The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis

Abstract

Mouse oocytes respond to DNA damage by arresting in meiosis I through activity of the Spindle Assembly Checkpoint (SAC) and DNA Damage Response (DDR) pathways. It is currently not known if DNA damage is the primary trigger for arrest, or if the pathway is sensitive to levels of DNA damage experienced physiologically. Here, using follicular fluid from patients with the disease endometriosis, which affects 10% of women and is associated with reduced fertility, we find raised levels of Reactive Oxygen Species (ROS), which generate DNA damage and turn on the DDR-SAC pathway. Only follicular fluid from patients with endometriosis, and not controls, produced ROS and damaged DNA in the oocyte. This activated ATM kinase, leading to SAC mediated metaphase I arrest. Completion of meiosis I could be restored by ROS scavengers, showing this is the primary trigger for arrest and offering a novel clinical therapeutic treatment. This study establishes a clinical relevance to the DDR induced SAC in oocytes. It helps explain how oocytes respond to a highly prevalent human disease and the reduced fertility associated with endometriosis.

Integrated Eutopic Endometrium and Non‐Depleted Serum Quantitative Proteomic Analysis Identifies Candidate Serological Markers of Endometriosis

“…The exact pathophysiology of endometriosis related to infertility is still unknown. Endometriosis can be detrimental to fertility directly by distorting tubo‐ovarian anatomy, or indirectly by invoking inflammatory and oxidative damage on the oocytes resulting in poorer quality oocytes. A noninvasive method of diagnosis is not available and currently, endometriosis can be only definitively diagnosed through laparoscopic surgery.…”

Advanced oxidation protein products from the follicular microenvironment and their role in infertile women with endometriosis

“…Certain inflammatory factors in the FF, including tumor necrosis factor α and interleukin-17A, have also been reported to adversely affect oocytes (43,44). The FF in EM patients may induce oxidative stress reaction in oocytes and cause DNA damage (45). In addition, AOPPs in the plasma induce endoplasmic reticulum stress in various cells (46)(47)(48)(49), and this stress has been observed to cause phenotypic alterations and death in cells (50,51).…”

Early Embryo Development in Women with Endometriosis: A Retrospective Cohort Study

“…The number of oocytes on the folliculogram > 14 mm was an arbitrary level of cut-off taken to compare the oocyte retrieval rates between the two groups from follicles that were most likely mature at the time of oocyte collection. This is of particular interest because work from our group and others have shown possibility of oocyte DNA damage as a sequelae of endometriosis which impacts on follicular maturation and development (Hamdan et al, 2016, Mansour et al, 2010.…”

“…suggest that oocyte and embryo development were poorer when exposed to follicular and peritoneal uid of women with endometriosis (Da Broi et al, 2014, Mansour et al, 2010, Hamdan et al, 2016. Studies on oocyte recipient cycles showed poorer reproductive outcome in recipients who received oocytes from women with endometriosis, thus, strongly suggesting that the oocyte quality of women with endometriosis is compromised (Diaz et al, 2000, Simon et al, 1994, although the vast majority of previous studies directly examining the impact of endometriosis oocyte and embryo quality and development fail to conclude that endometriosis detrimentally impact on oocyte and/or embryo quality as observed in ART cycles (Filippi et al, 2014, Reinblatt et al, 2011a, Dong et al, 2013, Al-Fadhli et al, 2006, Lin et al, 2012, Mekaru et al, 2013, Suzuki et al, 2005.…”