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

Introduction: 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.

Methods: 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.

Results And Discussion: 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.