Abstract
In middle-aged women, the decline of ovarian follicle reserve below a critical threshold marks menopause, leading to hormonal, inflammatory, and metabolic changes linked to disease. The highest incidence and mortality of sporadic ovarian cancer (OC) occur at post-menopause, while OC risk is reduced by full-term pregnancies during former fertile life. Herein, we investigate how parity history modulates the ovarian transcriptome related to such declining follicle pool and systemic inflammation in reproductively-aged mice. Female C57BL/6 mice were housed under multiparous and virgin (nulliparous) breeding regimens from adulthood until estropause. The ovaries were then subjected to follicle count and transcriptional profiling, while a cytokine panel was determined in the sera. As expected, the follicle number was markedly decreased just by aging. Importantly, a significantly higher count of primordial and total follicles was observed in aged multiparous relative to aged virgin ovaries. Consistently, among the 65 genes of higher expression in aged multiparous ovaries, 27 showed a follicle count-like pattern, 21 had traceable evidence of roles in follicular/oocyte homeostasis, and 7 were transforming-growth factor beta (TGF-β)/bone morphogenetic protein (BMP) superfamily members. The remaining genes were enriched in cell chemotaxis and innate-immunity, and resembled the profiles of circulating CXCL1, CXCL2, CXCL5, CSF3, and CCL3, chemokines detected at higher levels in aged multiparous mice. We conclude that multiparity during reproductive life promotes the retention of follicle remnants while improving local (ovarian) and systemic immune-innate surveillance in aged female mice. These findings could underlie the mechanisms by which pregnancy promotes the long-term reduced OC risk observed at post-menopause.
Highlights
Aging is characterized by a wide range of cumulative damage that affects tissue homeostasis, predisposing to disease initiation
We recently described the reproductive records, circulating gonadotropin levels, systemic inflammatory status, and intraperitoneal tumor spread in estropausal C57BL6 female mice, as well as the differential accumulation of lipofuscin and hemosiderin in the ovaries of these animals according to their divergent parity history [18,22]
Regardless of parity status, the aged ovary expressed a high content of genes involved in immune/inflammatory response, cell adhesion, TNF synthesis, proteolysis, and wound healing, reflecting a low-grade chronic inflammation due to endogenous tissue damage, which is characteristic of senescence-associated secretory phenotype (SASP)
Summary
Aging is characterized by a wide range of cumulative damage that affects tissue homeostasis, predisposing to disease initiation. The declining follicle number has been recently proposed to play a role in ovarian cancer (OC) etiology by promoting a pre-neoplastic phenotype of the ovarian surface epithelium (OSE) [3,4,5], a cell layer claimed to be the origin of the most frequent OC variant, the epithelial OC [6]. The post-menopausal ovary develops several age-related morphological alterations, such as stromal fibrosis, vascular remodeling, OSE invaginations, and epithelial inclusion cysts, the latter regarded as pre-neoplastic lesions [9,10]. Consistent with these changes, OC incidence and mortality steadily increase with age, reaching a maximum during the peri-menopause and early post-menopause periods [11]. Most of the observed menopause manifestations synergize with the age-dependent systemic low-grade inflammation underlying the development of chronic diseases, including OC [12]
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