Abstract：
OBJECTIVE: Does hyperandrogenaemia affect the function of ovarian granulosa cells by activating ferroptosis, and could this process be regulated by endoplasmic reticulum stress?
METHODS: Levels of ferroptosis and endoplasmic reticulum stress in granulosa cells were detected in women with and without polycystic ovary syndrome (PCOS) undergoing IVF. Ferroptosis and endoplasmic reticulum stress levels of ovarian tissue and follicle development were detected in control mice and PCOS-like mice models, induced by dehydroepiandrosterone. An in-vitro PCOS model of KGN cells was constructed with testosterone and ferroptosis inhibitor Fer-1. Endoplasmic reticulum stress inhibitor, tauroursodeoxycholate (TUDCA), determined the potential mechanism associated with excessive induction of ferroptosis in granulosa cells related to PCOS, and levels of ferroptosis and endoplasmic reticulum stress were detected.
RESULTS: Activation of ferroptosis and endoplasmic reticulum stress occurred in granulosa cells of women with PCOS and the varies of PCOS-like mice. The findings in KGN cells demonstrated that testosterone treatment results in elevation of oxidative stress levels, particularly lipid peroxidation, and intracellular iron accumulation in granulosa cells. The expression of genes and proteins associated with factors related to ferroptosis, mitochondrial membrane potential and ultrastructure showed that testosterone activated ferroptosis, whereas Fer-1 reversed these alterations. During in-vitro experiments, activation of endoplasmic reticulum stress induced by testosterone treatment was detected in granulosa cells. In granulosa cells, TUDCA, an inhibitor of endoplasmic reticulum stress, significantly mitigated testosterone-induced ferroptosis.
CONCLUSIONS: Ferroptosis plays a part in reproductive injury mediated by hyperandrogens associated with PCOS, and may be regulated by endoplasmic reticulum stress.
METHODS: Levels of ferroptosis and endoplasmic reticulum stress in granulosa cells were detected in women with and without polycystic ovary syndrome (PCOS) undergoing IVF. Ferroptosis and endoplasmic reticulum stress levels of ovarian tissue and follicle development were detected in control mice and PCOS-like mice models, induced by dehydroepiandrosterone. An in-vitro PCOS model of KGN cells was constructed with testosterone and ferroptosis inhibitor Fer-1. Endoplasmic reticulum stress inhibitor, tauroursodeoxycholate (TUDCA), determined the potential mechanism associated with excessive induction of ferroptosis in granulosa cells related to PCOS, and levels of ferroptosis and endoplasmic reticulum stress were detected.
RESULTS: Activation of ferroptosis and endoplasmic reticulum stress occurred in granulosa cells of women with PCOS and the varies of PCOS-like mice. The findings in KGN cells demonstrated that testosterone treatment results in elevation of oxidative stress levels, particularly lipid peroxidation, and intracellular iron accumulation in granulosa cells. The expression of genes and proteins associated with factors related to ferroptosis, mitochondrial membrane potential and ultrastructure showed that testosterone activated ferroptosis, whereas Fer-1 reversed these alterations. During in-vitro experiments, activation of endoplasmic reticulum stress induced by testosterone treatment was detected in granulosa cells. In granulosa cells, TUDCA, an inhibitor of endoplasmic reticulum stress, significantly mitigated testosterone-induced ferroptosis.
CONCLUSIONS: Ferroptosis plays a part in reproductive injury mediated by hyperandrogens associated with PCOS, and may be regulated by endoplasmic reticulum stress.
摘要：
目的：高雄激素血症是否通过激活铁凋亡影响卵巢颗粒细胞的功能，
方法：在接受试管婴儿的多囊卵巢综合征（PCOS）患者中检测到颗粒细胞的铁细胞凋亡和内质网应激水平。在对照小鼠和PCOS样小鼠模型中检测卵巢组织和卵泡发育的铁凋亡和内质网应激水平,脱氢表雄酮诱导。用睾酮和铁凋亡抑制剂Fer-1构建KGN细胞的体外PCOS模型。内质网应激抑制剂,牛磺熊去氧胆酸盐（TUDCA），确定与PCOS相关的颗粒细胞过度诱导铁凋亡的潜在机制，并检测铁性凋亡和内质网应激水平。
结果：在PCOS女性和不同的PCOS样小鼠的颗粒细胞中发生铁细胞凋亡和内质网应激的激活。在KGN细胞中的发现表明，睾酮治疗导致氧化应激水平升高，特别是脂质过氧化，和颗粒细胞内的铁积累。铁死亡相关因子相关基因和蛋白的表达,线粒体膜电位和超微结构显示睾酮激活铁凋亡，而Fer-1逆转了这些改变。在体外实验中,在颗粒细胞中检测到睾酮处理诱导的内质网应激的激活。在颗粒细胞中，TUDCA,内质网应激的抑制剂，显著减轻睾酮诱导的铁凋亡。
结论：Ferroptosis在PCOS相关的高雄激素介导的生殖损伤中起作用，并且可能受内质网应激的调节。
方法：在接受试管婴儿的多囊卵巢综合征（PCOS）患者中检测到颗粒细胞的铁细胞凋亡和内质网应激水平。在对照小鼠和PCOS样小鼠模型中检测卵巢组织和卵泡发育的铁凋亡和内质网应激水平,脱氢表雄酮诱导。用睾酮和铁凋亡抑制剂Fer-1构建KGN细胞的体外PCOS模型。内质网应激抑制剂,牛磺熊去氧胆酸盐（TUDCA），确定与PCOS相关的颗粒细胞过度诱导铁凋亡的潜在机制，并检测铁性凋亡和内质网应激水平。
结果：在PCOS女性和不同的PCOS样小鼠的颗粒细胞中发生铁细胞凋亡和内质网应激的激活。在KGN细胞中的发现表明，睾酮治疗导致氧化应激水平升高，特别是脂质过氧化，和颗粒细胞内的铁积累。铁死亡相关因子相关基因和蛋白的表达,线粒体膜电位和超微结构显示睾酮激活铁凋亡，而Fer-1逆转了这些改变。在体外实验中,在颗粒细胞中检测到睾酮处理诱导的内质网应激的激活。在颗粒细胞中，TUDCA,内质网应激的抑制剂，显著减轻睾酮诱导的铁凋亡。
结论：Ferroptosis在PCOS相关的高雄激素介导的生殖损伤中起作用，并且可能受内质网应激的调节。
