小儿尿道下裂是一种常见泌尿系统出生缺陷，发病率逐年上升。研究表明胚胎期受邻苯二甲酸酯类环境内分泌干扰物的暴露与尿道下裂的形成密切相关，睾丸Leydig细胞是其重要的靶细胞。我们前期研究发现染毒后仔鼠睾丸Leydig细胞内的Gstm3和Nrf2的表达上调，进一步通过ChIPseq和其它功能实验证实Nrf2在Gstm3启动子区富集并启动该基因的表达；转录组测序发现过表达Gstm3可以显著上调雄激素受体信号通路，有效拮抗Leydig细胞的毒性损伤。我们推测：Nrf2-Gstm3通过介导Ar通路对DBP致尿道下裂起到拮抗作用，减少尿道下裂的发生。拟体外过表达及基因敲除Gstm3，并应用Nrf2-Gstm3激动剂非马沙坦在基因敲除鼠中验证此一系列表型变化，全面系统地评价“Nrf2-Gstm3-Ar轴”参与DBP诱导的尿道下裂损伤的保护机制，为提供合理有效的干预措施提供理论依据。

Hypospadias is a common congenital malformation in urology with an increasing incidence. Studies show that hypospadias has a close relationship with DBP exposure in embryonic phase. The Leydig cell is the most important target. Our previous study indicates that Gstm3 and Nrf2 up-regulated in Leydig cells in fetal testis after DBP exposure. The ChIPseq assay and other functional experiments suggested that Nrf2 was enriched in the transcription starting site in Gstm3 and initiated its expression. The overexpression of Gstm3 could be able to up-regulate androgen receptor pathway through RNAseq data, and increase the androgen output, which could be resistant to the DBP injury. Our hypothesis is that Nrf2-Gstm3 could protect Leydig cell from DBP toxicity through Ar signaling pathway. We plan to investigate the phenotype changes by overexpression or knockout in vitro, and observe the changes in vivo by using Fimasartan in Gstm3-/- mouse to systematically evaluate protective mechanism of Nrf2-Gstm3-Ar axis in DBP toxicity injury in Leydig cells.