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.