我国人群邻苯二甲酸酯暴露评估及DINP影响哮喘发作的机制研究

发布时间：2018-03-19 05:18

本文选题：邻苯二甲酸酯　切入点：DEHP　出处：《复旦大学》2013年硕士论文　论文类型：学位论文

【摘要】：邻苯二甲酸酯(phthalates)主要作为增塑剂使用,添加到塑料中以增强塑料产品的弹性、透明度、耐用性和使用寿命。随着phthalates的广泛使用,大量phthalates进入生态环境,通过食物链富集,最终经呼吸、饮食、饮水等途径,进入人体,可在尿液、血液、乳汁、脂肪、精液等人体样品中检出。近年来,对phthalates的环境和人体监测数据呈指数性增长,但儿童作为高暴露人群,其体内phthalates内暴露数据亟待补充。邻苯二甲酸二乙基己酯(di-2-ethylhexyl phthalate, DEHP)和邻苯二甲酸二异壬酯(diisononyl phthalate, DINP)是目前使用量最大的两类phthalates,具有生殖发育毒性和一定的免疫毒性。己有研究显示,DEHP暴露对哮喘发作呈现免疫佐剂作用,但关于DINP暴露与哮喘之间的关联研究仍较为缺乏,特别是敏感窗口期暴露的影响。本研究以探索我国一般人群phthalates暴露全貌为目的,纳入、分析了2000年到2012年公开发表的61篇文献,利用地理信息系统(geographic information system,GIS)分析该类化学物在环境介质中的浓度及地理分布状况,利用经验公式计算长江三角洲和珠江三角洲地区非职业暴露人群的phthalates摄入量。结果显示,过去12年里,我国大部分地区的phthalates环境污染逐渐加重,且污染程度存在地区差异,以广东省和我国北部地区污染最为严重；珠江三角洲地区phthalates和DEHP的人群每日摄入量分别为128.6和61.3μg/kg体重,明显高于长江三角洲地区人群(33.9和24.7μg/kg体重)。在探索我国一般人群暴露水平的基础上,本研究重点分析了高暴露人群(儿童)DEHP和DINP代谢物的内暴露水平。采用高效液相色谱-双质谱联用技术测定了2012年上海市嘉定区学龄期儿童393例尿液样品中DEHP代谢物MEHP、MEHHP、 MEOHP和DINP代谢物MiNP的浓度。结果显示,学龄期儿童普遍检出MEHP、 MEHHP和MEOHP的暴露,且MEHP、MEHHP、和MEOHP的暴露中位数分别为1.20、8.79和3.39μg/L:MiNP的检出水平相对较低,检出范围为未检出～13.37μg/L,检出率为21.6%；儿童年龄与其体内的phthalates水平呈显著负相关。鉴于儿童是哮喘的高发病人群,低年龄儿童是邻苯二甲酸酯的高暴露人群,且DINP的儿童暴露有上升的趋势,因此本研究利用动物实验探索DINP生命早期暴露与哮喘的关联及其影响哮喘发作可能的作用机制。在宫内暴露和哺乳期(孕7天(gestational day (GD)7)至出生后21天(postnatal day (PND)21)), Wistar孕鼠灌胃染毒DINP(染毒浓度分别为5、50和500mg/kg/d,溶剂对照为玉米油组)；分别于PND22、PND23、PND37对仔鼠进行OVA致敏,PND44天开始对其进行OVA雾化激发,连续激发两天。最后一次雾化激发后,测定其气道阻力和肺顺应性,观察肺组织病理切片,并测定PI3K/Akt信号通路相关细胞因子的浓度。数据显示,与玉米油对照组相比,50mg/kg/d DINP染毒组仔鼠的气道反应性增强,嗜酸性粒细胞比例增多,Akt磷酸化程度、NF-κB转录活性和Th2细胞因子表达均增强,并与玉米油对照组间存在统计学差异；而5和500mg/kg/d DINP剂量组未发现明显免疫促进作用。由此可见,一定剂量DINP宫内和哺乳期染毒可增强OVA对F1代仔鼠哮喘发作的激发作用,具促敏作用,而PI3K/Akt信号通路是其促敏作用的可能机制之一。
[Abstract]:Phthalic acid esters (two phthalates) is mainly used as a plasticizer is added to the plastic plastic products in order to enhance the flexibility, transparency, durability and service life. With the widespread use of phthalates, a large number of phthalates into the ecological environment, enriched through the food chain, eventually by breathing, eating, drinking and other ways to enter the human body, can in the urine, blood, milk, fat, and other human semen samples were detected. In recent years, the phthalates environment and human monitoring data exponentially, but children as high exposure group, the phthalates in vivo exposure data to be added.
The adjacent benzene two formic acid two ethylhexyl (di-2-ethylhexyl phthalate, DEHP) and the adjacent benzene two formic acid two isononylphtalate (diisononyl phthalate DINP) is currently using two kinds of phthalates maximum, with reproductive and developmental toxicity and immune toxicity. It has been showed that DEHP exposure showed immune adjuvant effect on asthma. But the research on association between DINP exposure and asthma are still relatively poor, especially the effects of exposure to sensitive window period.
