Abstract
The progressive and physiological decline in ovarian function depends on the rate of follicular loss by atresia, contributing to the reduction in ovarian reserve. Genetics and environmental factors play important roles in ovarian senescence and in the onset of ovarian dysfunctions such as diminished ovarian reserve. A better understanding of the mechanisms underlying ovarian aging and their regulation by genetic and environmental factors is needed to evaluate ovarian reserve and to predict fertility potential by identification of more accurate and less invasive markers. We report transcriptomic data (i) implicating novel (e.g. EIF2 signalling) and well-known pathways (e.g. TGFβ signalling), and (ii) defining a unique set of non-coding RNA (ncRNA), both associated with ovarian function. The latter includes miRNAs (e.g. Mir143 and Mir145), snoRNAs (e.g. Snord16a and Snora34), and one lncRNA (Gas5), which are differentially expressed in middle-aged ovaries (12 months) vs young-aged (3 months) from CD1 mice. Experimental analysis confirms that ovary lifespan varies across genetic backgrounds in mice and, genetics influences the response to environmental perturbations such as diet. Moreover, the identified ncRNAs were verified in a model of reproductive dysfunction promoted by the environmental toxicant ethylenthiourea. We also report the increase of miRNA143 and miRNA145 in follicular fluid of women with diminished ovarian reserve. Their levels inversely correlate with the hormonal profile and with the number of the oocytes recruited upon hormonal stimulation. Overall, we report a transcriptomic signature for ovarian dysfunction in vivo that provides a valuable resource for translational research in human reproductive aging.
Highlights
The decline in fertility over time results from ovarian aging, which is characterized by quantitative and During this period, ovarian health is decliningOfficial journal of the Cell Death Differentiation AssociationCuomo et al Cell Death Discovery (2018)4:112 asymptomatically
Confidence in the differential gene set was enhanced by the fact that among genes with reduced expression were transcripts previously associated with ovarian aging: antiMüllerian hormone (Amh, logFC −1.01, P 4.58E-02), follicle stimulating hormone receptor (Fshr, logFC −1.49, P 4.66E-02) and bone morphogenetic protein[15] (Bmp[15], logFC −1.40, P 2.62E-02)
We verified by qRT-PCR the differential expression of these genes and of other established markers of physiological ovarian aging: aromatase, Cyp19a1; activin-βA, Inhba; inhibin-α, Inha; growth differentiation factor 9, Gdf[9] (Fig. 1B and Table S2, Supplementary information)
Summary
Official journal of the Cell Death Differentiation Association. Cuomo et al Cell Death Discovery (2018)4:112 asymptomatically. Genetic and environmental factors affect ovary lifespan by modulating risk of ovarian dysfunctions such as diminished ovarian reserve (DOR) and premature ovarian failure (POF)[4]. Studies correlating menopausal age with genetic variation suggest a genetic component in determining life of the follicle pool[5] and reproductive lifespan[6,7]. Mutations in oocyte-derived bone morphogenetic protein 15 (BMP15) and in oocyte-derived growth differentiation factor 9 (GDF9), both TGF-β family members involved in follicular development, are variably associated with DOR and POF8. Inhibin A (INHA), a negative modulator of pituitary follicle stimulating hormone (FSH) synthesis, is another candidate gene for POF
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
