Single-cell and bulk transcriptional profiling of mouse ovaries reveals novel genes and pathways associated with DNA damage response in oocytes.

Immature oocytes enclosed in primordial follicles stored in female ovaries are under constant threat of DNA damage induced by endogenous and exogenous factors. Checkpoint kinase 2 (CHEK2) is a key mediator of the DNA damage response in all cells. Genetic studies have shown that CHEK2 and its downstream targets, p53 and TAp63, regulate primordial follicle elimination in response to DNA damage, however the mechanism leading to their demise is still poorly characterized. Single-cell and bulk RNA sequencing were used to determine the DNA damage response in wildtype and Chek2-deficient ovaries. A low but oocyte-lethal dose of ionizing radiation induces a DNA damage response in ovarian cells that is solely dependent on CHEK2. DNA damage activates multiple ovarian response pathways related to apoptosis, p53, interferon signaling, inflammation, cell adhesion, and intercellular communication. These pathways are differentially employed by different ovarian cell types, with oocytes disproportionately affected by radiation. Novel genes and pathways are induced by radiation specifically in oocytes, shedding light on their sensitivity to DNA damage, and implicating a coordinated response between oocytes and pre-granulosa cells within the follicle. These findings provide a foundation for future studies on the specific mechanisms regulating oocyte survival in the context of aging, as well as therapeutic and environmental genotoxic exposures.

CHEK2 signaling is the key regulator of oocyte survival after chemotherapy.

Cancer treatments can damage the ovarian follicle reserve, leading to primary ovarian insufficiency and infertility among survivors. Checkpoint kinase 2 (CHEK2) deficiency prevents elimination of oocytes in primordial follicles in female mice exposed to radiation and preserves their ovarian function and fertility. Here, we demonstrate that CHEK2 also coordinates the elimination of oocytes after exposure to standard-of-care chemotherapy drugs. CHEK2 activates two downstream targets-TAp63 and p53-which direct oocyte elimination. CHEK2 knockout or pharmacological inhibition preserved ovarian follicle reserve after radiation and chemotherapy. However, the lack of specificity for CHEK2 among available inhibitors limits their potential for clinical development. These findings demonstrate that CHEK2 is a master regulator of the ovarian cellular response to damage caused by radiation and chemotherapy and warrant the development of selective inhibitors specific to CHEK2 as a potential avenue for ovario-protective treatments.

Endometrioma Within the Anterior Abdominal Wall Causing Cyclic Abdominal Pain.

Lesions from endometriosis contain endometrial glands and stroma outside the uterine cavity. The lesions occur in the pelvis but are also found in the bowel, diaphragm, and pleural cavity. Endometriosis within the extraperitoneal abdominal wall is rare, though, and usually within c-section scars (incidence is .03%-.5%). The typical triad includes: mass in the abdominal wall, cyclical pain, and history of previous abdominal surgery. We present the case of a 28-year-old female with a past history of cesarean section and obesity (BMI = 31) who presented with approximately 3 years of abdominal pain which was "waxing and waning" in severity depending on her menstrual cycle. Multiple doctors and US imaging did not reveal a diagnosis. During consultation, she had a palpable 3 cm mass several centimeters above and right of her abdominal incision. She underwent a CT showing an inflamed subcutaneous mass abutting her anterior rectus sheath. She underwent wide excision which confirmed the diagnosis of endometrioma. This case demonstrates the need for good history and physical exam skills, as well as proficiency in reviewing radiographic imaging. Due to habitus and pain, the physical exam was difficult. However, there was a firm mass upon deep palpation. Her initial imaging was "negative," but review of the images revealed only intraperitoneal views and further imaging revealed the mass. There must be high clinical suspicion for this disease because failure to remove all tissue (including the surrounding fibrosis and desmoplastic tissue) or biopsy can lead to spread of residual endometrial cells and recurrence.