新型有机污染物三-(2,3-二溴丙基）异氰脲酸酯(TBC)的内分泌干扰效应和生殖毒性研究

Heterocyclic brominated flame retardant tris-(2,3-dibromopropyl) isocyanurate(TBC) is the substitute of regular brominated flame retardants such as polybrominated diphenyl ethers(PBDEs) and tetrabromobisphenol A (TBBPA). It has been batch produced and used domestically. However, TBC is recently proven to be a new environmental persistent organic pollutant, and its potential environmental effects and ecological risk should be taken seriously. Our research focuses on the action sites and pathways though which TBC suppresses hepatic vitellogenin synthesis and hinders gonad development in adult zebrafish（Danio rerio）. By utilizing different in vitro and in vivo bioassay models of endocrine disrupting chemicals (EDCs) and calculating the quantitative structure activity relationship of TBC and estrogen receptor, the molecular mechanism of endocrine toxic effects caused by TBC can be revealed. Meanwhile, zebrafish will be exposed to low-doses of TBC according to environmental concentrations for a full lifetime, in order to study TBC's toxicity effects on growth, development, reproduction and offspring. Furthermore, whether TBC could cause reproductive toxicity through disrupting the functions of endocrine system and the precise mechanism will be discussed. These results can be provided as scientific evidences for evaluating the ecosystem risk and environmental health effects caused by TBC, as well as guiding for production and application of brominated flame retardants and its substitutes.

杂环溴化阻燃剂- - 三-(2,3-二溴丙基）异氰脲酸酯（TBC）是溴代联苯醚类、四溴双酚A等多种常规溴化阻燃剂的替代产品，在国内已逐渐批量生产及应用，但它最近被证明是一种具有环境持久性的新型有机污染物，其潜在的环境危害和生态风险值得关注。本项目重点研究TBC抑制斑马鱼体内卵黄蛋白原合成、阻碍成鱼性腺发育的作用位点及途径，通过结合利用多种内分泌干扰物离体、活体生物测试模型，并计算TBC与雌激素受体的定量构效关系，以揭示TBC产生内分泌干扰效应的分子致毒机制；同时选择斑马鱼作为模式动物，进一步研究环境浓度下TBC长期低剂量暴露对斑马鱼生长、发育、繁殖及子代的毒性效应，着重探讨TBC是否通过干扰正常内分泌系统功能造成潜在生殖毒性及其具体的作用途径，最终为准确评估TBC这种新型有机污染物的生态风险和环境健康效应，并为溴化阻燃剂及其替代产品的生产和应用提供科学依据。

本项目利用离体及活体动物模型，并结合分子对接模拟方法，研究了三-（2,3）二溴丙基异氰脲酸酯（TBC）对哺乳动物肺部的毒性效应和产生内分泌干扰效应的分子作用机制。研究结果表明， TBC暴露可以引起Balb/c小鼠和Wistar大鼠肺部的损伤，肺泡间隔增厚，TBC具有明显的呼吸毒性，这与TBC造成斑马鱼鱼鳔充气缺陷的结果一致； TBC可通过干扰H295R细胞中类固醇激素合成代谢过程中关键基因的表达，抑制H295R细胞合成与分泌雌二醇和睾酮，产生内分泌干扰效应；TBC可以显著抑制雌激素依赖的MCF- 7细胞的增殖，并能显著降低细胞中雌二醇所诱导的pS2基因转录，表现出抗雌激素效应，同时可以通过干扰雌激素与雌激素受体ER的结合而抑制MVLN细胞中雌二醇所诱导的荧光素酶活性；分子对接模拟结果提示TBC可能结合在表面结合口袋，阻碍随后的共激活辅因子的招募，从而抑制ER的活性，产生抗雌激素效应；此外，TBC可以显著抑制雌二醇诱导的斑马鱼胚胎中卵黄蛋白原基因的表达，进一步证实了TBC的抗雌激素效应。本研究揭示了TBC对生物体呼吸器官的损伤作用及其引起内分泌干扰效应的分子作用机制，为评估TBC的生物毒性和环境健康风险提供了可靠的科学依据。

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