基于斑马鱼发育早期双酚S暴露对其生命后期神经行为影响的表观遗传学研究

Recently, there is a growing field of research investigating the latent effects of early life exposure to stressors including environmental chemicals, known as the developmental origins of health and disease (DOHaD). Bisphenol S (BPS), as a BPA replacement, has become widespread consumer and commercial use. Thus, its health risk has been widely concerned. BPS can affect the developmental nervous system in animals; however, whether exposure to BPS in early life could induce neurotoxicological effects in later life is still unclear. Using zebrafish as a model, the objective of this proposal will be to reveal neurotoxicity of BPS in later life, explore its potential epigenetic mechanisms in zebrafish following exposure to BPS at the developmental critical window. We will assess larval or adult neurobehavior in zebrafish exposed to BPS during developmental sensitive period; analyze BPS-induced epigenetic inheritance of neurotoxicity in larval or adult zebrafish by cross-acting interference with development of a zebrafish’s nervous system; analyze the correlation between differentially expressed genes and DNA methylation in brain and explore epigenetic regulatory mechanisms of neurotoxicity in zebrafish exposure to BPS in early life. The results of this proposal will be helpful to further understand the toxic effects of BPS, provide useful information for evaluating the health risks of BPS, and be of great significance for further understanding of the interaction between epigenetics and environmental exposures.

近年来，基于“健康与疾病的发育起源”理论，越来越多的研究关注生命早期环境化学品暴露对后期健康的影响。作为双酚A的替代品，双酚S（BPS）的健康风险受到广泛关注。BPS具有潜在的发育神经毒性，但关于生命早期BPS暴露是否影响后期健康还不清楚。本项目以斑马鱼为模式生物，研究发育早期BPS暴露对后期的神经毒性效应，用表观遗传学手段探明生命早期BPS暴露对后期神经毒性的机理。研究内容包括通过对斑马鱼发育敏感期进行BPS暴露，考察幼鱼和成鱼的神经行为变化；从表观遗传学方面分析BPS是如何通过干扰斑马鱼神经发育来引发幼鱼和成鱼神经系统缺陷的；最后用组学技术，从脑组织中差异表达基因和DNA甲基化关联性分析早期BPS暴露导致后期神经毒性的表观遗传调控机理。通过本研究，深入对BPS毒性效应的认识，为评价BPS的健康风险提供可借鉴的资料，也为进一步丰富对表观遗传和环境暴露及其发生机制的认识有着重要意义。

本项目以斑马鱼为模式生物，研究发育早期BPS暴露对后期的神经毒性效应，用表观遗传学手段探明生命早期BPS暴露对后期神经毒性的机理。研究结果表明通过对斑马鱼发育敏感期进行BPS暴露，发现 BPS 在环境相关浓度下可对斑马鱼胚胎产生显着的神经毒性，包括运动受限、移动距离缩短和中枢神经系统细胞凋亡。免疫荧光测定显示斑马鱼脑内的小胶质细胞和星形胶质细胞均被BPS显着激活，表明存在神经炎症反应。此外，环境浓度BPS暴露显著抑制了周围运动神经元的发育。转录组数据表明神经元发育过程和细胞凋亡途径受到BPS暴露的显著影响，这与表型结果一致。DNA甲基酶在BPS暴露后不同阶段有不同的表达变化，表明BPS可改变斑马鱼胚胎DNA甲基化水平。然而，DNA甲基化测序研究表明所选关键基因（gap43）的启动子区域未显示 DNA 甲基化状态显著变化。总之，环境相关浓度BPS暴露能通过诱导神经炎症和中枢神经系统细胞凋亡，导致斑马鱼后期生命阶段的神经系统功能异常。本项目还研究了双酚类其他物质如BPA、BPAF和TBBPS等对斑马鱼神经系统的影响，表明该类物质均具有神经毒性效应。通过本研究，深入对BPS毒性效应的认识，为评价BPS的健康风险提供可借鉴的资料，也为进一步丰富对表观遗传和环境暴露及其发生机制的认识有着重要意义。