孕晚期饮水消毒副产物暴露生物标志与妊娠结局的关系

发布时间：2018-03-24 06:26

  本文选题：生物标志　切入点：消毒副产物　出处：《华中科技大学》2015年博士论文

【摘要】：妊娠结局与母亲孕产期的健康状况、营养水平、环境有害因素暴露和个体遗传背景有密切关系,其中环境因素在妊娠结局发生过程中起着重要作用。孕期任何环境危险因素的暴露均可导致早产、流产、宫内发育迟缓(intrauterine growth retardation, IUGR)、低出生体重(low birth weight, LBW)和出生缺陷等不良妊娠结局的发生。氯化消毒副产物(disinfection by-products, DBPs)是饮用水氯化消毒过程中,化学消毒剂与水源水中的有机污染物发生反应产生的一类环境污染物,广泛存在于人们的日常生活饮用水中。孕妇可通过消化道、皮肤和呼吸道等多种途径直接接触各种DBPs。毒理学研究已表明某些DBPs具有生殖发育毒性,可引起实验动物早产、自发性流产、子代存活率降低、出生体重降低以及出生缺陷等各种不良妊娠结局的发生。国外围绕孕期DBPs暴露和妊娠结局的关系开展了大量流行病学研究,但是研究结论并不一致。目前,大部分流行病学研究采用管网水中DBPs浓度作为外暴露标志进行DBPs暴露致不良妊娠结局的风险评估,极少研究使用体内DBPs生物标志进行暴露风险评估。 本文采用队列研究,围绕DBPs暴露和妊娠结局的关系开展流行病学调查。通过使用产妇孕晚期血液三卤甲烷(trihalomethanes, THMs)和尿液三氯乙酸(trichloroacetic acid, TCAA)为暴露生物标志,评估个体DBPs内暴露水平,以新生儿生长发育指标作为妊娠结局的效应指标,分析DBPs暴露与妊娠结局之间的关联,探讨DBPs暴露生物标志在流行病学调查中的可行性及其影响因素,提供基于我国女性人群的DBPs暴露致生殖损害的基础研究资料。 第一部分孕晚期血液THMs水平与妊娠结局的关系 目的：以产妇孕晚期血液THMs含量作为饮水DBPs暴露生物标志,探讨产妇孕晚期饮水THMs暴露与妊娠结局的关系。 方法：采用前瞻性队列研究,以2011年7月～2012年6月在湖北省武汉市某医院和2012年10月～2013年12月在湖北省孝感市某医院分娩的1184名产妇为研究对象,采用顶空固相微萃取气相色谱法(solid-phase micro-extraction gas chromatography, SPME-GC)测定产妇孕晚期血液中四种THMs浓度,包括三氯甲烷(chloroform, TCM),一溴二氯甲烷(bromodichloromethane, BDCM),二溴一氯甲烷(dibromochloromethane, DBCM)和三溴甲烷(bromoform, TBM)。血TCM、Br-THMs (BDCM、DBCM和TBM的浓度之和)和总三卤甲烷(total THMs, TTHMs; Br-THMs和TCM浓度之和)水平按三分位数分组,血BDCM、DBCM和TBM水平则以检出限(limit of detection, LOD)和检出浓度的中位数分为三组,采用多元线性回归模型和Logistic回归模型分析探讨产妇孕晚期THMs暴露和妊娠结局之间的关系。妊娠结局指标包括新生儿出生体重、出生身长、出生体质指数(body mass index, BMI)、胎龄、小于胎龄儿(small for gestational age, SGA)和身长别体重。根据中国儿童健康检查服务技术规范,分别以出生BMI和身长别体重为指标,将新生儿分为生长发育水平低于中等水平和高于中等水平两组。 结果：产妇孕晚期血液中TCM、BDCM、DBCM和TBM的检出率分别为92.5%、57.4%、33.5%和22.6%。TCM、Br-THMs和TTHMs的中位数分别为50.7ng/L、5.6ng/L、57.7ng/L,范围分别为未检出～480.3ng/L、未检出～40.2ng/L、未检出～486.7ng/L。在1184名单胎活产的新生儿中,SGA有60例(5.1%),出生BMI低于中等水平的有247例(20.9%),身长别体重低于中等水平的有240例(20.3%)。 多元线性回归分析结果表明产妇孕晚期血TTHMs水平升高与出生体重降低(Pfor trend=0.03)、血BDCM和DBCM水平升高与出生身长减少(P for trend=0.04, P for trend=0.02)、血TCM和TTHMs水平升高与出生BMI减少(P for trend=0.03, P for trend=0.01)均存在剂量—反应关系。Logistic回归分析结果发现与TTHMs低暴露组(44.2ng/L)相比,中暴露组(44.2～74.4ng/L)和高暴露组(74.4ng/L) SGA发生风险增加(OR=2.91,95%CI:1.32,6.42; OR=2.25,95%CI:1.01,5.03),产妇孕晚期血TTHMs水平增高与SGA发生风险增加存在建议性剂量—反应关系(P for trend=0.08)。 结论：产妇孕晚期血THMs水平增高可引起新生儿出生体重降低、出生身长减少、SGA发生风险增加,提示孕晚期THMs暴露可能影响妊娠结局。 第二部分孕晚期尿TCAA水平与妊娠结局的关系 目的：以产妇孕晚期TCAA作为饮水DBPs的暴露生物标志,探讨产妇孕晚期饮水TCAA暴露与妊娠结局的关系。 方法：选择2011年7月～2012年6月在湖北省武汉市某医院和2012年10月～2013年12月在湖北孝感市某医院分娩的1306名产妇为研究对象,采用液液萃取气相色谱法(liquid-liquid extraction-gas chromatography, LLE-GC)测定产妇孕晚期晨尿中TCAA浓度,将尿TCAA浓度按四分位数分组,采用多元线性回归模型和Logistic回归模型分析产妇孕晚期尿TCAA浓度与妊娠结局之间的关系。妊娠结局指标包括新生儿出生体重、出生身长、出生BMI、胎龄、SGA和身长别体重。根据中国儿童健康检查服务技术规范,分别以出生BMI和身长别体重为指标,将新生儿分为生长发育水平低于中等水平和高于中等水平两组。 结果：产妇孕晚期尿TCAA的检出率为97.9%,检出范围为未检出～82.5μg/L,中位数为6.7μg/L,平均值为8.7μg/L。在1306名单胎活产的新生儿中,SGA有68例(5.2%),新生儿出生BMI低于中等水平的有307例(23.5%),身长别体重低于中等水平的新生儿有256例(19.6%)。 