EPHA受体在电磁辐射损伤新生神经元轴突生长中的调控机制

It is reported that electromagnetic fields (EMF) exposure impairs brain development. However, the injury targets and the underlying mechanisms are unclear. In our previous researches, we found that radio frequency EMF exposure caused impairment of neurite outgrowth in new-born neurons during brain development. To reveal the underlying mechanisms, we carried out RNA-seq analysis and found that Epherins receptor A4 and 5 (EPHA4/5) could play a critical role in EMF-induced injury of neurite outgrowth. Our followed experiments also confirmed this finding. EPHA4/5 play an important role in brain development. However, how EMF regulates the expression and functions of EPHA are unknown. Previous researches indicated that TRPC1 calcium signaling might involve in this process. Based on these findings, we proposed the following hypothesis: EMF exposure regulate the expression and functions of EPHA4/5 through TRPC1-mediated calcium signaling, which finally caused injury of neurite outgrowth and brain development. Our project will focus on the following subjects: the dose- and time-dependent effects of EMF exposure on neurite outgrowth of new-born neurons; does EMF regulated EPHA expression and functions thorough TRPC1 signaling and the role and mechanisms of EPHA4/5 in EMF-induced injury of neurite outgrowth. Our project would reveal the critical target which EMF exposure acts on brain development and also would uncover the underlying mechanisms. These finding could enhance our understanding about the biological effects of EMF exposure and help us exploring effective protective approaches for EMF exposure.

电磁辐射暴露影响脑发育，其具体靶点及分子机制不明。我们前期研究发现，射频电磁辐射暴露能够损伤新生神经元轴突生长，通过转录组测序以及分子生物学实验分析，我们发现Ephrins(EPH)受体家族成员EPHA4与5在这一过种中发挥了关键作用。EPHA4/5是调控脑发育的关键分子，但电磁辐射对EPHA的调控机制及其在介导轴突损伤中的作用不明，前期研究提示TRPC1钙信号可能参与了电磁辐射对EPHA受体的调控作用。我们假设：电磁辐射通过TRPC1钙信号调控EPHA4/5表达与功能，损伤新生神经元轴突生长及脑发育。本项目主要研究：电磁辐射对新生神经元轴突生长的损伤特点及时效量效关系；电磁辐射通过TRPC1钙信号调控EPHA受体的机制及其在介导轴突生长损伤中的作用。本项目有望揭示电磁辐射损伤脑发育的新靶点及分子机制，为理解电磁辐射生物学效应及提出医学防护措施奠定实验基础。

随着电磁技术及无线通讯技术的发展，职业与人居环境电磁暴露健康危害已成为公众所关注的焦点问题之一，阐明电磁辐射暴露敏感靶器官效应特点及机制对于提出科学的暴露限值，消除公众恐慌，保护职业暴露人群均具备较大的意义。本项目依据前期研究结果，以电磁辐射暴露所致新生神经元突起生长为主要观察靶点，以神经干细胞诱导分化神经元及维A酸诱导的Neuro2A细胞建立培养细胞模型，以妊娠期小鼠建立动物暴露模型，开展了相应的效应及机制研究。通过细胞实验发现，SAR为4 W/Kg，频率为1800 MHz射频电磁辐射暴露能够明显抑制分化神经元的突起生长，主要表现为突起总长度降低，分叉点减少等；并且在动物模型研究也发现，1800 MHz射频电磁辐射暴露能够影响子代小鼠皮层神经元的突起生长，其主要表现为树突的复杂性降低，树突棘的密度减少，并且可以导致子代鼠成年后神经行为功能的改变。进一步的机制研究表明，EPHA5受体及其下游信号CREB/RhoA参与调控了电磁辐射暴露对神经元突起生长的抑制作用，通过活性小分子化合物FSK调控该信号通路的活性可以拮抗电磁辐射暴露所致神经元突起损伤。本项目研究揭示了电磁辐射暴露致脑发育损伤的新靶点及其分子机制，为全面揭示电磁辐射暴露所致健康危害提供了新的实验证据，实验数据有助于更精确的提出不同暴露模式下的损伤阈值，为提出新的医学防护措施提供了新的思路。