低剂量三氯生长期暴露诱导雌性小鼠青春期性成熟的分子机制研究

三氯生是一类广泛添加于个人护理用品的高效广谱性抗菌剂，在环境介质和人体尿液中普遍残留。已有流行病学调查发现三氯生暴露水平与女孩青春期发动时相提前显著正相关，提示三氯生暴露是诱导雌性青春期性成熟提前的环境风险因素。然而,目前尚无环境剂量三氯生长期暴露对雌性小鼠青春期性成熟影响的动物实验研究，其调控机制尚不明确。本研究拟评估低剂量三氯生长期暴露对雌性小鼠青春期性成熟和下丘脑-垂体-卵巢轴的影响，进一步深入解析三氯生通过调控Kiss-1/PcG促进下丘脑GnRH脉冲释放，通过PKC/c-Raf/ERK1/2/IEGs通路调控垂体促性腺激素合成，以及通过TGF-β/Smad4通路调控卵巢雌激素合成，从而诱导青春期性成熟提前的分子机制。本研究将为防治因三氯生暴露引起的女孩青春期发动时相提前提供科学依据和理论基础，对于准确全面评价此类化合物的健康风险和保障儿童健康具有重要意义。

Triclosan, a class of widely used antibacterial agents with high efficiency, are ubiquitously detected in the environment as well as the urine samples of human beings. Previous epidemiological studies have demonstrated that triclosan exposure was significantly and positively associated with earlier pubertal timing in girls, which suggested that triclosan might be potential environmental risk factors for the acceleration of pubertal sexual maturity in girls. However, whether environmental doses exposure of triclosan accelerate sexual maturity in female mice is still unknown, and the regulation mechanism remains unclear. In this study, we will investigate the acceleration of low-dose triclosan exposure on pubertal sexual maturity and hypothalamic-pituitary-ovary axis of female mice by both in vivo and in vitro tests. We will explore the regulation mechanism of triclosan on the GnRH pulse releasing in the hypothalamus through Kiss-1/PcG. The regulation mechanism of triclosan on the synthesis of gonadotropins in the pituitary through PKC/c-Raf/ERK1/2/IEGs pathway as well as the synthesis of estradiol in the ovary through TGF-β/Smad4 pathway will be further investigated. This study will provide a theoretical basis and a scientific proof to prevent and cure the acceleration of pubertal timing induced by triclosan exposure in females, and will be of great significance for the accurate and comprehensive evaluation of the health risks of triclosan and the protection of children health.