典型对羟基苯甲酸酯通过干扰下丘脑-垂体-性腺轴诱导性成熟的作用机制

对羟基苯甲酸酯是一类目前个人护理产品中最常用的防腐剂，在环境介质和人体中普遍检出。已有流行病学调查发现对羟基苯甲酸酯暴露与儿童性成熟提前相关。然而，目前关于这类化学品诱导性成熟的作用机制尚不明确。我们前期的研究结果发现对羟基苯甲酸酯诱导下丘脑和垂体合成激素，提示其可能通过干扰下丘脑-垂体-性腺（HPG）轴影响性成熟。本项目拟以目前最为广泛使用的对羟基苯甲酸甲酯（MePB）为典型化学品，评估围产期低剂量暴露MePB对小鼠性成熟的影响和对HPG轴的激活；进一步深入解析MePB通过Kiss1/GPR54和Oct1/Msx1/Dlx2通路调控下丘脑神经元发育、以及通过GnRH/GnRHR和PKC/ERK通路调控垂体促性腺激素合成的分子机制。通过本项目研究，为准确、全面评估对羟基苯甲酸酯的环境安全与健康风险提供科学依据和理论基础，对于加强这类化学品风险管理和保障儿童健康具有重要科学意义和社会意义。

Parabens, a class of the most commonly used preservatives in personal care products, are widely detected in environmental media and the human body. Previous epidemiological studies have demonstrated that paraben exposure was associated with early sexual maturity in children. However, the regulation mechanism of parabens on sexual maturity remains unclear. Our preliminary data showed that parabens induced hormone production from hypothalamic and pituitary cells, suggesting that parabens may affect sexual maturity by interfering with the hypothalamic-pituitary-gonad (HPG) axis. In this project, we will use methylparaben (MePB), which is the most widely used preservative in personal care products, as a typical paraben to assess the acceleration of sexual maturity and the activation of HPG axis in mice after perinatal low-dose exposure. We will further investigate the regulation mechanism of MePB on hypothalamic GnRH neuron development through Kiss1/GPR54 and Oct1/Msx1/Dlx2 pathways, as well as the regulation mechanism of MePB on the synthesis of gonadotropins in pituitary cells through GnRH/GnRHR and PKC/ERK pathways. This project will be of scientific and social significance to provide a scientific basis and a theoretical basis for accurate and comprehensive assessment of the environmental safety and health risks of parabens, and provide an important reference for determining future directions of management of parabens and preventive measures of children health.