PAHs). Urinary 8-hydroxy-2-deoxyguanosine (8-OH-dG) and 1-hydroxypyrene (1-OHP) are biological markers of oxidative DNA damage and PAHs metabolism, respectively. In this study, we investigated whether polymorphisms of glutathione S-transferase (GSTM1 and GSTT1) can modulate the relationship between urinary 8-OH-dG and 1-OHP concentrations among the COWs. METHODS: This was a cross-sectional study. Between February and November of 2001, 53 topside-oven and 130 side-oven workers with the presence of GSTM1 and GSTT1 genotypes were investigated. RESULTS: Urinary 1-OHP and 8-OH-dG concentrations (mean +/- SD) in the topside-oven workers with the presence of GSTM1 were 107.2 +/- 107.9 and 15.3 +/- 9.7 ng/ml, respectively, which were not significantly different from those in the absence of GSTM1 (84.1 +/- 104.5 and 12.8 +/- 14.1 ng/ml). The similar insignificant results were also noted in the sideoven workers. For GSTT1 polymorphism, the results remained insignificant. In contrast, individual excretion of urinary 8-OH-dG and 1-OHP concentrations were still highly correlated (Spearman correlation coefficients: r = 0.43, P < 0.0001, n = 183). CONCLUSIONS: GST may not play a role in the regulation of metabolism of urinary biological markers in COWs.     

GSTM1及GSTT1和GSTP1基因多态性对尿中1-羟基芘水平的影响

目的 研究GSTM1、GSTT1和GSTP1基因多态性对多环芳烃接触工人尿中1-羟基芘(1-OHP)水平的影响.方法 分别选取2个炼焦厂共447名多环芳烃职业接触工人(接触组)和某线材厂220名非职业接触工人(对照组)作为研究对象,采用高效液相色谱法测定尿中1-OHP水平,采用线性回归统计模型分析GSTM1和GSTT1缺失型及GSTP1 I105V位点的多态性对不同人群尿中1-OHP水平的修饰作用.结果 接触组工人尿中1-OHP浓度为4.61 μmol/mol Cr,明显高于对照组(0.34μmol/mol Cr),差异有统计学意义(P＜0.05).接触类别和吸烟分别是影响尿中1-OHP水平的主要因素,在控制各混杂因素的影响后,线性回归分析显示,接触组尿中1-OHP水平和GSTP1 I105V位点多态性有关(单基因分析,P=0.012;多基因分析,P=0.011),对总体样本,单基因模型和多基因模型均显示,尿中1-OHP水平可能和GSTT1缺失型多态有关(P=0.055),多基因交互作用分析显示,GSTT1和GSTP1基因多态对接触组尿中1-OHP水平具有交互作用.结论 谷胱甘肽硫转移酶(GSTs)基因的多态性对接触多环芳烃工人尿中1-OHP水平有影响.

Abstract：

Objective To investigate the modification of GSTM1, GSTT1 and GSTP1 gene polymorphisms on urinary 1-hydroxypyrene (1-OHP) excretions in workers under different exposure levels. Methods Four hundred and forty-seven occupationally exposed workers from two coking plants and 220 control workers from a wire rod plant were genotyped to analyze the modification of GSTM1, GSTT1 and GSTP1 gene polymorphisms on urinary 1-OHP excretions. Results The urinary 1-OHP concentration in exposed group was much higher than that in control group (4.61 vs 0.34 μmol/mol Cr, P＜0.05). Occupational exposure levels and cigarette smoking were of the dominating factors affecting 1-OHP excretions in urine. After controlling potential confounders, decreased excretion of urinary 1-OHP was associated with GSTP1 I105V AG + GG genotype in coke oven workers (single-gene model, P=0.012; multi-gene model, P=0.011 ) and with GSTT1 null type in the analysis including all subjects (P=0.055 in both single-gene and multi-gene models). GSTT1 and GSTP1 were interacted on the urinary concentrations of 1-OHP. Conclusion Urinary 1-OHP concentrations can be modified by GSTM1, GSTT1 and GSTP1 gene polymorphisms, indicating that these genes are involved in the metabolism of polycyclic aromatic hydrocarbons.     

