Date Published: March 15, 2018
Author(s): Ulises Urzua, Carlos Chacon, Renato Espinoza, Sebastián Martínez, Nicole Hernandez.
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.
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 . In the mammalian ovary, 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 .
The risk of OC increases during the postmenopause and decreases with parity and oral contraceptive use during prior fertile age. Systemic exposure to progesterone (progestins) and decreased ovulatory cycles characterize these reproductive conducts. Here we show evidence of differential accumulation of both hemosiderin and lipofuscin in the postreproductive mouse ovary (>20 months old) according to its previous parity history. Aged virgin—nulliparous—ovaries contained significantly higher amounts of the two pigments, a finding that correlated with increased levels of oxidative DNA damage. Based on morphology and studies by other authors, these two residual substances would be contained in multinucleated enlarged macrophage clusters. Provided that ferric iron present in hemosiderin is reduced to ferrous iron, the diffusion of the latter across ovarian stroma and its uptake by lipofuscin would be an important source of endogenous ROS. The precise mechanism by which hemosiderin and lipofuscin accumulates in the ovary as a function of parity and age deserves further research.