本文選題：生物標(biāo)志　切入點(diǎn)：消毒副產(chǎn)物　出處：《華中科技大學(xué)》2015年博士論文

【摘要】：妊娠結(jié)局與母親孕產(chǎn)期的健康狀況、營(yíng)養(yǎng)水平、環(huán)境有害因素暴露和個(gè)體遺傳背景有密切關(guān)系,其中環(huán)境因素在妊娠結(jié)局發(fā)生過(guò)程中起著重要作用。孕期任何環(huán)境危險(xiǎn)因素的暴露均可導(dǎo)致早產(chǎn)、流產(chǎn)、宮內(nèi)發(fā)育遲緩(intrauterine growth retardation, IUGR)、低出生體重(low birth weight, LBW)和出生缺陷等不良妊娠結(jié)局的發(fā)生。氯化消毒副產(chǎn)物(disinfection by-products, DBPs)是飲用水氯化消毒過(guò)程中,化學(xué)消毒劑與水源水中的有機(jī)污染物發(fā)生反應(yīng)產(chǎn)生的一類(lèi)環(huán)境污染物,廣泛存在于人們的日常生活飲用水中。孕婦可通過(guò)消化道、皮膚和呼吸道等多種途徑直接接觸各種DBPs。毒理學(xué)研究已表明某些DBPs具有生殖發(fā)育毒性,可引起實(shí)驗(yàn)動(dòng)物早產(chǎn)、自發(fā)性流產(chǎn)、子代存活率降低、出生體重降低以及出生缺陷等各種不良妊娠結(jié)局的發(fā)生。國(guó)外圍繞孕期DBPs暴露和妊娠結(jié)局的關(guān)系開(kāi)展了大量流行病學(xué)研究,但是研究結(jié)論并不一致。目前,大部分流行病學(xué)研究采用管網(wǎng)水中DBPs濃度作為外暴露標(biāo)志進(jìn)行DBPs暴露致不良妊娠結(jié)局的風(fēng)險(xiǎn)評(píng)估,極少研究使用體內(nèi)DBPs生物標(biāo)志進(jìn)行暴露風(fēng)險(xiǎn)評(píng)估。 本文采用隊(duì)列研究,圍繞DBPs暴露和妊娠結(jié)局的關(guān)系開(kāi)展流行病學(xué)調(diào)查。通過(guò)使用產(chǎn)婦孕晚期血液三鹵甲烷(trihalomethanes, THMs)和尿液三氯乙酸(trichloroacetic acid, TCAA)為暴露生物標(biāo)志,評(píng)估個(gè)體DBPs內(nèi)暴露水平,以新生兒生長(zhǎng)發(fā)育指標(biāo)作為妊娠結(jié)局的效應(yīng)指標(biāo),分析DBPs暴露與妊娠結(jié)局之間的關(guān)聯(lián),探討DBPs暴露生物標(biāo)志在流行病學(xué)調(diào)查中的可行性及其影響因素,提供基于我國(guó)女性人群的DBPs暴露致生殖損害的基礎(chǔ)研究資料。 第一部分孕晚期血液THMs水平與妊娠結(jié)局的關(guān)系 目的：以產(chǎn)婦孕晚期血液THMs含量作為飲水DBPs暴露生物標(biāo)志,探討產(chǎn)婦孕晚期飲水THMs暴露與妊娠結(jié)局的關(guān)系。 方法：采用前瞻性隊(duì)列研究,以2011年7月～2012年6月在湖北省武漢市某醫(yī)院和2012年10月～2013年12月在湖北省孝感市某醫(yī)院分娩的1184名產(chǎn)婦為研究對(duì)象,采用頂空固相微萃取氣相色譜法(solid-phase micro-extraction gas chromatography, SPME-GC)測(cè)定產(chǎn)婦孕晚期血液中四種THMs濃度,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的濃度之和)和總?cè)u甲烷(total THMs, TTHMs; Br-THMs和TCM濃度之和)水平按三分位數(shù)分組,血BDCM、DBCM和TBM水平則以檢出限(limit of detection, LOD)和檢出濃度的中位數(shù)分為三組,采用多元線(xiàn)性回歸模型和Logistic回歸模型分析探討產(chǎn)婦孕晚期THMs暴露和妊娠結(jié)局之間的關(guān)系。