饮水型砷暴露对人群甲基化代谢能力的影响

目的探讨饮水型砷暴露对人群甲基化代谢能力的影响。方法以带有砷化物预处理装置的原子吸收分光光度计测定砷暴露人群及无砷暴露对照人群血、尿中无机砷(iAs)、甲基胂(MMA)、二甲基胂(DMA)含量。以iAs、MMA及DMA的总和表示总胂(tAs)水平;以(MMA+DMA)/tAs及DMA/(MMA+DMA)分别计算一甲基化率(PMI)和二甲基化率(SMI)水平。结果砷暴露人群血中iAs、MMA、DMA、tAs及PMI水平均显著高于相应对照人群的水平,而SMI水平显著低于对照人群。尿中MMA水平分别与血中PMI及SMI水平呈显著正相关(r=0.419,P<0.01)及负相关(r=-0.326,P<0.05)。暴露组和对照组血中各种砷化物水平及甲基化率水平在男女间差异无显著性。结论砷暴露人群与无砷暴露人群相比甲基化率有差异,PMI显著增高,SMI显著降低。人群甲基化率无显著性别差异。     

中国人群谷胱甘肽转移酶M1和T1的基因多态性分析:系统综述及吉林省结核涂阳人群研究

目的 了解谷胱甘肽转移酶M1(GSTM1)和T1(GSTT1)基因多态性在中国人群及吉林省结核涂阳人群中的分布.方法 采用系统综述方法,以"GSTM1/GSTT1+多态性"为关键词搜索国内发表于2009年1月以前、研究类型为横断面研究或队列研究基线的文献,经综合分析获得GSTM1、GSTT1基因多态性分布信息.以吉林省14个县(区)2007年11月至2008年5月间的全部结核涂阳病例(共1120名)为研究对象,采用多重PCR法检测GSTM1、GSTT1基因型.结果 系统综述得到中国人群GSTM1、GSTT1基因纯合缺失型和GSTM1-GSTT1联合缺失基因型频率分别为54.2%、46.8%和26.2%,其中以汉族为主的人群分别为53.4%、44.9%和25.5%;本研究中吉林省结核涂阳人群相应频率分别为57.2%、20.4%和13.7%,GSTM1、GSTT1基因型及组合基因型分布的性别、年龄差异无统计学意义(P>0.05).与系统综述结果相比,本研究人群GSTM1纯合缺失基因型频率偏高(P=0.016),GSTT1纯合缺失基因型和GSTM1-GSTT1联合缺失基因型频率明显偏低(P值均<0.001).结论 GSTM1、GSTT1基因多态性分布存在种族差异;本研究人群结果与系统综述结果的统计学差异可能是由于前者样本量较大、既往研究对象多为南方人群所致.     

As3MT、N6AMT1基因-环境交互作用对砷暴露所致皮肤损伤影响

目的探讨砷甲基转移酶(As3MT)和N-6-腺嘌呤特异性DNA甲基转移酶1(N6AMT1)基因多态性及基因-环境交互作用与砷暴露所致皮肤损伤(AISL)的关联性。方法于2010年9月到2011年12月在内蒙古五原县入选饮水型砷暴露人群335人,65例被确诊患有AISL。应用MassARRAY~(?)分子量阵列平台检测基因型,高效液相色谱-电感耦合等离子体质谱联用法测定尿砷代谢物,砷暴露时间由其高砷水饮用时间确定,多因子降维法与岭回归模型分析基因型、环境因素的单独效应及基因-环境的交互作用。结果 As3MT基因rs3740400位点CA/AA基因型、N6AMT1基因rs 1006903位点GC/CC基因型和尿二甲基胂酸(DMA)升高为AISL的独立危险因素(P0.05)。rs3740400位点基因型-尿无机砷(iAs)-单甲基胂酸(MMA)的交互作用与AISL发生风险间存在显著的统计学关联(OR=0.62, 95%CI=0.41～0.94,P=0.024),模型的验证样本准确率为0.577 6,交叉验证一致性为9/10。结论 As3MT、N6AMT1基因多态性及尿砷化合物水平均与AISL独立相关,rs3740400位点基因型、尿iAs和MMA的交互作用在慢性砷中毒的发生发展中具有重要作用。     

