PDF(Pubmed)
Abstract：
Acrolein (ACR) is a ubiquitous environmental pollutant and byproduct of lipid peroxidation that has been implicated in male infertility. However, the molecular mechanisms underlying ACR-induced toxicity in Sertoli cells remain unclear. Given its role in inducing oxidative stress, we examined whether ferroptosis, an iron-dependent form of regulated cell death, could mediate ACR toxicity in Sertoli cells. We also tested if hydrogen sulfide (H2S), which has antioxidant and ACR detoxifying properties, could protect Sertoli cells from ACR-induced ferroptosis. ACR exposure decreased Sertoli cell viability, increased protein carbonylation and p38 MAPK phosphorylation, indicating oxidative injury. ACR also depleted glutathione (GSH), downregulated the cystine importer SLC7A11, increased intracellular ferrous iron (Fe2+) and lipid peroxidation, suggesting activation of ferroptosis. Consistently, the ferroptosis inhibitor deferoxamine (DFO) markedly attenuates ACR-induced cell death. Further studies revealed that ACR-induced ferroptotic changes were prevented by exogenous H2S and exaggerated by inhibition of endogenous H2S production. Furthermore, H2S also suppressed GPX4 inhibitor RSL3-induced intracellular ACR accumulation and ferroptosis. In summary, our study demonstrates that ACR induces ferroptotic cell death in Sertoli cells, which can be prevented by H2S through multiple mechanisms. Targeting the H2S pathway may represent a therapeutic strategy to mitigate ACR-induced Sertoli cell injury and preserve male fertility.
摘要：
丙烯醛（ACR）是一种普遍存在的环境污染物，是脂质过氧化的副产物，与男性不育有关。然而,ACR诱导的支持细胞毒性的分子机制尚不清楚.鉴于其在诱导氧化应激中的作用，我们检查了铁性凋亡，一种依赖铁的调节细胞死亡形式，可以介导Sertoli细胞中的ACR毒性。我们还测试了硫化氢(H2S)具有抗氧化和ACR解毒特性，可以保护支持细胞免受ACR诱导的铁凋亡。ACR暴露降低了支持细胞活力，增加蛋白质羰基化和p38MAPK磷酸化，表明氧化损伤。ACR还耗尽了谷胱甘肽（GSH），下调胱氨酸导入体SLC7A11，增加细胞内亚铁（Fe2+）和脂质过氧化，提示铁凋亡的激活。始终如一，铁凋亡抑制剂去铁胺(DFO)显著减弱ACR诱导的细胞死亡。进一步的研究表明，外源性H2S可以防止ACR诱导的铁细胞变化，并通过抑制内源性H2S的产生而加剧。此外，H2S还抑制GPX4抑制剂RSL3诱导的细胞内ACR积累和铁凋亡。总之,我们的研究表明，ACR诱导支持细胞中的铁细胞死亡，H2S可以通过多种机制预防。靶向H2S途径可以代表减轻ACR诱导的支持细胞损伤和保持男性生育力的治疗策略。
