LSD1-Apelin-13在七氟烷诱导的孕早期胎儿神经系统毒性的作用及其机制研究

The commonly used inhalation anesthetic sevoflurane could permeate rapidly through the placental barrier, and thus cause toxicity to the central nervous system of the developing fetus which is becoming a major health issue in clinical when pregnant women accept non-obstetric surgery under general anesthesia. In our previous studies, we found that sevoflurane induced learning and memory impairment in fetal and offspring mice and inhibited the neurongenesis of both human and mouse embryonic stem cells-drived neuron in vitro at clinically relevant concentration; we also found sevoflurane reduced the self-renewal of mouse embryonic stem cells and inhibited autophagy of it through LSD1-Apelin-13 signaling. These result leading us to the hypothesis that sevoflurane cause the reduction of human embryonic stem cells-drived neuron by lowering the self-renewal of human embryonic stem cells which lead to premature differentiation. Therefore, we use the directed differentiation of neural precursors and neuron from human embryonic stem cells to access the toxcity of sevoflurane in neurongenesis. The result of current study may provide a novel idea for preventing the toxcity of inhalation anesthetics for fetal developing brain in clinical.

孕早期妇女接受非产科手术全身麻醉时，吸入麻醉药七氟烷对胎儿后续的神经系统发育的影响一直是孕妇和医生关注的焦点。我们发现七氟烷处理后的孕早期孕鼠其子代记忆能力受到损害；七氟烷抑制自噬的发生，进而降低胚胎干细胞自我更新能力并使其在分化成为神经元过程中引起神经元发育减少，其机制可能是通过调节LSD1-Apelin-13信号通路。Aplin-13可在血浆中被检测到，可以作为临床靶点来及时检测和治疗七氟烷的神经发育毒性，为此，我们拟通过培养人胚胎干细胞并诱导其向神经元分化并对其使用七氟烷处理，模拟临床孕早期妇女接受非产科手术全身麻醉，系统性的研究七氟烷对胎儿整个神经发育过程的毒性，并探讨自噬的抑制在七氟烷诱导的孕早期胎儿神经系统毒性的作用及其机制是否通过调节LSD1-Apelin-13信号通路，从而为孕早期妇女接受非产科手术全身麻醉时及时检测或选择性的使用麻醉药物降低麻醉对胎儿发育的影响提供依据。

孕早期妇女接受非产科手术全身麻醉时，吸入麻醉药七氟烷对胎儿后续的神经系统发育的影响一直是孕妇和医生关注的焦点。我们发现七氟烷处理后的孕早期孕鼠其子代记忆能力受到损害；七氟烷抑制自噬的发生，进而降低胚胎干细胞自我更新能力并使其在分化成为神经元过程中引起神经元发育减少，其机制可能是通过调节LSD1-Apelin-13信号通路。Aplin-13可在血浆中被检测到，可以作为临床靶点来及时检测和治疗七氟烷的神经发育毒性，为此，我们拟通过培养人胚胎干细胞并诱导其向神经元分化并对其使用七氟烷处理，模拟临床孕早期妇女接受非产科手术全身麻醉，系统性的研究七氟烷对胎儿整个神经发育过程的毒性，并探讨自噬的抑制在七氟烷诱导的孕早期胎儿神经系统毒性的作用及其机制是否通过调节LSD1-Apelin-13信号通路，从而为孕早期妇女接受非产科手术全身麻醉时及时检测或选择性的使用麻醉药物降低麻醉对胎儿发育的影响提供依据。