AUTHOR=Schröder Sarah K. , Krizanac Marinela , Kim Philipp , Kessel Jan C. , Weiskirchen Ralf 

TITLE=Ovaries of estrogen receptor 1-deficient mice show iron overload and signs of aging

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1325386

DOI=10.3389/fendo.2024.1325386

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>Estrogens are crucial regulators of ovarian function, mediating their signaling through binding to estrogen receptors. The disruption of the estrogen receptor 1 (<italic>Esr1</italic>) 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 <italic>Esr1</italic>-deficient ovaries showing massive expression of lipocalin 2, a regulator of iron homeostasis.</p></sec><sec><title>Methods</title><p>Therefore, we examined the consequences of depleting <italic>Esr1</italic> in mouse ovaries, focusing on iron metabolism. For that reason, we compared ovaries of adult <italic>Esr1</italic>-deficient animals and age-matched wild type littermates. </p></sec><sec><title>Results and discussion</title><p>We found increased iron accumulation in <italic>Esr1</italic>-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 <italic>Esr1</italic>-deficient ovarian stroma. The depletion of <italic>Esr1</italic> 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 <italic>Esr1</italic>-deficient ovaries were characterized by iron accumulation and strong autofluorescence. Finally, deletion of <italic>Esr1</italic> 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 <italic>Esr1</italic> deficiency triggers mechanisms similar to those associated with aging.</p></sec>