环境浓度双酚S对斑马鱼免疫系统的干扰作用及机理研究

Bisphenol S (BPS) has long been thought as a “safe” substitute for bisphenol A (BPA). Therefore, like BPA, it has been introduced into the aquatic ecosystems by anthropogenic activities. It is concerning that many studies have found that the concentrations of BPS in aquatic environments or human body fluids has reached or even exceeded the levels of BPA. However, unlike BPA, very little research has been carried out to evaluate the toxicity of BPS to aquatic organisms. Therefore, this project seeks to evaluate the toxicity of environmental levels of BPS to the immune system using the wildtype zebrafish and macrophages transgenic zebrafish through measurements of the following outcomes: the levels of immune related genes and proteins, numbers of the macrophages, and the development of immune organ. The project also will compare the toxicity of BPS and BPA on zebrafish’s immune system by conducting experiments at the same concentration levels. Lastly, the project explores how BPS interrupts fish immune system through an innovative experimental strategy-combined exposure with receptor antagonist and implemented receptor knock-out strategies. The project is expected to not only illustrate the immunotoxicity of BPS but also to demonstrate its action mechanisms. Because fish immune system is the most important defensive system against environmental toxins, the findings have implications for fish reproduction and conservation.

双酚S是双酚A典型代用品，已经被人类活动广泛引入水生生态系统中。更令人担忧的是，在许多区域，双酚S在环境水体和人体体液中浓度已经达到甚至超过双酚A的水平。然而，国内外关于双酚S的毒性研究尤其对水生生物的毒性研究还鲜有报道。本项目以模式生物野生斑马鱼和绿色荧光标记的巨噬细胞转基因斑马鱼为研究对象，研究环境浓度下双酚S对斑马鱼免疫基因、蛋白、细胞和器官的干扰作用，并在相同暴露浓度下比较双酚S和双酚A对斑马鱼免疫毒性的大小，最后通过拮抗剂共暴露和受体基因抑制的方法，结合多色荧光标记和共聚焦显微技术，探索双酚S对斑马鱼免疫系统的干扰途径。免疫系统是鱼类抵抗外界环境污染最重要的保卫系统，阐明双酚S对斑马鱼的免疫毒性效应及其作用机制，对保障鱼类种群繁育具有重要的科学意义。

BPS是一类典型的BPA替代物，可以用来合成聚碳酸酯、环氧树脂、增塑剂等物质的前体物质。因为BPS具有和BPA类似的化学结构，且比BPA更为稳定的化学性质，近年已经被广泛应用在BPA free（不含双酚A）的产品上。本研究阐明环境相关水平BPS对斑马鱼的幼鱼的生长发育及系统的干扰效应，能够显著诱导斑马鱼炎症因子表达，干扰免疫相关蛋白和基因的水平，显著抑制斑马鱼的免疫功能并影响斑马鱼的免疫系统。于此同时，选择相同浓度的BPS和BPA暴露斑马鱼胚胎，发现了BPS的作用毒性和BPA的毒性作用类似，且作用程度也相当。因此BPS并不是一类安全的BPA类似物，尤其对于鱼类的免疫系统。此外，应用抑制剂技术，项目分次探索了BPS干扰鱼类免疫系统的常见通路，实验发现BPS具有和BPA非常类似的干扰作用模式，能够显著干扰经典免疫通路NF-κB通路，并通过NF-κB通路介导BPS的鱼类免疫毒性作用。该项研究将促进我们对于硬骨鱼发育过程中的各种生物效应有更进一步的认识，并且有可能将此作为BPS暴露下评估毒性效应的生物指标之一。