四溴双酚A干扰斑马鱼胚胎建立血液循环的机制研究

Tetrabromobisphenol A (TBBPA) has been widely used in the world, which make it was detected in human samples such as maternal and infant serum as well as maternal milk. The development and growth of fetus and infant is known to depend on normal function of thyroid hormone. Recently, research findings report that TBBPA is a thyroid-disrupting environmental chemical, and the concentration of TBBPA in serum of infant is higher than that in their mother. Therefore, it is urgently needed to investigate the developmental toxicity of TBBPA. Our previous works have shown that TBBPA interfered the establishment of blood circulation in zebrafish embryos, however, the relevant molecular mechanism of TBBPA toxicity during this process are still unclear. By employing techniques of developmental biology, analytical chemistry, genetics, theoretical arithmetic and bioinformatics, we propose here to investigate 1) the effects of TBBPA on the development and differentiation of heart, blood and vasculature in zebrafish embryo, 2) the effects of TBBPA on the transformation of thyroid hormone, 3) the interaction between TBBPA and thyroid hormone receptor, 4) the regulatory function of TBBPA on the blood circulation-relate genes and signal via thyroid hormone signal. It is expected that this study will significantly advance our understanding of developmental toxicology of TBBPA, providing essential information useful for risk assessment and management of TBBPA application.

四溴双酚A在全球的广泛应用使其在人体样品如母婴血清和产妇乳汁中均有检出。婴幼儿的发育和生长依赖正常的甲状腺激素作用，而研究表明四溴双酚A具有甲状腺激素干扰作用，且其在婴幼儿体内的浓度远高于成人，因此四溴双酚A的发育毒性效应研究十分重要。申请人前期的研究发现四溴双酚A阻碍斑马鱼胚胎建立血液循环，但对其致毒的分子机制尚不清楚。本项目拟运用发育生物学、分析化学、遗传学、理论计算科学和生物信息学等研究技术手段，研究四溴双酚A对斑马鱼胚胎心脏、血液和血管发育分化的影响，四溴双酚A的不同内暴露剂量对甲状腺激素形态转化的影响，四溴双酚A与甲状腺激素受体的相互作用，四溴双酚A通过甲状腺激素信号对血液循环相关的基因和信号的调控。本研究旨在揭示四溴双酚A通过甲状腺激素信号产生发育毒性效应的分子机制，为四溴双酚A的环境风险评价提供科学依据。

四溴双酚A在环境和人体中广泛检出。本项目围绕四溴双酚A潜在的毒性效应和健康危害，运用分析化学、发育生物学、遗传学等技术手段，以小鼠和斑马鱼为模型，重点开展了环境暴露剂量下四溴双酚A的毒性效应与分子机制研究。取得主要成果如下：. （1）分析了来自中国10个省市的孕妇血清样品中双酚类化合物，其中TCBPA和TBBPS是首次在中国孕妇血清样品中被检出。. （2）分析了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β（THRβ）的蛋白表达水平，明确TBBPA的毒性靶器官和靶分子；揭示TBBPA通过THRβ介导的PI3K/NF-κB信号通路导致小鼠子宫炎症损伤的分子调控机制；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。. （3）系统刻画了TBBPA对斑马鱼胚胎发育的毒理学作用的过程，发现TBBPA诱导的血液循环障碍；全面分析了TBBPA暴露在转录组水平对胚胎发育的毒性影响，提示通过改变Bmp活性梯度干扰胚胎在早期发育背腹轴图式形成是TBBPA发挥毒性作用的潜在分子机制，利用多种发育遗传学手段证明了TBBPA通过甲状腺激素受体(TR)介导的Bmp信号的致毒分子机制；阐明了TBBPA干扰胚胎早期发育背腹轴图式形成的过程，揭示了甲状腺激素受体介导Bmp活性梯度上调是TBBPA早期发育毒性作用的分子起始事件。. 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。