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题名	典型有机磷酸酯类阻燃剂对稀有鮈鲫的胚胎发育毒性及神经毒性的研究
作者	袁立来
学位类别	博士后
答辩日期	2016-07
授予单位	中国科学院研究生院
授予地点	北京
导师	王子健 ; 查金苗
关键词	稀有鮈鲫，有机磷酸酯阻燃剂，暴露实验，胚胎发育毒性，神经毒性，转录组, 基因表达 rare minnow, OPFRs, exposure tests, developmental toxicity，neurotoxicity，transcriptome，gene expression
学位专业	环境科学
中文摘要	随着溴系阻燃剂被逐步禁用，有机磷酸酯阻燃剂（OPFRs）作为其替代品被大量的生产和使用，目前，OPFRs在许多环境样品被检测到，例如：室内的空气和尘埃，污水、饮用水、河流湖泊等。不仅如此，这类物质还在生物系统中被发现，例如：鱼类及贝类的组织中。由于广泛存在于各种环境介质中，OPFRs对人和动物潜在的危害性不容忽视；然而，目前有关这类物质毒性的评估和研究还十分不足。尽管如此，研究者们利用各种模式生物测试平台评估了OPFRs诱发的相关毒性效应，发现OPFRs暴露可能导致多种毒性效应，主要包括：细胞、遗传毒性及氧化应激效应，致癌致畸效应，内分泌干扰效应，神经毒性效应以及胚胎发育毒性。虽然这些研究报道了OPFRs诱导的不同类型的毒性效应，但针对这些毒性效应的潜在作用机制的研究还十分不足，因此OPFRs的毒性作用机制还亟待进行大量的研究。本文选取了两个常见的OPFRs：一个氯取代的OPFRs---TDCPP和一个芳烃取代的OPFRs---TPP，以我国特有物种稀有鮈鲫为实验动物，来研究这两个不同取代基的OPFRs对稀有鮈鲫的胚胎发育毒性及神经毒性，主要研究内容包括：       1） TDCPP和TPP对稀有鮈鲫的胚胎发育毒性；本文拟在稀有鮈鲫上对两者的胚胎毒性的致畸效应进行详细对比；然后本文以胚胎发育过程中的心脏毒性为重点，对两者的心脏毒性表型进行详细对比，在此基础上进一步研究两者诱导的心脏毒性机制的异同。       2） TDCPP和TPP对稀有鮈鲫的神经毒性；本研究以CPF为阳性对照，由于CPF的神经毒性包括急性神经毒性以及慢性神经毒性，本文通过短期高浓度的急性暴露实验以及21天相对较低的浓度暴露，来对比研究TDCPP和TPP对稀有鮈鲫的急性神经毒性以及慢性神经毒性效应。       经过相关研究，主要结论如下：       1）在96hpf，TDCPP暴露主要导致稀有鮈鲫幼鱼躯干弯曲，而TPP最显著的畸形特征为严重的心包水肿； TDCPP和TPP暴露均能导致胚胎心脏毒性，包括：心包水肿，心率过缓以及显著增长的SV-BA间距；另外，TDCPP和TPP对稀有鮈鲫胚胎心脏毒性有显著差别，TPP暴露组SV-BA间距显著大于TDCPP组，且心包水肿的概率高达45.7%；而TDCPP组心率变缓效应更显著。       2）CPF与TPP导致的心率过缓效应与mAChR受体有关（或部分相关）；而TDCPP导致的心率过缓效应与mAChR受体无关。        3） 转录组测序筛选的差异表达基因在各暴露组间有差别，但是TDCPP和TPP各暴露组筛选到的心脏毒性相关的信号通路相似。在筛选到的心脏毒性相关信号通路中，主要是与心脏循环系统相关的通路和与心血管疾病相关的信号通路；而筛选的差异表达基因大致分成两大类：一类是心脏肌细胞组成成分相关蛋白；第二类主要是与心肌细胞离子、离子通道及受体相关基因；通过相关验证，表明TDCPP和TPP对稀有鮈鲫胚胎Ca2+ 和 Na+运输过程可能产生干扰，从而导致心肌兴奋-收缩偶联的障碍；       4）TDCPP对胆碱酯酶和神经递质系统影响不显著， TPP虽然对AChE活性表现出一定的抑制效应，但抑制程度远小于CPF，表明OPFRs的急性神经毒性效应不显著；TDCPP和TPP对神经营养因子相关基因有显著的效应，表明与OPs类似，OPFRs也可能通过影响神经营养因子等靶点导致动物的慢性神经毒性。
英文摘要	The phasing out of commercial brominated flame retardants has resulted in a gradual increase in the production and use of organophosphate flame retardants (OPFRs). At present, OPFRs have been detected at high concentrations in various environmental samples, including household dust, indoor air, drinking water, and sediment, as well as biotic samples, such as fishes and mussels. Due to widespread in various environmental media, the potential toxicity of OPFRs to humans and animals can not be ignored. Unfortunately, there are very limited toxicity and health dataavailable for OPFRs.Although little is known about OPFR toxicity, recent studies have shown that exposure to OPFRs has the potential to cause carcinogenic changes, oxidative stress, endocrine disruption, and neurological effects in different organisms.       Although the toxic effects of OPFRs have been studied, the related mechanism remains unclear. In this study, a chlorinated phosphate esters (TDCPP) and an aryl phosphate esters (TPP) were selected to investigate the developmental toxicity and neurotoxicity in Chinese rare minnow. The main contents include:       1) The developmental toxicity of rare minnow embro following TDCPP and TPP exposure. First, the teratogenic effects of rare minnow embro exposed to TDCPP and TPP will be studied. Then, we will focus on the cardiotoxicity induced by TDCPP and TPP, and study the related mechanism.       2) The neurotoxicity of rare minnow following TDCPP and TPP exposure. The purpose was to compare the potential neurotoxicity of the OPFRs with the insecticide CPF in Chinese rare minnow using an acute toxicity test and a 21-day fish assay.       The main conclusions are as follows:       1) Trunk curvature was observed as the main phenotype in 96 hpf rare minnow larvae exposed to TDCPP, while pericardial edema was the main phenotype for TPP exposure. Both TDCPP and TPP induced cardiac toxicity in rare minnow larvae, including pericardial edema, increasing SV-BA distance and bradycardia;       2) The bradycardia induced by CPF and TPP may be related to mAChR, but not for TDCPP.       3) The results of the RNA-seq revealed two categories of pathways in rare minnow embryo following TDCPP and TPP exposure, one is related to cardiovascular circulation, another is cardiovascular diseases; The results of RNA-seq and other results in Chapter 4 indicated that the Ca2+ and Na+ transport in ventricular myocytes may be affected by TDCPP and TPP, a mechanism that may explan the cardiac toxicity observed in rare minnow embryo.       4) The OPFRs had no significant effects on cholinesterase activities in both acute tests and low-dose tests, with the exception of TPP, indicating that unlike OPs (e.g., CPF), OPFRs are not typical neurotoxins. However, TDCPP and TPP did have widespread effects on neurotrophic factor genes, indicating that similar to OPs, TDCPP and TPP may elicit neurological effects by targeting neurotrophic factors and their receptors in Chinese rare minnow.
内容类型	学位论文
源URL	[http://ir.rcees.ac.cn/handle/311016/37042]
专题	生态环境研究中心_环境水质学国家重点实验室
推荐引用方式 GB/T 7714	袁立来. 典型有机磷酸酯类阻燃剂对稀有鮈鲫的胚胎发育毒性及神经毒性的研究[D]. 北京. 中国科学院研究生院. 2016.

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