Department of Urology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou 213003, Jiangsu Province, China; Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, China.
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210009, China.
Sci Total Environ. 2021 Aug 20;783:146898. doi: 10.1016/j.scitotenv.2021.146898. Epub 2021 Apr 9.
Di-n-butylphthalate (DBP) has been listed as an environmental priority pollutant in China due to its distinct biotoxicity. Epidemiological studies have shown that exposure to DBP is closely related to a series of congenital and acquired defects in the male reproductive system. The oxidative stress injury caused by DBP plays an important role in these defects. Previous studies have demonstrated that the Keap1/Nrf2 antioxidative pathway plays a protective role in DBP-induced oxidative stress injury. However, the further molecular regulation mechanism of the activation of Nrf2 pathway remains unclear. Here, we demonstrate that DBP caused testicular oxidative stress injury and Nrf2 pathway was activated in response to the injury in vivo and in vitro. Moreover, we validated that reduced level of USP15 attenuates DBP-induced oxidative stress injury through restraining the ubiquitylation and degradation of Nrf2. Notably, USP15 is confirmed as a target of miR-135b-5p and miR-135b-5p mediated inhibition of USP15 is involved in the DBP-induced oxidative stress injury. Collectively, these findings indicated that decreased level of USP15 functions a significant protective effect on the oxidative stress injury of testis caused by DBP via regulating the Keap1/Nrf2 signaling pathway.
邻苯二甲酸二正丁酯（DBP）已被列为中国环境优先污染物，因为它具有明显的生物毒性。流行病学研究表明，DBP 的暴露与男性生殖系统的一系列先天性和后天性缺陷密切相关。DBP 引起的氧化应激损伤在这些缺陷中起着重要作用。先前的研究表明，Keap1/Nrf2 抗氧化途径在 DBP 诱导的氧化应激损伤中起保护作用。然而，Nrf2 通路激活的进一步分子调控机制尚不清楚。在这里，我们证明 DBP 在体内和体外均可引起睾丸氧化应激损伤，并激活 Nrf2 通路。此外，我们验证了 USP15 的减少水平通过抑制 Nrf2 的泛素化和降解来减轻 DBP 诱导的氧化应激损伤。值得注意的是，USP15 被确认为 miR-135b-5p 的靶标，miR-135b-5p 介导的 USP15 抑制参与了 DBP 诱导的氧化应激损伤。总之，这些发现表明，USP15 水平的降低通过调节 Keap1/Nrf2 信号通路，对 DBP 引起的睾丸氧化应激损伤起到显著的保护作用。