多元线性回归分析结果表明,与对照组相比(4.8μg/L),产妇孕晚期TCAA高暴露组(10.0gg/L)的新生儿平均出生体重降低了96.8g(95%CI：-158.23,-35.36),平均出生BMI减少了0.35kg/m2(95%CI:-0.57,-0.13). Logistic回归分析结果表明,与TCAA对照组(4.8μg/L)相比,产妇孕晚期TCAA高暴露组(10.01ag/L)的新生儿出生BMI (OR=1.83,95%CI:1.22,2.73)和身长别体重(OR=1.90,95%CI:1.23,2.94)低于中等水平的风险增加。 结论：产妇孕晚期尿TCAA浓度增高可能与新生儿出生体重降低、出生BMI减少有关,提示孕晚期饮水TCAA暴露可能影响妊娠结局。 第三部分孕晚期饮水DBPs内暴露水平影响因素的研究 目的：调查孕晚期DBPs内暴露水平的影响因素,为饮水DBPs暴露评估提供科学依据。 方法：从2011年～2013年在湖北武汉市和孝感市参加DBPs暴露与妊娠结局关系队列研究的产妇中,选择892名同时提供血样和尿样的产妇作为研究对象,采用广义线性回归模型分析探讨产妇孕晚期DBPs内暴露水平的影响因素;从892名产妇中选择居住在某同一水厂供水区域内的354名产妇为研究对象,监测孕期居住地管网水中THMs和TCAA的浓度,采用广义线性回归模型分析探讨产妇孕晚期DBPs内暴露水平和管网水中DBPs浓度及其他影响因素之间的关系。 结果：①血TCM水平在武汉市(β=-0.22,P0.01)、冬季采样(β=-0.30,P0.01)、产前BMI高(β=-0.01,P0.05)、饮水煮沸(β=-0.15,P0.05)和家庭收入高(β=-0.20,P0.01)的产妇中含量较低；②血Br-THMs (BDCM、DBCM和TBM浓度之和)在孝感市(β=-0.08,P0.01)、秋季采样(β=-0.11,P0.01)、和妊娠期糖尿病(β=-0.10,P0.05)的产妇中含量较低；③血TTHMs (TCM和Br-THMs浓度之和)水平在武汉市(β=-0.11,P0.01)、冬季采样(β=-0.17,P0.01)、饮水煮沸(β=-0.12,P0.05)和家庭收入高(≥5000元)(β=-0.14,P0.05)的产妇中含量较低；④尿TCAA浓度在冬季采样的产妇中比春季低(p=-0.30,P0.01),且与管网水TCAA浓度呈正相关(β=0.49,P0.01)。 结论：研究地区、生物样本采样季节、管网水DBPs浓度、饮水煮沸、产前BMI、妊娠期糖尿病和家庭收入都可能影响DBPs内暴露水平,在今后开展孕产妇人群DBPs暴露风险评估的流行病学研究中应该予以考虑。
[Abstract]:And the outcome of mother pregnancy pregnancy health status, nutrition level, exposure to harmful environmental factors closely related to the individual genetic background, environmental factors play an important role in the process of pregnancy outcome in pregnancy. Any environmental risk factors exposure can lead to premature birth, abortion, intrauterine growth retardation (intrauterine growth, retardation, IUGR), low birth weight (low birth weight, LBW) and birth defects and other adverse pregnancy outcomes. Disinfection by-products (disinfection by-products DBPs) is the chlorination of drinking water disinfection process, chemical disinfectants and organic pollutants in water has a class of environmental pollutants produced by the reaction, widely exists in people's daily life drinking water. Pregnant women through the digestive tract, toxicology study of various DBPs. direct contact with the skin and respiratory tract and other ways have shown that some DBPs have reproductive Developmental toxicity, can cause animal spontaneous abortion, premature birth, offspring survival rate, low birth weight and birth defects and other adverse pregnancy outcomes occurred during pregnancy DBPs exposure. Studies on the pregnancy outcome of carried out a large number of epidemiological studies, but the conclusions are not consistent. At present, most epidemiological studies by the concentration of DBPs in water as a sign of external exposure exposure risk assessment of adverse pregnancy outcome DBPs, very few studies of exposure risk assessment using in vivo DBPs biomarkers.
