视黄酸信号通路介导PBDEs对鱼类神经行为毒性与机制研究

The neurobehavioral toxicity of polybrominated diphenyl ethers (PBDEs) and the underlying mechanisms are becoming a new heated scientific question. Retinoic acid signaling pathway has multiple functions, is closely correlated with the development of the neural and visual systems, and therefore influences the biological behavior. The applicant of the present proposal has done some primary studies and found that PBDEs showed neurobehavioral toxicity on zebrafish (Danio rerio) and influenced the retinoic acid signaling pathway and the development of eyes. The present proposal will study the retinoic acid signaling pathway, development of the visual system, and the neurobehavioral toxicity, using zebrafish as the model organism. First, the neurobehavioral toxicity of PBDEs and OH-PBDEs will be studies. Then, we will use the synthesis, transportation, degradation and receptor binding of the retinoid as the indicators of the retinoic acid signaling pathway, to investigate the effects on the retinoic acid signaling pathway and the mechanisms. Then, we will analyze the influence of PBDEs on the visual system development through morphologic observations and the expression levels of visual proteins. Combining the results from the aforementioned three parts, we will reveal the correlation among the retinoic acid signaling pathway, development of the visual system, and the neurobehavioral toxicity, and the underlying mechanisms. Moreover, we will also study the interactions between the thyroid and the retinoic acid signaling pathways. The achievements of the proposal will elucidate the health effects of aquatic PBDEs, showing important environmental and ecological significance.

PBDEs的神经行为毒性与机制是其健康效应的一个热点科学问题。视黄酸信号通路具有多种重要功能，与神经系统和视觉系统发育密切相关，影响生物运动行为。申请者前期探索已观察到PBDEs对斑马鱼的神经行为毒性及其对视黄酸信号通路和眼睛发育的影响。本项目围绕视黄酸信号通路-视觉系统发育-神经行为毒性，以斑马鱼为模式生物，阐明PBDEs及其羟基代谢产物神经行为毒性，从视黄类物质的合成、转运、降解、受体结合等视黄酸信号通路系统水平上，研究PBDEs对斑马鱼视黄酸信号通路作用与机制，在形态学、视蛋白基因转录与表达水平上研究PBDEs对视觉系统发育的影响，阐明视黄酸信号通路作用、视觉系统发育损伤、神经行为毒性三者之间关系，揭示PBDEs的神经行为毒性机理，并探索PBDEs诱导甲状腺素与视黄酸信号通路相互作用。研究成果对阐明水环境PBDEs的健康效应具有重要的环境与生态学意义。

本项目围绕视黄酸信号通路-视觉行为-神经毒性，以模式动物斑马鱼为模型，选取代表性的PBDEs及其衍生物对发育阶段斑马鱼从胚胎囊胚期暴露至仔鱼期，通过研究PBDEs对斑马鱼仔鱼神经行为、视觉行为、视觉系统、视黄酸信号通路、甲状腺激素信号通路的干扰及交互作用，从表观-内在的角度揭示PBDEs神经行为毒性的机制，为PBDEs的生态风险评价提供相应依据。项目进行过程中建立了污染物对斑马鱼仔鱼的行为学效应测试方法；优化了视黄类物质（包含同分异构体）的提取及检测方法；从视黄酸信号通路的关键性物质代谢，关键基因表达、信号转导等全面探讨PBDEs及其衍生物对视黄酸信号通路的干扰；初步建立了PBDEs诱导视黄酸信号通路和甲状腺激素信号通路交互作用的模型。结果发现PBDEs及其衍生物可以诱导斑马鱼仔鱼神经行为学效应，对视觉行为和视觉系统有干扰作用，可以影响视黄酸信号通路，并诱导视黄酸信号通路与甲状腺激素信号通路之间的交互作用。项目对阐明PBDEs及其衍生物的健康效应具有重要的意义。同时研究PBDEs对鱼类运动行为的影响与机制，对水环境PBDEs生态风险评价更具有生态学和环境意义。