USP15 participates in DBP-induced testicular oxidative stress injury through regulating the Keap1/Nrf2 signaling pathway.
USP15 participates in DBP-induced testicular oxidative stress injury through regulating the Keap1/Nrf2 signaling pathway.
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DOI：
10.1016/j.scitotenv.2021.146898
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发表时间：
2021-04
期刊：
影响因子：
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通讯作者：
Lei Zhang;Xian Gao;Zhiqiang Qin;Xiaokai Shi;Kaiqiang Xu;Shangqian Wang;Min Tang;W. Wang
中科院分区：
文献类型：
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作者：
Lei Zhang;Xian Gao;Zhiqiang Qin;Xiaokai Shi;Kaiqiang Xu;Shangqian Wang;Min Tang;W. Wang
邻苯二甲酸二丁酯（DBP）具有明显的生物毒性，已被列为我国环境优先污染物。流行病学研究表明，DBP暴露与男性生殖系统的一系列先天性和获得性缺陷密切相关。DBP引起的氧化应激损伤在这些缺陷中起重要作用。已有研究表明，Keap 1/Nrf 2抗氧化通路在DBP诱导的氧化应激损伤中起保护作用。然而，Nrf 2通路激活的进一步分子调控机制仍不清楚。在此，我们证明了DBP引起睾丸氧化应激损伤，并且在体内和体外损伤中Nrf 2通路被激活。此外，我们验证了USP 15水平的降低通过抑制Nrf 2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，USP 15被证实为miR-135 b-5 p的靶点，并且miR-135 b-5 p介导的USP 15抑制参与DBP诱导的氧化应激损伤。这些结果表明，降低USP 15的表达水平可能通过调节Keap 1/Nrf 2信号通路对DBP引起的睾丸氧化应激损伤具有显著的保护作用。
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.