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Se\u2010methylselenocysteine (SMC) is a major selenium compound found in selenium\u2010rich plants, which possesses unique biological properties such as antioxidants. However, the effect of SMC on DEHP\u2010induced testicular injury and the specific mechanism remains unknown. In this study, 50 mice were randomly divided into 5 groups and were given corn oil (Control), DEHP, low\u2010dose SMC (L\u2010SMC), moderate\u2010dose SMC (M\u2010SMC), or high\u2010dose SMC (H\u2010SMC). The sperm quality of the mice in each group was determined, and HE staining and transmission electron microscopy (TEM) were applied to observe testicular morphology, and testicular tissues were collected for the subsequent molecular biological analyses. The TM4 cell line was applied in vitro for mechanism validation. Our results showed that DEHP could lead to decreased sperm quality and blood\u2013testis barrier damage in mice, which could be alleviated by SMC. Mitochondrial damage accompanied by accumulation of total iron content, MDA, and 4\u2010HNE, as well as downregulation of antioxidants SOD, GSH, and GSH\u2010Px were observed after DEHP treatment, which exhibited a typical ferroptosis feature. In vitro experiments confirmed that SMC promoted upregulation of GPX4 in TM4 cells and was able to alleviate DEHP metabolite MEHP\u2010induced ferroptosis and promote the expression of cell junction key proteins ZO\u20101, Occludin, and Connexin 43, which could be inhibited by the GPX4 inhibitor RSL3 or the Nrf2 inhibitor ML385. Overall, the above results suggest that SMC ameliorates the DEHP\u2010induced ferroptosis in testicular Sertoli cells, protects the blood\u2013testis barrier, and prevents sperm aberrations via the Nrf2\/GPX4 axis.<\/jats:p>","DOI":"10.1002\/tox.24425","type":"journal-article","created":{"date-parts":[[2024,10,3]],"date-time":"2024-10-03T09:53:58Z","timestamp":1727949238000},"page":"191-203","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Se\u2010Methylselenocysteine Ameliorates <scp>DEHP<\/scp>\u2010Induced Ferroptosis in Testicular Sertoli Cells via the Nrf2\/<scp>GPX4<\/scp> Axis"],"prefix":"10.1002","volume":"40","author":[{"given":"Weilin","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Urology Minda Hospital of Hubei Minzu University  Enshi China"},{"name":"Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases Minda Hospital of Hubei Minzu University  Enshi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases Minda Hospital of Hubei Minzu University  Enshi China"},{"name":"Department of Laboratory Medicine Minda Hospital of Hubei Minzu University  Enshi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Urology Minda Hospital of Hubei Minzu University  Enshi China"},{"name":"Hubei Provincial Key Laboratory of Occurrence and Intervention of Rheumatic Diseases Minda Hospital of Hubei Minzu University  Enshi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenchao","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan 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