GSTT1和GSTM1基因多态性与砷中毒易感性的相关性研究

目的 探讨GSTT1、GSTM1基因多态性与砷中毒易感性的相关性.方法 选择某工业性砷污染区常住居民中的174名砷中毒患者(病例组)和92名正常人(对照组)作为研究对象.应用多重PCR技术检测GSTM1和GSTT1基因多态性.结果 病例组GSTM1( )的百分比(39.66%)高于对照组(27.17%),两组间差异有统计学意义(P＜0.05);GSTM1( )人群患砷中毒的危险性是GSTM1(-)的人群的1.7611倍(95%CI为1.0154～3.0546).病例组GSTT1( )的百分比(60.34%)高于对照组(45.65%),两组差异有统计学意义(P＜0.05);GSTY1( )人群患砷中毒的危险性是GSTT1(-)的人群的1.811 6倍(95%CI为1.087 4～3.018 2).GSTM1和GSTY1同时为非空白基因型人群患砷中毒的危险性是GSTM1和GSTT1同时为空白基因型人群的3.083 3倍(95%CI为1,414 8～6.719 6).结论 GSTT1和GSTM1基因多态性与砷中毒的发生可能有关,在相同砷暴露环境下,GSTT1和GSTM1空白基因型个体患砷中毒的危险性可能更低.     

GSTT1及GSTM1基因多态性与饮水型砷中毒关系

目的 探讨GSTT1、GSTM1基因多态性与饮水型地方性砷中毒易感性的关系.方法 对新疆砷中毒病区慢性砷中毒患者96例、病区内对照组73人以及非病区外对照组89人,应用聚合酶链反应( PCR)技术进行GSTT1 、GSTM1基因多态性的检测,分析不同基因型与砷中毒发病风险的关系.结果 GSTT1、GSTM1基因型在3组间的分布,差异无统计学意义;GSTT1和GSTM1基因多态性在不同砷暴露人群中的发病风险,差异均无统计学意义(x2=1.483,P=0.476;x2=1.852,P=0.396);GSTT1(+)+GSTM1(+)、GSTT1(+)+GSTM1(-)以及GSTT1(-)+ GSTM1(+)基因型在3组间的构成比,差异均无统计学意义(x2=0.05,P=0.975;x2=5.841,P=0.054;x2=1.887,P=0.387);病例组中GSTT1(-)+GSTM1(-)的构成比(38.9％)明显高于外对照组(22.5％)(x2=5.828,P =0.016);砷中毒人群表现GSTT1(-)+GSTM1(-)基因型是健康人群的1.733倍(OR=1.733,95％ CI=1.093～2.748).结论 GSTT1、GSTM1基因可能与新疆奎屯饮水型地方性砷中毒无关联,但是GSTM1空白基因型频率在砷中毒人群中有升高趋势;GSTT1与GSTM1基因联合空白型可能与饮水型地方性砷中毒有关联.     

高砷暴露致皮肤损伤人群尿砷代谢产物分析

目的 探讨高砷暴露致皮肤损伤人群尿砷代谢的特点.方法 应用氢化物发生.冷阱捕获.原子吸收分光光度法测定高砷暴露地Ⅸ(水砷浓度分别为0.21、0.24、0.36 mg/L)皮肤损伤组人群(77人)和未见皮肤损伤对照组人群(77人,性别、年龄1:1配比)尿中无机砷(iAs)、一甲基胂酸(MMA)和二甲基胂酸(DMA)含量.以iAs、MMA及DMA的总和表示总砷(tAs)水平;以iAs/tAs、MMMtAs和DMA/tAs分别计算iAs%、MMA%、DMA%;以(MMA+DMA)/tAs及DMM(MMA+DMA)分别计算一甲基化率(FMR)和二甲基化率(SMR)水平.结果 皮肤损伤组人群与对照组人群相比尿中各形态砷化合物及总砷含量差异无统计学意义(JD>0.05),而皮肤损伤组尿iAs%水平高于对照组,DMA%、FMR和SMR水平低于对照组差异均有统计学意义(P<0.05).皮肤损伤组人群中男性SMR水平显著低于女性,且尿中MMA%显著高于女性(P<0.05).结论 高砷暴露情况下,出现皮肤损伤症状的人群对砷的甲基化能力较低.

