Abstract
Cyclophosphamide (CTX) is widely used in various cancer therapies and in immunosuppression, and patients can still have babies after CTX chemotherapy. CTX directly causes primordial follicle loss with overactivation and DNA damage-induced apoptosis. Previous studies have shown that maternal exposure to CTX before conception increases the incidence of birth abnormalities and alters the methylation of genes in the oocytes of offspring. Mice were treated with a single dose of CTX (100 mg/kg) at post-natal day 21 and sacrificed 47 days later when primordial follicles surviving chemotherapy developed to the antral stage. Acute DNA damage and acceleration of the activation of primordial follicles after CTX treatment were repaired within several days, but the remaining follicle numbers remarkably decrease. Although partial surviving primordial follicle were developed to mature oocyte, oocyte quality hemostasis was impaired exhibiting aberrant meiosis progression, abnormal spindle and aneuploidy, mitochondrial dysfunction and increased endoplasmic reticulum stress. Thereafter, embryo development competency significantly decreased with fewer blastocyst formation after CTX exposure. CTX treatment resulted in alteration of DNA methylations and histone modifications in fully grown GV oocytes. Single-cell RNA-seq revealed CTX treatment suppressed multiple maternal genes’ transcription including many methyltransferases and maternal factor YAP1, which probably accounts for low quality of CTX-repaired oocyte. In vitro addition of lysophosphatidic acid (LPA) to embryo culture media to promote YAP1 nuclear localization improved CTX-repaired embryo developmental competence. This study provides evidence for the consistent toxic effect of CTX exposure during follicle development, and provide a new mechanism and new insights into future clinical interventions for fertility preservation.
Highlights
With advancements in diagnosis and treatment, the survival rate of patients with childhood malignant cancer has increased
We counted follicles and found that the numbers of both non-growing and growing follicles after CTX exposure were reduced significantly, while the number of atretic follicles was increased (Figure 1H). These results suggest overactivation and acute DNA damage in oocytes that can be repaired in surviving primordial follicles but long-term adverse effects on ovarian and follicle development
Cyclophosphamide (CTX) is a widely used chemotherapeutic and immunosuppressive agent to treat a range of tumors and other autoimmune diseases
Summary
With advancements in diagnosis and treatment, the survival rate of patients with childhood malignant cancer has increased. Cancer treatment may affect ovarian function and oocyte competency (Winship et al, 2018; Spears et al, 2019). Cyclophosphamide (CTX) is one of the most prevalent alkylating chemotherapy drugs and is widely used in the treatment of breast cancer, lymphoma, leukemia and various of childhood and adult malignant tumors (Cronin et al, 2018). CTX can directly cause primordial follicle loss with DNA damage-induced apoptosis and overactivation. CTX stimulates the PI3K-PTEN-AKT pathway in parallel, which disrupts the balance regulation of dormant primordial follicles and causes follicle reserve loss. In vivo animal models show a disruption in lipid peroxidation and reduced superoxide dismutase activity, which eventually damage ovarian function (Detti et al, 2013; Saleh and Mansour, 2016)
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