Cyclophosphamide chemotherapy induces early p53-directed cytotoxic gene expression changes in ovarian gonadotoxicity

Abstract

The alkylating chemotherapeutic cyclophosphamide (CPA) is gonadotoxic, commonly resulting in depletion of ovarian primordial follicles and leading to infertility and premature menopause in female cancer patients. However, the mechanisms underlying the early stages of CPA-induced ovarian damage are unclear, limiting our ability to prevent gonadotoxicity. This study provides a comprehensive temporal exploration of the transcriptomic profiles of ex vivo intact mouse ovaries exposed to CPA. Analyses of CPA responses from 8 to 36 hours revealed an important early role of p53 signaling. Bioinformatic analyses showed early increases in expression of specific gene clusters associated with apoptosis, DNA damage responses, and cell cycling, while expression of autophagy-associated genes was decreased. Several transcription factors, including E2F family members, likely drive early apoptosis-induced damage and p53 pathway activation. These findings provide mechanistic insight into CPA-induced ovarian toxicity, providing new avenues for the development of protective interventions.