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四溴双酚A 的生殖毒性效应及分子机制研究
Alternative TitleReproductive Toxicology and Molecular Mechanisms of Tetrabromobisphenol A in Mice
张文娟
Subtype博士后
Thesis Advisor宋茂勇
2019-12
Degree Grantor中国科学院生态环境研究中心
Place of Conferral北京
Degree Name理学
Degree Discipline环境科学
Keyword四溴双酚a,炎症,子宫,细胞因子,甲状腺激素受体 Tetrabromobisphenol a, Inflammation, Uterus, Cytokines, Thyroid Hormone Receptor .
Abstract

       四溴双酚A(TBBPA)作为世界范围内生产量和使用量巨大的溴代阻燃剂,
在环境介质中广泛分布,对生态环境和人类健康存在潜在危害。在毒理学研究发
现TBBPA 具有内分泌干扰毒性、免疫毒性、神经毒性和肝脏毒性,但是缺少与
人体内暴露水平相关的内暴露剂量下的毒性效应及机制的研究。本研究首先建立
分析人体血液中TBBPA 内暴露水平方法,明确我国女性人群中TBBPA 的内暴
露水平;建立TBBPA 的动物暴露模型,确定小鼠血液与人群血液中TBBPA 的
内暴露水平相近;分析TBBPA 在人群内暴露水平下对小鼠的毒性效应,发现
TBBPA 可导致小鼠子宫炎性损伤,降低甲状腺激素受体(THR)的蛋白表达
水平;为验证THR在TBBPA 致小鼠子宫炎症损伤的分子调控机制,用GC-1
(THR特异性激活剂)激活THR,发现TBBPA 诱导的小鼠子宫炎性损伤恢
复,提示TBBPA 通过THR介导的PI3K/NF-B 信号通路导致小鼠子宫炎症损
伤;利用生物信息学技术分析预测TBBPA 可增加女性罹患子宫内膜癌风险。综
上,本研究在人群内暴露水平相关内暴露浓度下评价TBBPA 的毒性效应和分子
调控机制,预测TBBPA 污染对人群的健康风险,为综合评价TBBPA 的环境健
康危害以提供科学依据。

Other Abstract

      Tetrabromobisphenol A (TBBPA) as brominated flame retardant was used in plastic products and widely distributed in environmental and biological samples, which had potential harm to ecological environment and human health. Toxicological studies showed that TBBPA has endocrine-disrupting toxicity, immunotoxicity, neurotoxicity
and hepatotoxicity, but limited publications report that toxicological effects and of TBBPA at environmental relate or real human internal exposure dose. In this study, we analyzed the internal exposure level of TBBPA in blood of women and mice by liquid chromatography-tandem mass spectrometry, and established the TBBPA exposure model in mice. The toxicological effects of TBBPA on mice at internal exposure of
human relevant dose. The results showed that TBBPA caused inflammatory injury in the mouse uterus, down-regulated the protein expression of thyroid hormone receptor  (THR) in mice uterus, and clarified the toxic target organs and target molecules of TBBPA. To identify the role of THR in TBBPA-induced inflammatory injury in mice uterus, the expression of THR was up-regulated by GC-1 (a special activator) in mice and cells. The results found that the inflammatory injury and expression of regulators in uterus of mice were returned to normal by GC-1, which indicated that TBBPA induced inflammatory injury in mice uterus via THR-mediated PI3K/NF-B signaling pathway. Analysis of bioinformatics predicted that TBBPA increased the risk of endometrial cancer in women. In conclusion, we found that toxic effects and molecular
mechanisms of TBBPA at internal exposure of human relevant dose and predicted the health risk of TBBPA in human, and provided scientific basis for comprehensive assessment of environmental health hazard of TBBPA.

Pages112
Language中文
Document Type学位论文
Identifierhttp://ir.rcees.ac.cn/handle/311016/42353
Collection环境纳米技术与健康效应重点实验室
Recommended Citation
GB/T 7714
张文娟. 四溴双酚A 的生殖毒性效应及分子机制研究[D]. 北京. 中国科学院生态环境研究中心,2019.
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