Effect of polymorphic metabolizing genes on micronucleus frequencies among benzene-exposed shoe workers in China

It is well-known that metabolism of benzene is required for the induction of toxicity and consequent health problems. Therefore, genetic variation in benzene (BZ) metabolism genes can influence health outcomes. However, large population studies are needed to provide more evidence for such relationship. We have conducted a large population investigation (385 BZ-exposed shoe workers and 197 matched healthy controls) on the association between inheritance of certain BZ metabolizing genes and the expression of micronuclei (MN). The latter was based on the cytokinesis-blocked MN assay. We analyzed the polymorphisms of GSTM1, GSTT1, GSTP1 (rs1695), CYP2E1 (rs3813867), CYP2E1 (rs2031920), CYP2E1 (rs6413432), mEH exon 3 (rs1051740), mEH exon 4 (rs2234922). Univariate Poisson regression analysis demonstrated that the BZ-exposed workers had significantly increased MN frequency compared with the controls (FR = 1.84, 95% CI: 1.56–2.18; P < 0.001), and showed a cumulative exposure dose–response relationship. The CYP2E1 rs3813867 mutant allele (CC + GC) (FR 1.15, 95% CI 1.02–1.29; P = 0.020) and rs2031920 variant allele (CT + TT) (FR = 1.23, 95% CI: 1.09–1.37, P < 0.01) was associated with higher MN frequency significantly compared with the wild genotype separately. Furthermore, the MN frequency in rs2031920 variant allele (CT + TT) (FR = 1.17, 95% CI: 1.04–1.31, P < 0.01) was also higher than the wild genotype when the age, gender and cumulative exposure dose was adjusted in Poisson regression. In addition, the CYP2E1, however, GSTM1null, GSTT1null, GSTP1 rs1695, rs6413432, rs1051740 and rs2234922 polymorphisms showed no association with MN frequency. Our results indicate that two promoter polymorphisms in the CYP2E1 gene, especially the rs2031920 variant allele, were involved with the BZ-induction of MN and may contribute to risk of cancer among exposed workers.     

谷胱甘肽S-转移酶M1基因型与石棉作业工人血液脂质过氧化水平的关系

目的　探讨谷胱甘肽S 转移酶M1(GSTM1)基因型与接触石棉的工人血液发生脂质过氧化的关系。方法　选择 94名石棉作业工人及 5 1名对照工人作为研究对象 ,通过问卷调查收集每个研究对象的一般情况、职业史等。同时测定血浆丙二醛 (MDA)的含量 ,分析淋巴细胞DNA中GSTM1的基因型。结果　石棉作业工人血浆MDA含量为 (0 .2 83± 0 .0 5 4)nmol/L ,明显高于对照组工人 [(0 .16 3± 0 .0 5 3)nmol/L],差异有显著性 (P <0 .0 1) ,但MDA含量与工龄和累积石棉接触剂量之间的相关关系不明显 ;对照组工人携带GSTM1- /-者血浆中的MDA含量 [(0 .190± 0 .0 34 )nmol/L]明显高于携带GSTM1+/+者[(0 .138± 0 .0 5 5 )nmo/L],差异有显著性 (P <0 .0 1) ,而石棉作业工人组虽也有类似趋势 ,但无统计学差异 (P >0 .0 5 ) ;对于石棉作业工人来说 ,在工龄相同或累积石棉接触剂量相同时 ,携带GSTM1- /-者的血浆MDA含量均高于携带GSTM1+/+者 ,但差异均无显著性 (P >0 .0 5 )。结论　接触石棉和GSTM1- /-基因型均与作业工人机体内脂质过氧化有关 ,但石棉的作用可能大于GSTM1基因型的作用。     