Abstract：

Objective To explore the characteristics of urine arsenic metabolism of people with skin lesion. Methods The levels of inorganic arsenic (iAs), monomethylated arsenic (MMA), dimethylated arsenic (DMA) in urine were detected with hydride generation-cold trap-atomic absorption spectroscopy among population exposed to higher levels of arsenide (0.24 ,0.36,0.21 mg/L), which consisted of skin lesion group(n=77) and non-skin lesion group (n=77,control group) in Apr.,2009 . Total arsenic (tAs) , iAs %, MMA%, DMA%, the first methylation ratio (FMR) and the secondary methylation ratio (SMR) were calculated as iAs + MMA+ DMA , iAs/tAs, MMA/tAs, DMA/tAs, (MMA + DMA)/ tAs and DMA/(MMA + DMA), respectively. Results No significant difference was observed in urinary concentrations of arsenic species and tAs between two groups (P>0.05), iAs% was much higher and the levels of FMR, SMR and DMA% were significantly lower in skin lesion group compared with the control (P<0.05). There were statistically significant differences in iAs% and SMR between males and females of the skin lesion group(P<0.05). Conclusion The arsenic methylation capacity of the persons with skin lesions is lower at high arsenic exposure.     

GSTM1、GSTT1及GSTP1基因多态性与子宫内膜异位症的相关性研究

目的:探讨唐山地区汉族妇女谷胱甘肽S-转移酶超家族成员GSTM1、GSTT1及GSTP1基因多态性与子宫内膜异位症遗传易感性的关系。方法:采用MD-PCR和RFLP-PCR技术检测94例子宫内膜异位症患者和102例对照妇女的GSTM1、GSTT1及GSTP1的基因型。结果:GSTM1、GSTT1、GSTP1各基因型在病例组和对照组中的分布,差异无统计学意义(P>0.05),携带AG基因型个体患病的风险是携带AA基因型个体的1.74倍,GSTP1各等位基因在各组中的分布无统计学差异。结论:未发现GSTM1、GSTT1、GSTP1基因多态性与子宫内膜异位症有关,尚不能认为GSTM1和GSTT1缺失基因型是子宫内膜异位症的易感基因型。     

GSTM1和GSTT1基因多态性与噪声性听力损失易感性的关系

目的探讨GSTM1和GSTT1基因多态性与噪声性听力损失易感性的关系。方法采用病例对照研究方法和多重聚合酶链反应(PCR)技术检测听损组123(118)例和对照组123(114)例的GSTM1和GSTT1基因缺失型频率,以2检验检测听损组和对照组基因型频率的差异。结果GSTM1基因在听损组和正常组的缺失率分别为69.1%和56.1%,差异具有统计学意义(P<0.05)。GSTM1(-)基因型携带者发生噪声性听力损失的危险性是携带GSTM1( )基因型者的1.75倍。GSTT1基因在听损组和正常组的缺失率为50.8%和57.9%,差异没有统计学意义(P>0.05)。联合分析表明,携带GSTM1(-)和GSTT1(-)基因型者发生噪声性听力损失的危险性虽稍高于携带GSTM1( )和GSTT1( )基因型者(OR=1.11,2=0.16,P>0.05),但差异无统计学意义,由此认为GSTM1和GSTT1基因之间可能不存在联合作用。结论GSTM1基因缺失可能是发生噪声性听力损失的易感因素之一。     

GSTT1基因、GSTM1基因多态性与乳腺癌易感性的病例-对照研究

目的探讨女性乳腺癌人群中,雌激素代谢酶GSTT1基因、GSTM1基因多态性与乳腺癌易感性的关系。方法采用聚合酶链反应(PCR)对天津市105例正常对照者和100例乳腺癌患者的GSTT1基因、GSTM1基因多态性进行检测,Logistic回归分析评估单个、联合基因以及雌激素暴露相关因素对罹患乳腺癌的危险度。结果GSTT1基因缺失型在两组间分布频率的差别有统计学意义(χ2=13.766,P=0.000),GSTM1基因在两组间分布频率的差别有统计学意义(χ2=13.135,P=0.000);联合基因型分析显示,随着GSTT1或GSTM1基因型缺失情况的出现,个体罹患乳腺癌的危险性增加(趋势性检验,χ2=27.011,P=0.000);GSTM1基因和GSTT1基因同时缺失的人群OR(95%CI)为12.338(3.621～22.042);多因素非条件Logistic回归分析结果显示:GSTT1基因和GSTM1基因缺失与乳腺癌的发生相关。结论雌激素代谢酶相关基因多态性与乳腺癌发生相关。     