This cohort study, carry out epidemiological investigations of the relationship between DBPs exposure on pregnancy outcomes and maternal pregnancy. Through the use of blood Three trihalomethanes (trihalomethanes, THMs) and urine (trichloroacetic acid three chloroacetic acid, TCAA) as a biomarker of exposure assessment, a DBPs exposure level, neonatal growth and development index as indicators of effect of pregnancy in the end, to analyze the association between DBPs exposure and outcome of pregnancy, explore the feasibility and influence of biomarkers in epidemiologic survey of factors of DBPs exposure, China's female population exposed to DBPs reproductive toxicity induced by basic research based on the data.
The relationship between blood THMs level and pregnancy outcome in the first part of the first trimester of pregnancy
Objective: To explore the relationship between THMs exposure and pregnancy outcome in the late pregnancy of pregnant women by taking the content of THMs in the late pregnant women as a biomarker for drinking water DBPs exposure.
Methods: a prospective cohort study from July 2011 to June 2012 in December 2013 in a hospital and Hubei city of Wuhan Province in October 2012 to 1184 delivery in a hospital in Xiaogan city of Hubei Province as the research object, using headspace solid phase microextraction gas chromatography (solid-phase micro-extraction gas chromatography, SPME-GC) for the determination of four kinds of THMs concentration in maternal pregnancy in the blood, including chloroform (chloroform, TCM), bromodichloromethane (bromodichloromethane, BDCM), dibromochloromethane (dibromochloromethane, DBCM) and three methyl bromide (bromoform, TBM). The levels of TCM, Br-THMs (BDCM, DBCM and TBM concentration and total trihalomethanes (three) and total THMs TTHMs; Br-THMs and the concentration of TCM and the level of the three percentile) according to the group, the blood BDCM, DBCM and TBM levels in the detection limit (limit of detection, LOD) and detected the median concentration divided into three groups. Using multiple linear regression model and Logistic regression model analysis to explore the relationship between maternal pregnancy and pregnancy outcomes between THMs exposure. Pregnancy outcomes included birth weight, birth length and birth weight (body mass index, BMI index), gestational age, gestational age (small for, gestational age, SGA) and body weight according to the China children health inspection service specification, were born BMI length and weight index of newborn can be divided into the growth level is lower than the medium level and higher than the average level of two groups.
Results: the third trimester maternal blood TCM, BDCM, DBCM and TBM detection rate were 92.5%, 57.4%, 33.5% and 22.6%.TCM, median Br-THMs and TTHMs were 50.7ng/L, 5.6ng/L, 57.7ng/L, were not detected detected ~ 480.3ng/L, ~ 40.2ng/L, ~ 486.7ng/L. were detected in 1184 singleton live births in newborns, there were 60 cases of SGA (5.1%), BMI was lower than the middle level of the 247 cases (20.9%), the length of weight below the middle level of the 240 cases (20.3%).