谷胱甘肽转硫酶M1和T1基因型与新疆哈萨克族食管癌的关系

目的 为探讨与致癌物代谢有关的谷胱甘肽转硫酶(GST)Tl和Ml基因多型性与哈萨克族食管癌易感性的关系。方法 采用聚合酶链(PCR)技术，分析新疆食管癌高发民族中GSTMl和GSTTl基因型分布的差异。结果 GSTMl基因在食管癌、癌旁正常粘膜对照组中缺失率分别为41．46％(17／41)、34．15％(14／41)；GSTTl基因缺失率的分别为48．78％(20／41)、51．22％(21／41)，差别均无显性。同时，在食管癌组织的高分化组、中低分化组中GSTTl和GSTMl基因缺失率分别为61．54％(8／13)、42．86％(12／28)、l5．38％(2／l3)、53．57％(14／28)，其中GSTMl基因缺失率在高、中低分化组中差别有统计学意义。结论 提示GSTMl基因多型性与哈萨克族食管癌组织病理分级相关。     

Glutathione S-transferases GSTM1 and GSTT1 polymorphisms and asbestosis

OBJECTIVE: In a nested case-control study, the authors investigated whether the deletion polymorphism of glutathione S-transferases GSTM1 and GSTT1 represents a risk factor for the development of asbestosis. METHODS: In total, 262 cases with asbestosis and 265 controls, selected from a cohort of 2080 workers occupationally exposed to asbestos, were genotyped for GSTM1 and GSTT1-null alleles. Cumulative exposure for each subject was available. RESULTS: Asbestosis was associated with cumulative exposure (odds ratio [OR]=3.21, confidence interval [CI] 2.43-4.23) and GSTT1-null genotype (OR=0.61, CI 0.40-0.94), but not with GSTM1-null genotype (OR=1.01, CI 0.71-1.43). The risk of GSTM1-null and GSTT1-null genotype for asbestosis did not change after adjustment by cumulative exposure, smoking, gender, and age. CONCLUSIONS: An important finding of this study is that GSTT1 gene deletion might have a protective effect on the development of asbestosis.     

NQO1、GSTT1和GSTM1基因多态性与慢性苯中毒的遗传易感性

目的探讨NQO1、GSTT1和GSTM1基因多态性与慢性苯中毒遗传易感性之间的关系。方法选择100名慢性苯中毒病例为病例组及90名同期接苯但无苯中毒表现的同工种工人为对照组,应用PCR-RFLP及多重PCR方法判定NQO1、GSTT1和GSTM1基因型。结果携带NQO1C609TT/T基因型(纯合突变型)个体发生苯中毒的危险性是具有C/T基因型(杂合型)和C/C基因型(野生型)个体的2.82倍(95%CI1.42～5.58,P<0.05),是具有C/C基因型(野生型)个体的2.94倍(95%CI1.25～6.90,P<0.05);携带GSTT1缺失(null)基因型个体发生苯中毒的危险性是具GSTT1非缺失(non-null)基因型个体的1.91倍(95%CI1.05～3.45,P<0.05),未发现GSTM1基因型与苯中毒的关系。同时携带NQO1C609TT/T基因型、GSTT1缺失、GSTM1缺失任何两种基因型的个体发生苯中毒的危险性均高于同时携带野生型及非缺失基因型的个体;并且同时携带NQO1C609TT/T基因型、GSTT1缺失与GSTM1缺失个体接苯时发生苯中毒的危险性最高,是NQO1C609TC/T基因型和C/C基因型、GSTT1非缺失型(non-null)与GSTM1非缺失型(non-null)个体的20.41倍(95%CI3.79～111.11,P<0.01)。结论基因之间的交互作用在苯中毒的发生中起重要作用。同时携带NQO1C609TT/T基因型、GSTT1缺失基因型和GSTM1缺失基因型个体发生苯中毒的风险最     

谷胱甘肽转硫酶M1和T1基因型与食管癌危险性:病例-对照研究

为探讨参与致癌物代谢的谷胱甘肽转硫酶（ＧＳＴ）Ｍ１和Ｔ１基因多型性与食管癌危险性的关系，以病例－对照分子流行病学方法，分析食管癌高发区河南林县的食管癌、食管上皮重度增生病例和性别、年龄配对的正常对照者（各４５例）的ＧＳＴＭ１和ＧＳＴＴ１基因型分布的差异。基因组ＤＮＡ来自研究对象的食管外科手术标本或细胞学检查获得的食管上皮细胞，以多重聚合酶链反应方法进行基因分型。结果：食管癌、食管上皮重度增生病例和