Di (2‐ethylhexyl) phthalate (DEHP) is an important plasticizer in industrial production, and its toxic effects on testes are widely recognized. Se‐methylselenocysteine (SMC) is a major selenium compound found in selenium‐rich plants, which possesses unique biological properties such as antioxidants. However, the effect of SMC on DEHP‐induced 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‐dose SMC (L‐SMC), moderate‐dose SMC (M‐SMC), or high‐dose SMC (H‐SMC). 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–testis barrier damage in mice, which could be alleviated by SMC. Mitochondrial damage accompanied by accumulation of total iron content, MDA, and 4‐HNE, as well as downregulation of antioxidants SOD, GSH, and GSH‐Px 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‐induced ferroptosis and promote the expression of cell junction key proteins ZO‐1, 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‐induced ferroptosis in testicular Sertoli cells, protects the blood–testis barrier, and prevents sperm aberrations via the Nrf2/GPX4 axis.

中文翻译：

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Se-甲基硒代半胱氨酸通过 Nrf2/GPX4 轴改善睾丸支持细胞中 DEHP 诱导的铁死亡


邻苯二甲酸二(2-乙基己基)酯(DEHP)是工业生产中重要的增塑剂，其对睾丸的毒性作用已被广泛认可。硒甲基硒代半胱氨酸（SMC）是富硒植物中发现的一种主要硒化合物，具有抗氧化剂等独特的生物特性。然而，SMC对DEHP所致睾丸损伤的影响及具体机制仍不清楚。在这项研究中，50只小鼠被随机分为5组，分别给予玉米油（对照）、DEHP、低剂量SMC（L-SMC）、中剂量SMC（M-SMC）或高剂量SMC（H）。 ‐SMC）。测定各组小鼠精子质量，并采用HE染色和透射电镜（TEM）观察睾丸形态，收集睾丸组织用于后续分子生物学分析。 TM4细胞系应用于体外进行机制验证。我们的结果表明，DEHP 会导致小鼠精子质量下降和血睾屏障损伤，而 SMC 可以缓解这种情况。 DEHP处理后观察到线粒体损伤，伴随着总铁含量、MDA和4-HNE的积累，以及抗氧化剂SOD、GSH和GSH-Px的下调，表现出典型的铁死亡特征。体外实验证实，SMC促进TM4细胞中GPX4的上调，能够缓解DEHP代谢物MEHP诱导的铁死亡，并促进细胞连接关键蛋白ZO-1、Occludin和Connexin 43的表达，而这些蛋白可被GPX4抑制抑制剂 RSL3 或 Nrf2 抑制剂 ML385。总体而言，上述结果表明 SMC 可改善 DEHP 诱导的睾丸支持细胞铁死亡，保护血睾屏障，并通过 Nrf2/GPX4 轴防止精子畸变。