妊娠結(jié)局指標(biāo)包括新生兒出生體重、出生身長(zhǎng)、出生體質(zhì)指數(shù)(body mass index, BMI)、胎齡、小于胎齡兒(small for gestational age, SGA)和身長(zhǎng)別體重。根據(jù)中國(guó)兒童健康檢查服務(wù)技術(shù)規(guī)范,分別以出生BMI和身長(zhǎng)別體重為指標(biāo),將新生兒分為生長(zhǎng)發(fā)育水平低于中等水平和高于中等水平兩組。 結(jié)果：產(chǎn)婦孕晚期血液中TCM、BDCM、DBCM和TBM的檢出率分別為92.5%、57.4%、33.5%和22.6%。TCM、Br-THMs和TTHMs的中位數(shù)分別為50.7ng/L、5.6ng/L、57.7ng/L,范圍分別為未檢出～480.3ng/L、未檢出～40.2ng/L、未檢出～486.7ng/L。在1184名單胎活產(chǎn)的新生兒中,SGA有60例(5.1%),出生BMI低于中等水平的有247例(20.9%),身長(zhǎng)別體重低于中等水平的有240例(20.3%)。 多元線(xiàn)性回歸分析結(jié)果表明產(chǎn)婦孕晚期血TTHMs水平升高與出生體重降低(Pfor trend=0.03)、血BDCM和DBCM水平升高與出生身長(zhǎng)減少(P for trend=0.04, P for trend=0.02)、血TCM和TTHMs水平升高與出生BMI減少(P for trend=0.03, P for trend=0.01)均存在劑量—反應(yīng)關(guān)系。Logistic回歸分析結(jié)果發(fā)現(xiàn)與TTHMs低暴露組(44.2ng/L)相比,中暴露組(44.2～74.4ng/L)和高暴露組(74.4ng/L) SGA發(fā)生風(fēng)險(xiǎn)增加(OR=2.91,95%CI:1.32,6.42; OR=2.25,95%CI:1.01,5.03),產(chǎn)婦孕晚期血TTHMs水平增高與SGA發(fā)生風(fēng)險(xiǎn)增加存在建議性劑量—反應(yīng)關(guān)系(P for trend=0.08)。 結(jié)論：產(chǎn)婦孕晚期血THMs水平增高可引起新生兒出生體重降低、出生身長(zhǎng)減少、SGA發(fā)生風(fēng)險(xiǎn)增加,提示孕晚期THMs暴露可能影響妊娠結(jié)局。 第二部分孕晚期尿TCAA水平與妊娠結(jié)局的關(guān)系 目的：以產(chǎn)婦孕晚期TCAA作為飲水DBPs的暴露生物標(biāo)志,探討產(chǎn)婦孕晚期飲水TCAA暴露與妊娠結(jié)局的關(guān)系。 方法：選擇2011年7月～2012年6月在湖北省武漢市某醫(yī)院和2012年10月～2013年12月在湖北孝感市某醫(yī)院分娩的1306名產(chǎn)婦為研究對(duì)象,采用液液萃取氣相色譜法(liquid-liquid extraction-gas chromatography, LLE-GC)測(cè)定產(chǎn)婦孕晚期晨尿中TCAA濃度,將尿TCAA濃度按四分位數(shù)分組,采用多元線(xiàn)性回歸模型和Logistic回歸模型分析產(chǎn)婦孕晚期尿TCAA濃度與妊娠結(jié)局之間的關(guān)系。妊娠結(jié)局指標(biāo)包括新生兒出生體重、出生身長(zhǎng)、出生BMI、胎齡、SGA和身長(zhǎng)別體重。根據(jù)中國(guó)兒童健康檢查服務(wù)技術(shù)規(guī)范,分別以出生BMI和身長(zhǎng)別體重為指標(biāo),將新生兒分為生長(zhǎng)發(fā)育水平低于中等水平和高于中等水平兩組。 