冶炼厂工人p15基因表达与砷及其代谢产物的关系

为探讨尿砷及其代谢产物对p15基因表达的影响,选取某砷冶炼厂76名一线作业工人为暴露组,非职业环境砷暴露的22名当地居民为对照组,采用原子吸收分光光度法检测尿砷各形态水平,计算一、二级甲基化指数;使用qRT PCR法检测外周血中淋巴细胞p15 mRNA的表达情况。结果显示,砷冶炼厂工人尿中无机砷(iAs)、一甲基胂酸(MMA)、二甲基胂酸(DMA)、总砷水平均高于对照组,二级甲基化指数(SMI)低于对照组,p15 mRNA的相对表达水平高于对照组,差异均有统计学意义(P005);尿中iAs (r=0492)、 MMA(r=0531)、 DMA (r=0526)、总砷(r=0531)、 MMA%(r=0340)与p15基因相对表达呈正相关(P005),p15的表达受SMI的影响且呈负相关(r=-0256),差异具有统计学意义(P005)。说明砷可导致职业接触人群中p15基因的相对表达上调,并且存在一定的剂量关系。     

Study on the relationship between GSTM1, GSTT1 gene polymorphisms and arsenic methylation level

OBJECTIVE: To investigate the relationship between genetic polymorphisms of GSTT1, GSTM1 and arsenic methylation level. METHODS: 247 residents in an industrial arsenic polluted village were randomly selected as subjects. The genetic polymorphisms of GSTM1 and GSTT1 were detected by multiple PCR method. Urinary inorganic arsenic (iAs), monomethylarsenic acid (MMA) and dimethylarsenic acid (DMA) concentrations were determined by ion chromatogram combined with HG-AFS. RESULTS: No significant differences in the relative proportion of urinary iAs, MMA and DMA were observed between the individuals with GSTT1 positive genotype and the individuals with GSTT1 null genotype. No significant differences in the relative proportion of urinary iAs, MMA and DMA were observed between the individuals with GSTM1 positive genotype and the individuals with GSTM1 null genotype. And no significant differences in the relative proportion of urinary iAs, MMA and DMA was observed among the individuals with different GSTM1 and GSTT1 associated genotype. CONCLUSION: The polymorphisms of GSTT1 and GSTM1 were not associated with arsenic metabolism level in the studied population.     

Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina

The susceptibility to arsenic-induced diseases differs greatly between individuals, possibly due to interindividual variations in As metabolism that affect retention and distribution of toxic metabolites. To elucidate the role of genetic factors in As metabolism, we studied how polymorphisms in six genes affected the urinary metabolite pattern in a group of indigenous women (n = 147) in northern Argentina who were exposed to approximately 200 microg/L As in drinking water. These women had low urinary percentages of monomethylated As (MMA) and high percentages of dimethylated As (DMA). MMA has been associated with adverse health effects, and DMA has the lowest body retention of the metabolites. The genes studied were arsenic(+III)methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferases mu 1 (GSTM1) and theta 1 (GSTT1). We found three intronic polymorphisms in AS3MT (G12390C, C14215T, and G35991A) associated with a lower percentage of MMA (%MMA) and a higher percentage of DMA (%DMA) in urine. The variant homozygotes showed approximately half the %MMA compared with wild-type homozygotes. These polymorphisms were in strong linkage, with high allelic frequencies (72-76%) compared with other populations. We also saw minor effects of other polymorphisms in the multivariate regression analysis with effect modification for the deletion genotypes for GSTM1 (affecting %MMA) and GSTT1 (affecting %MMA and %DMA). For pregnant women, effect modification was seen for the folate-metabolizing genes MTR and MTHFR. In conclusion, these findings indicate that polymorphisms in AS3MT-and possibly GSTM1, GSTT1, MTR, and MTHFR-are responsible for a large part of the interindividual variation in As metabolism and susceptibility.     

