四溴双酚A干扰幼鼠骨髓造血系统及致毒机制研究

Tetrabromobisphenol A has been reported as a thyroid hormone disruptor, and widely distributed in the environment. The abnormalities of thyroid hormone can affect the proliferation/differentiation of hematopoietic stem/progenitor cells (HSPCs) from bone marrow, causing hematopoiesis disorder in bone marrow. Our preliminary studies showed that TBBPA interfered with hematopoietic system in mice, but the mechanisms remain unclear. We hypothesized that TBBPA may disrupt hematopoiesis in bone marrow by affecting the proliferation/differentiation of HSPCs from bone marrow in immature mice. To validate this hypothesis, we propose here a study on the relation of TBBPA exposure with blood cells, hematopoiesis, and haemopoietic factors in bone marrow of mice. We will determine the toxicological effects of TBBPA on hematopoietic system in bone marrow, reveal the relationship between internal exposure dose of TBBPA and toxicological effects, and elucidate the mechanisms of TBBPA disrupting bone marrow hematopoietic system by examining the effects of TBBPA on the proliferation and hematopoiesis in HSPCs from bone marrow. We will further identify the key regulators of thyroid hormone signaling pathway , in order to clarify the main target molecules of TBBPA and the molecular mechanisms related to THRs-mediated thyroid hormone signaling pathway through which TBBPA interferes with hematopoiesis of bone marrow. This study will provide a sound scientific basis for a more accurate evaluation of the environmental health risks associated with TBBPA exposure.

四溴双酚A（TBBPA）是广泛分布于环境的甲状腺激素干扰物。甲状腺激素异常会影响骨髓造血干/祖细胞（HSPCs）增殖/分化，引起骨髓造血功能紊乱。前期研究提示TBBPA干扰小鼠骨髓造血系统，但其致毒机制并不清楚。本项目提出TBBPA可通过干扰骨髓HSPCs增殖/分化导致幼鼠骨髓造血系统紊乱的假设。拟在幼鼠模型研究TBBPA对幼鼠骨髓造血系统中血细胞、造血功能和造血因子的影响，明晰TBBPA对骨髓造血系统的毒性效应，并量化内暴露剂量与毒性效应的关系；在细胞模型研究TBBPA对骨髓HSPCs细胞增殖和造血功能的影响，明确TBBPA干扰骨髓造血系统的作用途径；分析TBBPA对甲状腺激素信号通路关键调控子的影响，厘清TBBPA的主要毒作用靶分子，揭示TBBPA通过甲状腺激素受体（THRs）介导甲状腺激素信号通路干扰骨髓造血系统的分子调控机制。为准确评估TBBPA的环境健康风险提供有效的科学依据。

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。TBBPA具有干扰内分泌的毒性、免疫毒性、神经毒性和肝脏毒性，但很少有研究报道TBBPA在环境相关或实际人体内部暴露剂量下的毒理学效应。本项目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生殖系统和造血系统的毒性效应，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，干扰骨髓干细胞髓系造血分化；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；利用转录组学技术揭示TBBPA干扰造血功能的分子机制。综上，本研究在人群内暴露水平相关内暴露浓度下评价TBBPA的生殖毒性和造血毒性效应及相应分子调控机制，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。.