結(jié)果：產(chǎn)婦孕晚期尿TCAA的檢出率為97.9%,檢出范圍為未檢出～82.5μg/L,中位數(shù)為6.7μg/L,平均值為8.7μg/L。在1306名單胎活產(chǎn)的新生兒中,SGA有68例(5.2%),新生兒出生BMI低于中等水平的有307例(23.5%),身長(zhǎng)別體重低于中等水平的新生兒有256例(19.6%)。 多元線(xiàn)性回歸分析結(jié)果表明,與對(duì)照組相比(4.8μg/L),產(chǎn)婦孕晚期TCAA高暴露組(10.0gg/L)的新生兒平均出生體重降低了96.8g(95%CI：-158.23,-35.36),平均出生BMI減少了0.35kg/m2(95%CI:-0.57,-0.13). Logistic回歸分析結(jié)果表明,與TCAA對(duì)照組(4.8μg/L)相比,產(chǎn)婦孕晚期TCAA高暴露組(10.01ag/L)的新生兒出生BMI (OR=1.83,95%CI:1.22,2.73)和身長(zhǎng)別體重(OR=1.90,95%CI:1.23,2.94)低于中等水平的風(fēng)險(xiǎn)增加。 結(jié)論：產(chǎn)婦孕晚期尿TCAA濃度增高可能與新生兒出生體重降低、出生BMI減少有關(guān),提示孕晚期飲水TCAA暴露可能影響妊娠結(jié)局。 第三部分孕晚期飲水DBPs內(nèi)暴露水平影響因素的研究 目的：調(diào)查孕晚期DBPs內(nèi)暴露水平的影響因素,為飲水DBPs暴露評(píng)估提供科學(xué)依據(jù)。 方法：從2011年～2013年在湖北武漢市和孝感市參加DBPs暴露與妊娠結(jié)局關(guān)系隊(duì)列研究的產(chǎn)婦中,選擇892名同時(shí)提供血樣和尿樣的產(chǎn)婦作為研究對(duì)象,采用廣義線(xiàn)性回歸模型分析探討產(chǎn)婦孕晚期DBPs內(nèi)暴露水平的影響因素;從892名產(chǎn)婦中選擇居住在某同一水廠供水區(qū)域內(nèi)的354名產(chǎn)婦為研究對(duì)象,監(jiān)測(cè)孕期居住地管網(wǎng)水中THMs和TCAA的濃度,采用廣義線(xiàn)性回歸模型分析探討產(chǎn)婦孕晚期DBPs內(nèi)暴露水平和管網(wǎng)水中DBPs濃度及其他影響因素之間的關(guān)系。 結(jié)果：①血TCM水平在武漢市(β=-0.22,P0.01)、冬季采樣(β=-0.30,P0.01)、產(chǎn)前BMI高(β=-0.01,P0.05)、飲水煮沸(β=-0.15,P0.05)和家庭收入高(β=-0.20,P0.01)的產(chǎn)婦中含量較低；②血Br-THMs (BDCM、DBCM和TBM濃度之和)在孝感市(β=-0.08,P0.01)、秋季采樣(β=-0.11,P0.01)、和妊娠期糖尿病(β=-0.10,P0.05)的產(chǎn)婦中含量較低；③血TTHMs (TCM和Br-THMs濃度之和)水平在武漢市(β=-0.11,P0.01)、冬季采樣(β=-0.17,P0.01)、飲水煮沸(β=-0.12,P0.05)和家庭收入高(≥5000元)(β=-0.14,P0.05)的產(chǎn)婦中含量較低；④尿TCAA濃度在冬季采樣的產(chǎn)婦中比春季低(p=-0.30,P0.01),且與管網(wǎng)水TCAA濃度呈正相關(guān)(β=0.49,P0.01)。 結(jié)論：研究地區(qū)、生物樣本采樣季節(jié)、管網(wǎng)水DBPs濃度、飲水煮沸、產(chǎn)前BMI、妊娠期糖尿病和家庭收入都可能影響DBPs內(nèi)暴露水平,在今后開(kāi)展孕產(chǎn)婦人群DBPs暴露風(fēng)險(xiǎn)評(píng)估的流行病學(xué)研究中應(yīng)該予以考慮。
[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.
緇撴灉錛氣憼琛，

本文編號(hào)：1657121