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Plin4 exacerbates cadmium-decreased testosterone level via inducing ferroptosis in testicular Leydig cells
Redox Biology ( IF 10.7 ) Pub Date : 2024-08-17 , DOI: 10.1016/j.redox.2024.103312
Xu-Dong Zhang 1 , Jian Sun 1 , Xin-Mei Zheng 1 , Jin Zhang 1 , Lu-Lu Tan 1 , Long-Long Fan 1 , Ye-Xin Luo 1 , Yi-Fan Hu 1 , Shen-Dong Xu 1 , Huan Zhou 1 , Yu-Feng Zhang 1 , Hao Li 1 , Zhi Yuan 1 , Tian Wei 1 , Hua-Long Zhu 2 , De-Xiang Xu 2 , Yong-Wei Xiong 2 , Hua Wang 2
Affiliation  

Strong evidence indicates that environmental stressors are the risk factors for male testosterone deficiency (TD). However, the mechanisms of environmental stress-induced TD remain unclear. Based on our all-cause male reproductive cohort, we found that serum ferrous iron (Fe2⁺) levels were elevated in TD donors. Then, we explored the role and mechanism of ferroptosis in environmental stress-reduced testosterone levels through in vivo and in vitro models. Data demonstrated that ferroptosis and lipid droplet deposition were observed in environmental stress-exposed testicular Leydig cells. Pretreatment with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, markedly mitigated environmental stress-reduced testosterone levels. Through screening of core genes involved in lipid droplets formation, it was found that environmental stress significantly increased the levels of perilipins 4 (PLIN4) protein and mRNA in testicular Leydig cells. Further experiments showed that Plin4 siRNA reversed environmental stress-induced lipid droplet deposition and ferroptosis in Leydig cells. Additionally, environmental stress increased the levels of METTL3, METTL14, and total RNA m6A in testicular Leydig cells. Mechanistically, S-adenosylhomocysteine, an inhibitor of METTL3 and METTL14 heterodimer activity, restored the abnormal levels of Plin4, Fe2⁺ and testosterone in environmental stress-treated Leydig cells. Collectively, these results suggest that Plin4 exacerbates environmental stress-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.

中文翻译:


Plin4 通过诱导睾丸 Leydig 细胞铁死亡而加剧镉导致的睾酮水平下降



强有力的证据表明环境压力源是男性睾酮缺乏症(TD)的危险因素。然而,环境应激引起TD的机制仍不清楚。根据我们的全因男性生殖队列,我们​​发现 TD 供体的血清亚铁 (Fe2⁺) 水平升高。然后,我们通过体内和体外模型探讨了铁死亡在环境应激降低的睾酮水平中的作用和机制。数据表明,在环境应激暴露的睾丸间质细胞中观察到铁死亡和脂滴沉积。使用 Ferrostatin-1 (Fer-1)(一种特定的铁死亡抑制剂)进行预处理,可显着缓解因环境压力而降低的睾酮水平。通过筛选参与脂滴形成的核心基因,发现环境应激显着增加了睾丸Leydig细胞中perilipins 4(PLIN4)蛋白和mRNA的水平。进一步的实验表明,Plin4 siRNA 可逆转环境应激诱导的 Leydig 细胞中的脂滴沉积和铁死亡。此外,环境压力增加了睾丸间质细胞中 METTL3、METTL14 和总 RNA m6A 的水平。从机制上讲,S-腺苷同型半胱氨酸(METTL3 和 METTL14 异二聚体活性的抑制剂)可恢复环境应激处理的 Leydig 细胞中 Plin4、Fe2⁺ 和睾酮的异常水平。总的来说,这些结果表明 Plin4 通过诱导睾丸 Leydig 细胞铁死亡,加剧环境应激导致的睾酮水平下降。
更新日期:2024-08-17
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