Metabolic profile in workers occupationally exposed to arsenic: role of GST polymorphisms

Arsenic is a well-known human carcinogen with a ubiquitous distribution in the natural environment. Chronic exposure to inorganic arsenic involves a biotransformation process that leds to the main excretion of organic methylated metabolites, such as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as the parental inorganic species. Interindividual variation in arsenic metabolism has been extensively reported, and polymorphisms in genes involved in such process could be related to changes in the arsenic excretion profile and the response to chronic exposures. Our analysis of the metabolic profiles in three groups of workers exposed to different arsenic exposure levels showed high amounts of inorganic arsenic and MMA in the most-exposed workers versus the least-exposed workers, in whom high amounts of DMA were observed. With respect to the role of different genetic polymorphisms in the glutathione S-transferase (GST) genes in the modulation of the urinary profiles, for the overall population only a tendency was just observed between GSTM1 null and MMA excretion as well as between GSTP1 val/val and DMA excretion.     

内蒙古不同浓度砷暴露人群尿砷代谢产物研究

目的 测定内蒙古地区饮用高砷水人群尿砷代谢产物，探讨不同人群砷代谢的特点。方法 采用氢化物发生原子吸收分光光度法检测尿中不同形态的砷代谢产物。结果 2个暴露组人群尿中无机砷（iAs，inorganic arserlic）、甲基砷（MMA，monomethylarsine）、二甲基砷（DMA．dimethylarsine）和总砷（TAs，total arserlic）均高于对照组（P〈0．05）；同样砷暴露水平下，尿中各形态砷含量及其相对比在不同性别问的差异均无统计学意义（P〉0．05），儿童DMA／MMA和DMA％高于成人（P〈0．05），MMA％低于成人（P〈0．05）；2个暴露组儿童、成人分别与对照组比较，暴露组MMA／ias、DMA／MMA、DMA／iAs、DMA％显降低（P〈0．05），而iAs％、MMA％显增高（P〈0．05）；高暴露组与低暴露组相比，儿童DMA／MMA、DMA／iAs、DMA％显增高（P〈0．05），iAs％、MMA％显降低（P〈0．05）。结论 相同砷暴露水平下，男女对砷的甲基化能力无差别，儿童二甲基化能力高于成人。高砷暴露可能降低人群对砷的生物甲基化能力。[编按]     

GSTM1及GSTT1基因多态性与宫颈癌关系的研究

目的：探讨GSTM1及GSTT1基因多态性与宫颈癌发生的关系.方法：采用以医院为基础的病例对照及分子流行病学研究方法,应用多重PCR技术检测125例宫颈癌病例和125例子宫肌瘤对照的GSTM1和GSTT1基因型.结果：病例组GSTM1基因纯合缺失率为58.4%,显著高于对照组43.2%（x^2=5.777,P=0.016）;GSTT1基因纯合缺失率在病例组和对照组分别为53.6%和44.0%,差别无统计学意义（x^2=2.305,P=0.129）;GSTM1和GSTT1联合缺失者患宫颈癌的危险性是两基因同时存在者的2.588倍（95%CI=1.285～5.212）.结论：GSTM1基因纯合缺失或GSTM1、GSTT1联合缺失可能与宫颈癌的发生有关.     

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。     

Arsenic methylation, GSTT1, GSTM1, GSTP1 polymorphisms, and skin lesions

OBJECTIVE: We investigated whether primary and secondary arsenic methylation ratios were associated with skin lesions and whether GSTT1, GSTP1, and GSTM1 polymorphisms modify these relationships. METHODS: A case-control study of 600 cases and 600 controls that were frequency matched on age and sex was conducted in Pabna, Bangladesh, in 2001-2002. Individual well water, urine, and blood samples were collected. Water arsenic concentration was determined using inductively coupled plasma mass spectrometry (ICP-MS). Urinary arsenic speciation was determined using high performance liquid chromatography hydride with generator atomic absorption spectrometry and ICP-MS. Genotyping was conducted using multiplex polymerase chain reaction and TaqMan. RESULTS: A 10-fold increase in primary methylation ratio [monomethylarsonic acid (MMA)/(arsenite + arsenate] was associated with a 1.50-fold increased risk of skin lesions (multivariate odds ratio = 1.50; 95% confidence interval, 1.00-2.26). We observed significant interaction on the multiplicative scale between GSTT1 wildtype and secondary methylation ratio [dimethylarsinic acid/MMA; likelihood ratio test (LRT), p = 0.01]. No significant interactions were observed for GSTM1 or GSTP1 or for primary methylation ratios. CONCLUSION: Our findings suggest that increasing primary methylation ratios are associated with an increase in risk of arsenic-related skin lesions. The interaction between GSTT1 wildtype and secondary methylation ratio modifies risk of skin lesions among arsenic-exposed individuals.     

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