Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-KIT

Abstract

This study investigated ovarian expressions of bone morphogenetic protein 15 (BMP15), growth differentiation factor 9 (GDF9), and C-KIT according to age in female mice to determine whether these factors can be served as new potential biomarkers of ovarian aging. Ovaries were collected from mice aged 10, 20, 30, and 40 weeks, and ovarian expressions of BMP15, GDF9, and C-KIT were examined by real-time PCR, Western blot, and immunohistochemistry. Follicle counts were measured on histological hematoxylin and eosin staining. In the second experiment to evaluate ovarian function, after superovulation with PMSG and hCG, the numbers of zygotes retrieved and embryo development rate were examined. Ovarian expressions of BMP15, GDF9, and C-KIT decreased with age. Follicle counts, numbers of retrieved zygotes, and embryo development rate were also significantly reduced in old mice over 30 weeks compared with young mice. These results indicate that these factors could be served as new potential biomarkers of ovarian aging. Impact statement Ovarian aging is becoming a more important issue in terms of fertility preservation and infertility treatment. Serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC) are being practically used as markers of ovarian aging as well as ovarian reserve in human. However, these factors have some drawbacks in assessing ovarian aging and reserve. Therefore, the identification of ovarian expressions of BMP15, GDF9, and C-KIT according to female could be applied as a potent predictor of ovarian aging. This work provides new information on the development of diagnosis and treatment strategy of age-related fertility decline and premature ovarian insufficiency.

Effects of Growth and Differentiation Factor 9 and Bone Morphogenetic Protein 15 overexpression on the steroidogenic metabolism in bovine granulosa cells in vitro

“…Some authors reported that the hormonal production of granulosa cells during folliculogenesis was modulated by the oocyte, which would secrete an inhibitor of P 4 , according to the stage of follicular development (El-Fouly et al, 1970;Vanderhyden & Macdonald, 1998). The oocyte-secreted signalling factors induce the expression of the genes associated with cumulus cells' differentiation and mitosis, in a paracrine way (Alam et al, 2018), such as GDF9 and BMP15 (Paulini & Melo, 2011), which could also serve as new potential biomarkers of ovarian ageing in mice (Park et al, 2020). The results of the current study demonstrated that the overexpression of these factors exerts an influence on the luteinization of bovine GCs cultured in vitro in a homologous system, and in an autocrine way, in agreement with the results of Li et al (2000).…”

Biomarkers of aging

“…BMP15, GDF9, and c-KIT play critical roles in folliculogenesis through interaction between oocytes and cumulus cells (Gilchrist et al, 2008). Ovarian expressions of BMP15, GDF9, and c-KIT decrease with age (Park et al, 2020), and their expression levels in cumulus granulosa cells could serve as potential biomarkers of ovarian aging and predicting oocyte developmental potential (Li et al, 2014).…”

Role of Granulosa Cells in the Aging Ovarian Landscape: A Focus on Mitochondrial and Metabolic Function

“…GDF9, signaling through the SMAD signaling pathway, upregulates the TZP-associated genes fascin homolog 1 (Fscn1), an actin bundling protein and myosin X (Myo10), an actin-based motor protein, both known to induce formation of filopodia (Bohil et al, 2006;Hashimoto et al, 2011;El-Hayek et al, 2018;Baena and Terasaki, 2019). With age, oocyte GDF9 expression declines (Li et al, 2014;Park et al, 2020;Gong et al, 2021) along with the expression of Fscn1 and Myo10, and the numbers of TZPs are reduced by approximately 40%, resulting in a marked decrease in gap junctional communication between the oocyte and the granulosa cells (El-Hayek et al, 2018).…”