Multiple linear regression analysis showed that elevated maternal pregnancy and blood TTHMs level and lower birth weight (Pfor trend=0.03), serum BDCM and DBCM levels and reduced birth length (P for trend=0.04 P, for trend=0.02), serum TCM and TTHMs levels and decreased BMI (P for trend=0.03 born P for, trend=0.01) there were dose response relationship between the results of.Logistic regression analysis found that the low exposure group (44.2ng/L and TTHMs) than in the exposed group (44.2 ~ 74.4ng/L) and high exposure group (74.4ng/L) increased risk of SGA (OR=2.91,95%CI:1.32,6.42; OR=2.25,95%CI:1.01,5.03), blood TTHMs levels in late pregnancy women at increased risk are recommended dose response with the increase of SGA (P for trend=0.08).
Conclusion: the increase of THMs level in the third trimester of pregnancy can cause birth weight loss, decrease in birth length, and increase the risk of SGA, suggesting that THMs exposure in late pregnancy may affect the outcome of pregnancy.
The relationship between the urine TCAA level and the pregnancy outcome in the second part of the late pregnancy
Objective: To explore the relationship between TCAA exposure and pregnancy outcome in the late pregnancy by using TCAA as a biomarker for drinking water DBPs in the late pregnancy.
Methods: from July 2011 to June 2012 in December 2013 in a hospital and Hubei city of Wuhan province in October 2012 to 1306 delivery in a hospital in Hubei city of Xiaogan as the research object, using liquid-liquid extraction gas chromatography (liquid-liquid extraction-gas chromatography, LLE-GC) TCAA levels were measured in maternal pregnancy urine, the urine TCAA concentration by four points digit grouping, using the relationship between the multiple linear regression model and Logistic regression model analysis of maternal pregnancy and urinary TCAA concentration and pregnancy outcome. Pregnancy outcomes included birth weight, birth length and gestational age, birth BMI, SGA length and weight. According to the Chinese child health inspection service specification, BMI and length respectively by birth weight index of newborn can be divided into the growth level is lower than the medium level and higher than the average level of two groups.
Results: the detection of urinary TCAA maternal pregnancy rate was 97.9%, the detection range is not detected ~ 82.5 g/L, the median was 6.7 g/L, the average value of 8.7 g/L. in 1306 singleton live birth newborns, there were 68 cases of SGA (5.2%), the birth of BMI below the middle level of the 307 cases (23.5%), length weight lower than the middle level of the newborn in 256 cases (19.6%).
Multiple linear regression analysis showed that compared with the control group (4.8 g/L), maternal pregnancy TCAA high exposure group (10.0gg/L) the average birth weight decreased by 96.8g (95%CI:-158.23, -35.36), the average birth BMI reduced 0.35kg/m2 (95%CI:-0.57, -0.13). Logistic regression analysis showed that with the TCAA control group (4.8 g/L) compared to maternal pregnancy TCAA high exposure group (10.01ag/L) of the BMI (OR=1.83,95%CI:1.22,2.73) and neonatal birth weight length (OR=1.90,95%CI:1.23,2.94) lower than the increased risk in the middle level.
Conclusion: the increase of urinary TCAA concentration in the third trimester of pregnancy may be related to the decrease of birth weight and the decrease of birth BMI, suggesting that TCAA exposure in late pregnancy may affect the outcome of pregnancy.
Study on the factors influencing the exposure level of drinking water DBPs in the third part of the third trimester
Objective: To investigate the factors affecting the level of DBPs exposure in the late pregnancy, and to provide a scientific basis for the assessment of DBPs exposure in drinking water.
Methods: from 2011 to 2013 in Hubei, Wuhan city and Xiaogan city in the maternal DBPs exposure and pregnancy outcomes in a cohort study, 892 at the same time provide the blood and urine of pregnant women as the research object, using the generalized linear regression model to analyze the influencing factors of maternal pregnancy and DBPs exposure; choose 354 women living in the water supply in the region from the 892 women as the research object, monitoring the concentration of THMs and TCAA in water residence during pregnancy, using the generalized linear regression model to explore the relationship between maternal pregnancy and DBPs exposure levels and DBPs concentrations in water and other factors.
缁撴灉锛氣憼琛，

本文编号：1657121