This study explores phthalates China in the general population exposure picture for the purpose of analysis included 61 papers published in 2000 to 2012, the use of geographic information system (geographic information system, GIS) and the concentration of chemical substances in environment medium physical distribution, non occupation exposure phthalates intake calculation the Yangtze River Delta and Pearl River Delta region using empirical formula. The results show that in the past 12 years, most of China's phthalates environmental pollution is aggravating gradually, the regional difference and the degree of pollution, to Guangdong province and North China's most serious pollution; phthalates and DEHP of the Pearl River Delta region people daily intake respectively. 128.6 and 61.3 g/kg body weight was significantly higher than that of the crowd in the Yangtze River Delta (33.9 and 24.7 g/kg body weight).
In the exploration of the general population in China based on the exposure level, this study focuses on the analysis of the high exposure group (children) DEHP and DINP metabolite exposure level. By high performance liquid chromatography - mass spectrometry for determination of Shanghai city in 2012 for Jiading District school-age children with 393 urine samples of DEHP metabolites of MEHP, MEHHP. The concentration of MEOHP and DINP metabolites of MiNP. The results showed that school-age children generally detected MEHP, MEHHP and MEOHP exposure, and MEHP, MEHHP, and MEOHP respectively. The median exposure detection level 1.20,8.79 and 3.39 g/L:MiNP is relatively low, the detection range is not detected ~ 13.37 g/L, the detection rate was 21.6%; a a significant negative correlation with the age of children in the level of phthalates.
In view of the high incidence of asthma in children is a group of patients, low age children is high population exposed to the adjacent benzene two formic acid ester, and DINP exposed children are on the rise, so this research using animal experiments to explore DINP early life exposure associated with asthma, asthma and its influence mechanism. In utero exposure and lactation (at day 7 (gestational day (GD) 7) to postnatal day 21 (postnatal) day (PND) 21), pregnant Wistar rats by gavage (DINP concentrations were 5,50 and 500mg/kg/d, for corn oil solvent control group); in PND22, PND23, PND37 of rats were sensitized by OVA PND44 day, started to carry on the OVA inhalation, excited for two consecutive days. The last time the atomization excitation, determination of the airway resistance and lung compliance, to observe the pathological section of lung tissue, concentration and determination of PI3K/Akt signaling pathway related cytokines. Data show that with corn oil Compared with the control group, 50mg/kg/d DINP airway reactivity in offspring were increased, the percentage of eosinophil increased phosphorylation of Akt, enhanced expression of NF- kappa B transcription activity and Th2 cytokines, and there were significant differences between the control group and corn oil; and 5 and 500mg/kg/d DINP dose group found no obvious immunological enhancement. Thus, a certain dose of DINP intrauterine and lactation exposure can enhance the effect of OVA on activation of F1 offspring asthma, and sensitive function, and PI3K/Akt signal pathway is one of the possible mechanism of promoting sensitization.

【学位授予单位】：复旦大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R135

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