Parity-Dependent Hemosiderin and Lipofuscin Accumulation in the Reproductively Aged Mouse Ovary.

Ulises Urzua,Nicole Hernandez,Renato Espinoza,Sebastián Martínez,Carlos Chacon

doi:10.1155/2018/1289103

Abstract

The progressive decline of the ovarian follicle pool leads to reproductive ageing. The latter is accompanied by age-related disorders, including various types of cancer. In fact, the highest rates of ovarian cancer (OC) occur at postmenopause while OC risk is significantly modulated by parity records during previous fertile life. We approached the age-parity relationship in the C57BL/6 mouse model and herein describe the presence of nonheme iron (hemosiderin) and deposits of the “age pigment” lipofuscin in reproductively aged mouse ovaries by applying conventional histochemical methods and autofluorescence. In addition, the 8-OHdG adduct was evaluated in ovarian genomic DNA. Both hemosiderin and lipofuscin were significantly higher in virgin compared to multiparous ovaries. The same pattern was observed for 8-OHdG. We conclude that nulliparity induces a long-term accumulation of iron and lipofuscin with concomitant oxidative damage to DNA in the mouse ovary. Since lipofuscin is a widely accepted senescence marker and given the recently postulated role of lipofuscin-associated iron as a source of reactive oxygen species (ROS) in senescent cells, these findings suggest a possible pathogenic mechanism by which nulliparity contributes to an increased OC risk in the postmenopausal ovary.

Highlights

Ageing is characterized by cumulative tissue and cell damage that impairs homeostasis and increases the risk of disease
Dysregulated oxidative stress concurrent with a depressed antioxidant defense is a predominant feature of such damage [1]. This age-related redox imbalance is paralleled by a steep decay in the quantity and quality of the follicular-oocyte reserve. This process culminates at menopause in women, a reproductive hallmark characterized by major systemic endocrine, metabolic, and inflammatory alterations, which together lead to higher risk of chronic pathologies including various types of cancer [2]
Though events requiring red blood cell (RBC) clearance have not been systematically studied in the mouse ovary, the postovulatory microhemorrhages preceding corpus luteum (CL) formation from follicle remains—sometimes called corpus hemorrhagicum—could be a source of iron from RBCs that after lifetime ovulations

Summary

Introduction

Ageing is characterized by cumulative tissue and cell damage that impairs homeostasis and increases the risk of disease. This age-related redox imbalance is paralleled by a steep decay in the quantity and quality of the follicular-oocyte reserve. This process culminates at menopause in women, a reproductive hallmark characterized by major systemic endocrine, metabolic, and inflammatory alterations, which together lead to higher risk of chronic pathologies including various types of cancer [2]. Multiparity reduces while nulliparity increases OC risk [3] The basis of this epidemiological evidence would be a tumor suppressor-like effect of progesterone and/or different degrees of ovulatory tear and repair stress to the ovarian surface epithelium (OSE), one of the candidate cell types where OC is thought to originate from [4]

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Conclusion