ARTS在邻苯二甲酸（2-乙基己基）酯诱导的小鼠睾丸间质细胞凋亡中的作用及机理研究

邻苯二甲酸（2-乙基己基）酯（DEHP）是工业中常用的增塑剂，也是一种重要的环境内分泌干扰物，可影响男性生殖功能。前期我们已经报道了DEHP可诱导小鼠睾丸间质细胞凋亡（Sun et al.，2018），然而分子机理仍不甚清楚。现阶段我们通过RNA-seq等方法进行筛选，发现DEHP可促进小鼠睾丸间质细胞内ARTS的表达，并发现在ARTS基因启动子区域存在4个p53的假定结合位点，提示ARTS可能受p53的调控。鉴于ARTS可诱导细胞凋亡，我们推测p53/ARTS信号通路可能参与了DEHP诱导的小鼠睾丸间质细胞凋亡。本课题通过ARTS基因条件性敲除小鼠和细胞实验，首先明确ARTS是否参与DEHP诱导的小鼠睾丸间质细胞凋亡；然后明确ARTS是否受p53调控；最终确定DEHP是否通过p53/ARTS信号通路诱导小鼠睾丸间质细胞凋亡。为深入探讨DEHP的男性生殖毒性机理提供新的理论基础和实验依据。

As one of the most important endocrine-disrupting chemicals (EDCs), di(2-ethylhexyl) phthalate (DEHP) has been widely used as a plasticizer in industry, which can significantly affect male reproductive functions. In our previous study, we found that DEHP could induce apoptosis of mouse Leydig cells (Sun et al.，2018); however, it is still unknown about the potential mechanism. Our preliminary results found that DEHP could up-regulate the level of ARTS in the mouse Leydig cells via RNA-seq. There are four putative binding sites of transcript factor p53 in the promoter sequence of ARTS gene via bioinformatics analysis, which indicates that ARTS could be regulated by p53. Inasmuch as ARTS can induce apoptosis, which implies that p53/ARTS signaling pathway is involved in DEHP-induced apoptosis of mouse Leydig cells. Therefore, we will test these hypotheses: (1) whether ARTS is involved in DEHP-induced apoptosis of mouse Leydig cells by the conditional deletion of ARTS gene specifically in the Leydig cells of the testis (ARTSflox/floxCyp17iCre) and in vitro cell line study, (2) whether ARTS could be regulated by p53 and (3) whether DEHP induces apoptosis of mouse Leydig cells via p53/ARTS signaling pathway. The present study will provide a novel insight into the mechanism for DEHP-induced male reproductive toxicity.