Research Article: The activated DNA double-strand break repair pathway in cumulus cells from aging patients may be used as a convincing predictor of poor outcomes after in vitro fertilization-embryo transfer treatment

Date Published: September 20, 2018

Publisher: Public Library of Science

Author(s): Xu-lei Sun, Hao Jiang, Dong-xu Han, Yao Fu, Jian-bo Liu, Yan Gao, Shu-min Hu, Bao Yuan, Jia-bao Zhang, Ronald Hancock.


Women with advanced maternal age exhibit low anti-Müllerian hormone (AMH) levels and an altered follicular environment, which is associated with poor oocyte quality and embryonic developmental potential. However, the underlying mechanism is poorly understood. The present study aimed to assesswhether aging patients exhibit an activated DNA double-strandbreak (DSB) repair pathway in cumulus cells and thus, an association with poor outcomes after in vitro fertilization-embryo transfer (IVF-ET) treatment. Cumulus cells from young (≤29 y) and aging (≥37 y) human female patients were collected after oocyte retrieval. Our results indicated that aging patients showed a higher rate of γ-H2AX-positive cells than in young patients (24.33±4.55 vs.12.40±2.31, P<0.05). We also found that the mRNA expression levels of BRCA1, ATM, MRE11 and RAD51 were significantly elevated in aging cumulus cells. Accordingly, significantly increased protein levels of phospho-H2AX, BRCA1, ATM, MRE11 and RAD51 could be observed in aging cumulus cells. Moreover, aging cumulus cells showed a more frequent occurrence of early apoptosis than young cumulus cells. This study found that increases in DSBs and the activation of the repair pathway are potential indicators that may be used to predictoutcomes after IVF-ET treatment.

Partial Text

Cumulus cells, which are layers of specialized granulosa cells encircling oocytes, are thought to be closely related to the growth and meiotic maturation of oocytes, not only through supplying nutrients or signaling molecules to oocytes via gap junctions [1,2] but also via the protection of oocytes from adverse environments or factors [3]. Notably, increasing evidence has demonstrated that apoptosis in cumulus cells plays a mediating role in impairing oocyte developmental potential [4–6]. Thus, many studies have attempted to identify efficient and convincing biological markers in cumulus cells to predict the quality of oocytes and their developmental competence [7–9]. For example, the expression of gremlin 1 (GREM1) and hyaluronan synthase 2 (HAS2) is correlated with the developmental ability of oocytes [8]. Telomere length in cumulus cells is predictive of the competence of oocytes and embryos but may not be sufficiently discriminating to be clinically useful because of the limited number of cumulus cells [10]. Loss of cumulus gene expression has been observed in abnormal or dysfunctional cumulus cells and, thus, is thought to be associated with poor performance of subsequent embryo development [9].

Age is an established risk factor inducing reduced embryonic development and poor IVF-ET outcomes. Although poor oocyte quality is believed to be involved in the impaired developmental potential, the detailed mechanism remains largely unknown. A better understanding of this process will provide an improved reference for predicting, or even preventing, such complications. Our research provides the first evidence that significant DNA DSBs and, thus, the repair pathway activated in response exist in cumulus cells of aging women. Considering that unrepaired DSBs are always implicated in triggering apoptosis, our observations imply that DSBs in cumulus cells may be an important factor inducing oocyte impairment.




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