环境中增塑剂DEHP暴露引起神经系统损伤的作用和机制探索

Di(ethylhexyl) phthalate (DEHP) is the most widely used phthalates in the world. It is used as softeners-plasticizers to improve the plasticity and the flexibility of materials. DEHP is reported to leach easily from solid polymer matrices into the environment. Human exposure to DEHP can occur via the dermal, inhalation, oral, and intravenous routes of exposure. Many reports have revealed potent toxicity of DEHP and its metabolites in rodents. Although extensive studies have been conducted on the DEHP-induced developmental toxicity, endocrine disruption and genotoxicity, there are limited studies on the neurotoxicity of DEHP on adult and aged brains. Moreover, the mechanism of the DEHP-induced neurotoxicity remains unclear. Our previous study suggested that DEHP exposure could induce oxidative-stress in neurological system of adult mice, possibly related to SIRT1. SIRT1 has been shown to have many important functions during neuron development, influencing brain structure through axon elongation, neurite outgrowth, and dendritic branching, as well as cellular fate of neuronal precursor cells. In the adult brain, SIRT1 can modulate synaptic plasticity and memory formation. In addition to its importance during normal brain aging, SIRT1 has also been shown to ameliorate a number of neurodegenerative disorders including Alzheimer’s and Parkinson’s disease. Recently, a novel SIRT1 signaling pathway was reported to regulate memory and plasticity through the post-transcriptional regulation of CREB and BDNF via miR-134. Thus, the present study is designed to assess the effect of DEHP on the adult and aged brains, as well as to investigate whether SIRT1/CREB pathway is involved in the DEHP-induced neurotoxicity. With this useful information, it would be helpful to establish the guideline of the safety limit value (ADI and TDI) of DEHP, as well as the therapy for DEHP-induced toxicity.

市场用量最大的邻苯二甲酸酯类增塑剂-邻苯二甲酸二乙基己酯(DEHP)是目前世界上最主要的环境污染物之一。由于具有拟雌激素和抗雄激素活性, DEHP 的生殖发育毒性已引起人们的广泛关注，但对于其他系统（如神经系统）影响的研究报道较少。DEHP神经毒性的研究主要集中于孕期和哺乳期暴露后对子代神经系统发育的影响，尚无研究指出DEHP对成熟及老化神经系统的影响及其机制。我们的前期研究发现，DEHP暴露可引起神经系统氧化损伤，并可导致成年小鼠的学习记忆能力下降，作用机制可能与脑内SIRT1信号传导通路有关。SIRT1在神经系统的发育成熟、抗氧化衰老方面具有重要作用，SIRT1/CREB信号通路可通过调节突触可塑性影响大脑的学习记忆能力。本课题拟探讨DEHP是否通过SIRT1/CREB通路影响神经系统，从而为塑化剂的安全性评价和合理应用，以及预防和治疗环境塑化剂污染物所引起的机体功能损伤提供理论依据。

市场用量最大的邻苯二甲酸酯类增塑剂-邻苯二甲酸二乙基己酯(DEHP)是目前世界上最主要的环境污染物之一。由于具有拟雌激素和抗雄激素活性, DEHP 的生殖发育毒性已引起人们的广泛关注，但对于其他系统（如神经系统）影响的研究报道较少。DEHP神经毒性的研究主要集中于孕期和哺乳期暴露后对子代神经系统发育的影响，尚无研究指出DEHP对成熟及老化神经系统的影响及其机制。基于此，本课题通过观察不同年龄小鼠DEHP暴露后神经行为学及氧化应激指标的变化来探讨DEHP对神经系统的损伤作用是否具有年龄差异。神经行为学研究结果显示，不同年龄组动物暴露DEHP后，学习记忆能力均受到损害；且老年组动物学习记忆能力受损更甚。同时，氧化应激各指标（MDA、ROS、SOD、GSH-Px）水平均发生变化，提示DEHP可引起神经系统的氧化损伤。Western Blots实验结果显示DEHP暴露后，SIRT1表达水平下降，，提示SIRT1蛋白与DEHP神经毒性作用相关。脑内CREB蛋白表达水平与对照组相比无统计学差异，提示DEHP神经毒性可能不通过SIRT1/CREB通路调节。另外，SIRT1诱导剂（白藜芦醇）和拮抗剂（烟酰胺）与DEHP共同暴露后，白藜芦醇可部分逆转DEHP所引起的ROS水平上升、抗氧化酶活性降低状况；而烟酰胺可加剧DEHP所引起的ROS水平上升、抗氧化酶活性降低状况；进一步明确了SIRT1在DEHP神经毒性中的作用。本课题的实验结果有助全面深入的理解DEHP的毒性，可以为DEHP及其他塑化剂的安全性评价和合理应用，以及预防和治疗环境塑化剂污染物所引起的机体功能损伤提供理论依据。