Schröder Sarah K, Krizanac Marinela, Kim Philipp, Kessel Jan C, Weiskirchen Ralf
Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen, Aachen, Germany.
Front Endocrinol (Lausanne). 2024 Feb 23;15:1325386. doi: 10.3389/fendo.2024.1325386. eCollection 2024.
Estrogens are crucial regulators of ovarian function, mediating their signaling through binding to estrogen receptors. The disruption of the estrogen receptor 1 () provokes infertility associated with a hemorrhagic, cystic phenotype similar to that seen in diseased or aged ovaries. Our previous study indicated the possibility of altered iron metabolism in -deficient ovaries showing massive expression of lipocalin 2, a regulator of iron homeostasis.
Therefore, we examined the consequences of depleting in mouse ovaries, focusing on iron metabolism. For that reason, we compared ovaries of adult -deficient animals and age-matched wild type littermates.
We found increased iron accumulation in -deficient animals by using laser ablation inductively coupled plasma mass spectrometry. Western blot analysis and RT-qPCR confirmed that iron overload alters iron transport, storage and regulation. In addition, trivalent iron deposits in form of hemosiderin were detected in -deficient ovarian stroma. The depletion of was further associated with an aberrant immune cell landscape characterized by the appearance of macrophage-derived multinucleated giant cells (MNGCs) and increased quantities of macrophages, particularly M2-like macrophages. Similar to reproductively aged animals, MNGCs in -deficient ovaries were characterized by iron accumulation and strong autofluorescence. Finally, deletion of led to a significant increase in ovarian mast cells, involved in iron-mediated foam cell formation. Given that these findings are characteristics of ovarian aging, our data suggest that deficiency triggers mechanisms similar to those associated with aging.
雌激素是卵巢功能的关键调节因子，通过与雌激素受体结合介导其信号传导。雌激素受体1（）的破坏会引发与出血性、囊性表型相关的不孕症，这种表型与患病或衰老卵巢中所见的相似。我们之前的研究表明，在缺乏的卵巢中，铁代谢可能发生改变，这些卵巢中大量表达脂质运载蛋白2，这是一种铁稳态调节因子。
因此，我们研究了小鼠卵巢中缺乏的后果，重点关注铁代谢。为此，我们比较了成年缺乏动物的卵巢和年龄匹配的野生型同窝小鼠的卵巢。
我们使用激光烧蚀电感耦合等离子体质谱法发现缺乏动物中铁积累增加。蛋白质免疫印迹分析和逆转录定量聚合酶链反应证实铁过载会改变铁的运输、储存和调节。此外，在缺乏的卵巢基质中检测到以含铁血黄素形式存在的三价铁沉积物。缺乏还与异常的免疫细胞格局有关，其特征是出现巨噬细胞衍生的多核巨细胞（MNGC）以及巨噬细胞数量增加，尤其是M2样巨噬细胞。与生殖衰老的动物相似，缺乏卵巢中的MNGC具有铁积累和强烈自发荧光的特征。最后，的缺失导致卵巢肥大细胞显著增加，肥大细胞参与铁介导的泡沫细胞形成。鉴于这些发现是卵巢衰老的特征，我们的数据表明缺乏触发了与衰老相关的类似机制。
