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H3K27me3 modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury [CUT&Tag]

ABSTRACT: Chemotherapy-induced ovarian damage and infertility are significant concerns for women of childbearing age with cancer, but the underlying mechanisms are still not fully understood. Our study revealed a close association between H3K27me3 and cyclophosphamide (CTX)-induced ovarian damage, especially in granulosa cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE236296 | GEO | 2023/11/22

REPOSITORIES: GEO

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Project description:Background The ovaries hold a limited supply of primordial follicles that form the ovarian reserve. Chemotherapy with cyclophosphamide (CTX) quickly depletes this reserve, causing premature ovarian insufficiency (POI), infertility, and lasting hormonal problems. Current options for preserving fertility—such as freezing eggs, embryos, or ovarian tissue—must be done before chemotherapy starts, so they avoid damage rather than protecting the ovaries during treatment. These approaches have major drawbacks, and drugs like GnRH agonists have not shown consistent protective effects. Hyperbaric oxygen therapy (HBOT) is beneficial in many medical areas, but whether it can protect against chemotherapy induced ovarian injury and how it might work are still unknown. Methods We used female ICR mice exposed to CTX either chronically (150 mg/kg per week for 4 weeks) or acutely (a single 200 mg/kg injection). Some mice also received HBOT (100% oxygen at 2.5 atmospheres absolute). We measured ovarian reserve (follicle counts and anti Müllerian hormone), oocyte quality, granulosa cell apoptosis (TUNEL and cleaved caspase 3), ovarian fibrosis (Masson’s trichrome and α SMA), and transcriptomic profiles. Results HBOT prevented CTX from depleting primordial follicles by stopping them from entering the growing pool too quickly, bringing follicle numbers back to nearly normal levels. It also improved oocyte quality in both models: in the chronic model, abnormal oocytes fell by 15%, and in the acute model, HBOT partly restored the number of oocytes and fully normalized their shape. HBOT reduced granulosa cell apoptosis as early as 24 hours after CTX and lessened the fibrosis caused by chronic CTX. Transcriptome analysis found 67 genes whose expression changed with HBOT, and pathway analysis pointed to the Hippo signaling pathway. We confirmed that HBOT restored the expression of YAP, a key protein in that pathway, using Western blot and immunofluorescence. Conclusions HBOT exerts multi‑target protective effects against CTX‑induced ovarian injury by preserving the primordial follicle pool, improving oocyte quality, suppressing granulosa cell apoptosis, and mitigating fibrosis. Mechanistically, transcriptomic and validation analyses implicate YAP signaling as a candidate mediator of HBOT’s protective actions. Given its established safety profile in clinical practice, HBOT represents a promising adjunctive strategy for fertility preservation in young cancer patients receiving gonadotoxic chemotherapy.

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H3K27me3 modulates aberrant transcription and apoptosis in cyclophosphamide-induced ovarian granulosa cell injury [CUT&Tag]

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